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Gou Y, Glat M, Damian V, Bryan CL, Phan BA, Faber CL, Trivedi A, Hwang MK, Scarlett JM, Morton GJ, Schwartz MW. AgRP neuron hyperactivity drives hyperglycemia in a mouse model of type 2 diabetes. J Clin Invest 2025; 135:e189842. [PMID: 40371641 PMCID: PMC12077889 DOI: 10.1172/jci189842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/12/2025] [Indexed: 05/16/2025] Open
Abstract
Growing evidence suggests that the pathogenesis of type 2 diabetes (T2D) involves dysfunctional central mechanisms, and, hence, the brain can be targeted to treat this disease. As an example, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) can normalize hyperglycemia for weeks or months in rodent models of T2D. Convergent evidence implicates inhibition of a particular subset of neurons as a mediator of this FGF1 effect. Specifically, AgRP neurons, which are located in the hypothalamic arcuate nucleus (ARC) and are hyperactive in Lepob/ob mice and other rodent models of T2D. To investigate whether chronic AgRP neuron inactivation mimics the antidiabetic action of FGF1, we directed an adeno-associated virus (AAV) containing a cre-inducible tetanus toxin-GFP (TeTx-GFP) cassette (or cre-inducible AAV GFP control) to the ARC of obese, diabetic male Lepob/ob mice in which cre recombinase is expressed solely by AgRP neurons (Lepob/ob AgRP-Cre mice). We report that over a 10-wk period of observation, hyperglycemia was fully normalized by AgRP neuron inactivation. In contrast, changes in energy homeostasis parameters (food intake, energy expenditure, body weight, and fat mass) were not observed. We conclude that in diabetic male Lepob/ob mice, AgRP neuron hyperactivity is required for hyperglycemia but is dispensable for obesity.
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Affiliation(s)
- Yang Gou
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Micaela Glat
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Vincent Damian
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Caeley L. Bryan
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Bao Anh Phan
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Chelsea L. Faber
- Ivy Brain Tumor Center, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Arikta Trivedi
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Matthew K. Hwang
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Jarrad M. Scarlett
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
- Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, Washington, USA
| | - Gregory J. Morton
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
| | - Michael W. Schwartz
- Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, Washington, USA
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Bazzazzadehgan S, Shariat-Madar Z, Mahdi F. Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM. Biomolecules 2025; 15:414. [PMID: 40149950 PMCID: PMC11940602 DOI: 10.3390/biom15030414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/26/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) encompasses a range of clinical manifestations, with uncontrolled diabetes leading to progressive or irreversible damage to various organs. Numerous genes associated with monogenic diabetes, exhibiting classical patterns of inheritance (autosomal dominant or recessive), have been identified. Additionally, genes involved in complex diabetes, which interact with environmental factors to trigger the disease, have also been discovered. These genetic findings have raised hopes that genetic testing could enhance diagnostics, disease surveillance, treatment selection, and family counseling. However, the accurate interpretation of genetic data remains a significant challenge, as variants may not always be definitively classified as either benign or pathogenic. Research to date, however, indicates that periodic reevaluation of genetic variants in diabetes has led to more consistent findings, with biases being steadily eliminated. This has improved the interpretation of variants across diverse ethnicities. Clinical studies suggest that genetic risk information may motivate patients to adopt behaviors that promote the prevention or management of T2DM. Given that the clinical features of certain monogenic diabetes types overlap with T2DM, and considering the significant role of genetic variants in diabetes, healthcare providers caring for prediabetic patients should consider genetic testing as part of the diagnostic process. This review summarizes current knowledge of the most common genetic variants associated with T2DM, explores novel therapeutic targets, and discusses recent advancements in the pharmaceutical management of uncontrolled T2DM.
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Affiliation(s)
- Shadi Bazzazzadehgan
- Department of Pharmacy Administration, School of Pharmacy, University of Mississippi, University, MS 38677, USA;
| | - Zia Shariat-Madar
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
| | - Fakhri Mahdi
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
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Nwakama CA, Durand-de Cuttoli R, Oketokoun ZM, Brown SO, Haller JE, Méndez A, Jodeiri Farshbaf M, Cho YZ, Ahmed S, Leng S, Ables JL, Sweis BM. Neuroeconomically dissociable forms of mental accounting are altered in a mouse model of diabetes. Commun Biol 2025; 8:102. [PMID: 39838110 PMCID: PMC11751097 DOI: 10.1038/s42003-025-07500-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 01/08/2025] [Indexed: 01/23/2025] Open
Abstract
Those with diabetes mellitus are at high-risk of developing psychiatric disorders, especially mood disorders, yet the link between hyperglycemia and altered motivation has not been thoroughly explored. Here, we characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on Restaurant Row, a naturalistic neuroeconomic foraging paradigm capable of behaviorally capturing multiple decision systems known to depend on dissociable neural circuits. Mice made self-paced choices on a daily limited time-budget, accepting or rejecting reward offers based on cost (delays cued by tone pitch) and subjective value (flavors), in a closed-economy system tested across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy overprioritizing high-value rewards. These foraging behaviors were driven by impairments in multiple decision-making processes, including the ability to deliberate when engaged in conflict and cache the value of the passage of time as sunk costs. Surprisingly, diabetes-induced changes in motivation depended not only on the type of choice being made, but also on the salience of reward-scarcity in the environment. These findings suggest that complex relationships between metabolic dysfunction and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt distinct computational processes leading to comorbid psychiatric vulnerabilities.
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Affiliation(s)
- Chinonso A Nwakama
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Romain Durand-de Cuttoli
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Zainab M Oketokoun
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Samantha O Brown
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jillian E Haller
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Biology, University of Scranton College of Arts and Sciences, Scranton, PA, 18510, USA
| | - Adriana Méndez
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Mohammad Jodeiri Farshbaf
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Y Zoe Cho
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Chemistry, Barnard College of Columbia University, New York, NY, 10027, USA
| | - Sanjana Ahmed
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Macaulay Honors College at CUNY Hunter, New York, NY, 10023, USA
| | - Sophia Leng
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Hunter College High School, New York, NY, 10128, USA
| | - Jessica L Ables
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Brian M Sweis
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Amanda B, Faizah Z, Pakpahan C, Aziz MA, Hamidah B, Ashari FY, Oceandy D. Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1: A Potential Compound to Improve Spermatogenesis in Mouse Model of Diabetes Mellitus. Biomedicines 2024; 12:2513. [PMID: 39595079 PMCID: PMC11591716 DOI: 10.3390/biomedicines12112513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/21/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: Spermatogenesis is a key process in male reproduction that, if it does not happen correctly, can lead to infertility, with diabetes being one of the most prevalent causes of spermatogenesis disruption. Currently, there is a lack of research examining the potential benefits of targeting cell proliferation to enhance spermatogenesis in this condition. XMU-MP1 has been identified as an inhibitor of MST1, a core component of the Hippo pathway, which is anticipated to promote proliferation and regeneration. This study aims to evaluate the effects of XMU-MP1 treatment on sperm and testicular characteristics in mice. Methods: We used the STZ-induced diabetic mouse model to investigate the impact of administering XMU-MP1 on testicular tissue and sperm parameters. This study compared the seminiferous tubules, specifically focusing on the diameter of the seminiferous tubule, the thickness of the seminiferous tubule epithelium, the ratio of the thickness of the seminiferous tubule epithelium to the diameter of the seminiferous tubules, and the lumen diameter of the seminiferous tubules. We also conducted a comparison of sperm parameters, including sperm concentration, progressive motility, total motility, total motility, and morphology. Results: XMU-MP1-treated mice had a larger spermatogenesis area and better sperm motility than control mice. Diabetic mice treated with XMU-MP1 also showed a trend toward improvements in the spermatogenesis area, sperm concentration, sperm motility, and sperm morphology, although these improvements were not statistically significant. Conclusions: XMU-MP1 serves as a potential compound to improve spermatogenesis in mice.
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Affiliation(s)
- Bella Amanda
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia; (Z.F.); (C.P.); (M.A.A.); (B.H.); (F.Y.A.)
- Airlangga University Teaching Hospital, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Zakiyatul Faizah
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia; (Z.F.); (C.P.); (M.A.A.); (B.H.); (F.Y.A.)
| | - Cennikon Pakpahan
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia; (Z.F.); (C.P.); (M.A.A.); (B.H.); (F.Y.A.)
- Airlangga University Teaching Hospital, Universitas Airlangga, Surabaya 60115, Indonesia
| | - M. Aminudin Aziz
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia; (Z.F.); (C.P.); (M.A.A.); (B.H.); (F.Y.A.)
| | - Berliana Hamidah
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia; (Z.F.); (C.P.); (M.A.A.); (B.H.); (F.Y.A.)
| | - Faisal Yusuf Ashari
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia; (Z.F.); (C.P.); (M.A.A.); (B.H.); (F.Y.A.)
| | - Delvac Oceandy
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK;
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Huerta-Chagoya A, Schroeder P, Mandla R, Li J, Morris L, Vora M, Alkanaq A, Nagy D, Szczerbinski L, Madsen JGS, Bonàs-Guarch S, Mollandin F, Cole JB, Porneala B, Westerman K, Li JH, Pollin TI, Florez JC, Gloyn AL, Carey DJ, Cebola I, Mirshahi UL, Manning AK, Leong A, Udler M, Mercader JM. Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes. Nat Genet 2024; 56:2370-2379. [PMID: 39379762 PMCID: PMC11549050 DOI: 10.1038/s41588-024-01947-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 09/10/2024] [Indexed: 10/10/2024]
Abstract
Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels' limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10-5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual's polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes.
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Affiliation(s)
- Alicia Huerta-Chagoya
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Philip Schroeder
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Ravi Mandla
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Graduate Program in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Jiang Li
- Department of Genomic Health, Geisinger, Danville, PA, USA
| | - Lowri Morris
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Maheak Vora
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Ahmed Alkanaq
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Dorka Nagy
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- National Heart and Lung Institute, Faculty of Medicine, London, UK
| | - Lukasz Szczerbinski
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Jesper G S Madsen
- Institute of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark
- The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Silvia Bonàs-Guarch
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Fanny Mollandin
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
| | - Joanne B Cole
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Bianca Porneala
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Kenneth Westerman
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Josephine H Li
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Toni I Pollin
- University of Maryland, School of Medicine, Baltimore, MD, USA
| | - Jose C Florez
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Endocrine Division, Massachusetts General Hospital, Boston, MA, USA
| | - Anna L Gloyn
- Department of Pediatrics, Division of Endocrinology, Stanford School of Medicine, Stanford, CA, USA
| | - David J Carey
- Department of Genomic Health, Geisinger, Danville, PA, USA
| | - Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | | | - Alisa K Manning
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Aaron Leong
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Endocrine Division, Massachusetts General Hospital, Boston, MA, USA
| | - Miriam Udler
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Josep M Mercader
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Li Y, Polychronakos C. Parsing the spectrum of allelic architectures in diabetes. Nat Genet 2024; 56:2297-2298. [PMID: 39402157 DOI: 10.1038/s41588-024-01950-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2024]
Affiliation(s)
- Yangxi Li
- Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Center for Children's Health, Hangzhou, Zhejiang, China
| | - Constantin Polychronakos
- Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Center for Children's Health, Hangzhou, Zhejiang, China.
- Endocrine Genetics Laboratory, Department of Pediatrics, The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
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Nwakama CA, Durand-de Cuttoli R, Oketokoun ZM, Brown SO, Haller JE, Méndez A, Farshbaf MJ, Cho YZ, Ahmed S, Leng S, Ables JL, Sweis BM. Diabetes alters neuroeconomically dissociable forms of mental accounting. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.04.574210. [PMID: 38260368 PMCID: PMC10802482 DOI: 10.1101/2024.01.04.574210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Those with diabetes mellitus are at high-risk of developing psychiatric disorders, yet the link between hyperglycemia and alterations in motivated behavior has not been explored in detail. We characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on a naturalistic neuroeconomic foraging paradigm called Restaurant Row. Mice made self-paced choices while on a limited time-budget accepting or rejecting reward offers as a function of cost (delays cued by tone-pitch) and subjective value (flavors), tested daily in a closed-economy system across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy that overprioritized high-value rewards. We discovered these foraging behaviors were driven by impairments in multiple decision-making systems, including the ability to deliberate when engaged in conflict and cache the value of the passage of time in the form of sunk costs. Surprisingly, diabetes-induced changes in behavior depended not only on the type of choice being made but also the salience of reward-scarcity in the environment. These findings suggest complex relationships between glycemic regulation and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt fundamentally distinct computational processes and could give rise to psychiatric vulnerabilities.
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8
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Juras JA, Pitra S, Smith BN. Systemic Glucose Regulation by a Hindbrain Inhibitory Circuit in a Mouse Model of Type 1 Diabetes. Neuroendocrinology 2024; 114:302-312. [PMID: 38194945 DOI: 10.1159/000536142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 01/04/2024] [Indexed: 01/11/2024]
Abstract
INTRODUCTION Previous work showed that increasing the electrical activity of inhibitory neurons in the dorsal vagal complex (DVC) is sufficient to increase whole-body glucose concentration in normoglycemic mice. Here we tested the hypothesis that deactivating GABAergic neurons in the dorsal hindbrain of hyperglycemic mice decreases synaptic inhibition of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) and reduces systemic glucose levels. METHODS Chemogenetic activation or inactivation of GABAergic neurons in the nucleus tractus solitarius (NTS) was used to assess effects of modulating parasympathetic output on blood glucose concentration in normoglycemic and hyperglycemic mice. Patch-clamp electrophysiology in vitro was used to assess cellular effects of chemogenetic manipulation of NTS GABA neurons. RESULTS Chemogenetic activation of GABAergic NTS neurons in normoglycemic mice increased their action potential firing, resulting in increased inhibitory synaptic input to DMV motor neurons and elevated blood glucose concentration. Deactivation of GABAergic DVC neurons in normoglycemic mice altered their electrical activity but did not alter systemic glucose levels. Conversely, stimulation of GABAergic DVC neurons in mice that were hyperglycemic subsequent to treatment with streptozotocin changed their electrical activity but did not alter whole-body glucose concentration, while deactivation of this inhibitory circuit significantly decreased circulating glucose concentration. Peripheral administration of a brain impermeant muscarinic acetylcholine receptor antagonist abolished these effects. CONCLUSION Disinhibiting vagal motor neurons decreases hyperglycemia in a mouse model of type 1 diabetes. This inhibitory brainstem circuit emerges as a key parasympathetic regulator of whole-body glucose homeostasis that undergoes functional plasticity in hyperglycemic conditions.
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Affiliation(s)
- J Anna Juras
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA
| | - Soledad Pitra
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Bret N Smith
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
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9
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Schroeder P, Mandla R, Huerta-Chagoya A, Alkanak A, Nagy D, Szczerbinski L, Madsen JGS, Cole JB, Porneala B, Westerman K, Li JH, Pollin TI, Florez JC, Gloyn AL, Cebola I, Manning A, Leong A, Udler M, Mercader JM. Rare variant association analysis in 51,256 type 2 diabetes cases and 370,487 controls informs the spectrum of pathogenicity of monogenic diabetes genes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.09.28.23296244. [PMID: 37808701 PMCID: PMC10557807 DOI: 10.1101/2023.09.28.23296244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
We meta-analyzed array data imputed with the TOPMed reference panel and whole-genome sequence (WGS) datasets and performed the largest, rare variant (minor allele frequency as low as 5×10-5) GWAS meta-analysis of type 2 diabetes (T2D) comprising 51,256 cases and 370,487 controls. We identified 52 novel variants at genome-wide significance (p<5 × 10-8), including 8 novel variants that were either rare or ancestry-specific. Among them, we identified a rare missense variant in HNF4A p.Arg114Trp (OR=8.2, 95% confidence interval [CI]=4.6-14.0, p = 1.08×10-13), previously reported as a variant implicated in Maturity Onset Diabetes of the Young (MODY) with incomplete penetrance. We demonstrated that the diabetes risk in carriers of this variant was modulated by a T2D common variant polygenic risk score (cvPRS) (carriers in the top PRS tertile [OR=18.3, 95%CI=7.2-46.9, p=1.2×10-9] vs carriers in the bottom PRS tertile [OR=2.6, 95% CI=0.97-7.09, p = 0.06]. Association results identified eight variants of intermediate penetrance (OR>5) in monogenic diabetes (MD), which in aggregate as a rare variant PRS were associated with T2D in an independent WGS dataset (OR=4.7, 95% CI=1.86-11.77], p = 0.001). Our data also provided support evidence for 21% of the variants reported in ClinVar in these MD genes as benign based on lack of association with T2D. Our work provides a framework for using rare variant imputation and WGS analyses in large-scale population-based association studies to identify large-effect rare variants and provide evidence for informing variant pathogenicity.
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Affiliation(s)
- Philip Schroeder
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Ravi Mandla
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine and Cardiovascular Research Institute, Cardiology Division, University of California, San Francisco, CA, USA
| | - Alicia Huerta-Chagoya
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Ahmed Alkanak
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Dorka Nagy
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- National Heart and Lung Institute, Faculty of Medicine, London, UK
| | - Lukasz Szczerbinski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, 15-276, Poland
- Clinical Research Centre, Medical University of Bialystok, Bialystok, 15-276, Poland
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Jesper G S Madsen
- Institute of Mathematics and Computer Science, University of Southern Denmark, Odense M, 5230, Denmark
- The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Joanne B Cole
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Bianca Porneala
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Kenneth Westerman
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Josephine H Li
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Toni I Pollin
- Emory University, Atlanta, Georgia, USA., Atlanta, GA, USA
| | - Jose C Florez
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Endocrine Division, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Anna L Gloyn
- Department of Pediatrics, Division of Endocrinology, Stanford School of Medicine, Stanford, CA, USA
| | - Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Alisa Manning
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Aaron Leong
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Endocrine Division, Massachusetts General Hospital, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Miriam Udler
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Josep M Mercader
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
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10
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Badran S, Doi SA, Hammouda A, Khoogaly H, Muneer M, Alkasem MJ, Abou-Samra AB, M Habib A. The impact of prior obesity surgery on glucose metabolism after body contouring surgery: A pilot study. BIOMOLECULES & BIOMEDICINE 2023; 23:873-882. [PMID: 37021835 PMCID: PMC10494840 DOI: 10.17305/bb.2023.8827] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/06/2023] [Accepted: 03/27/2023] [Indexed: 04/07/2023]
Abstract
Body contouring surgery enhances physical appearance by means of surgical subcutaneous fat removal (SSFR). However, it remains unclear how SSFR may affect glucose metabolism and its broader effects on the endocrine system, especially in individuals who have undergone obesity (bariatric) surgery. This study aimed to evaluate the impact of SSFR on glucose excursion and insulin resistance in such patients, by examining them over three visits (within 1 week before surgery, 1 week after surgery, and 6 weeks after surgery). The independent impact of SSFR and history of obesity surgery on glucose homeostasis was evaluated in 29 participants, of whom ten patients (34%) had a history of obesity surgery. Indices of glucose metabolism were evaluated using cluster robust-error logistic regression. Results indicated that SSFR led to a gross improvement in insulin resistance at 6 weeks after the surgery in all patient's irrespective of BMI, type 2 diabetes mellitus (T2D) status, or history of obesity surgery (OR 0.22; p = 0.042). However, no effect was observed on glucose excursion except for a transient increase at visit 2 (1 week after surgery) in those without prior obesity surgery. Interestingly, participants with a history of obesity surgery had approximately half the odds being in the upper tertile for HOMA-IR (OR 0.44; p = 0.142) and ten-folds lower odds of having severely abnormal glucose excursion (OR 0.09; p = 0.031), irrespective of their BMI, T2D status, or time post SSFR. In conclusion, this study showed that body contouring surgery through SSFR resulted in (at least) short-term improvement in insulin resistance (independent of the participant's BMI, T2D status, or history of obesity surgery) without affecting glucose excursion under the GTT. On the contrary, obesity surgery may have a long-term effect on glucose excursion, possibly due to sustained improvement of pancreatic ß-cell function.
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Affiliation(s)
- Saif Badran
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Suhail A Doi
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Atalla Hammouda
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Hoda Khoogaly
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Muneer
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Meis J Alkasem
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Abdul-Badi Abou-Samra
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
- Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation, Doha, Qatar
| | - Abdella M Habib
- College of Medicine, QU Health, Qatar University, Doha, Qatar
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11
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Zhao J, Feng Y, Rao Z, Li H, Xu J, Cui S, Lai L. Exercise combined with heat treatment improves insulin resistance in diet-induced obese rats. J Therm Biol 2023; 116:103651. [PMID: 37459707 DOI: 10.1016/j.jtherbio.2023.103651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 06/13/2023] [Accepted: 06/28/2023] [Indexed: 08/28/2023]
Abstract
Insulin resistance is a risk factor for various cardiovascular diseases, which seriously threaten human health. Thus, finding a safe, effective and economical strategy to treat insulin resistance is urgently needed. This study aimed to investigate the effects of exercise combined with heat treatment on the insulin sensitivity in skeletal muscle of diet-induced obese (DIO) rats. Obese rats were induced by a 10-week high-fat diet and were randomly divided into normal temperature + control (NC), normal temperature + exercise (NE), heat treatment + control (HC) and heat treatment + exercise (HE) groups for 7 weeks of incremental load endurance exercise and heat treatment (exposure to a high-temperature environment room). At the end of the 7-week intervention, we measured fasting blood glucose, serum fasting insulin, serum leptin, serum adiponectin, protein expression of HSF1/HSP27 and JAK2/STAT3 pathway in soleus (primarily composed of slow-twitch fibres) and extensor digitorum longus (primarily composed of fast-twitch fibres) muscles. The results showed that exercise combined with heat treatment can effectively improve insulin resistance by regulating HSF1/HSP27 and JAK2/STAT3 pathways in the slow-twitch muscle of DIO rats. Importantly, exercise combined with heat treatment is more effective in improving insulin resistance in DIO rats than exercise or heat treatment alone. Low-moderate intensity exercise that stimulates slow-twitch muscle, combined with heat treatment is an effective strategy to treat insulin resistance.
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Affiliation(s)
- Jiexiu Zhao
- Exercise Biological Center, China Institute of Sport Science, Beijing, China.
| | - Yiwei Feng
- Exercise Biological Center, China Institute of Sport Science, Beijing, China
| | - Zhijian Rao
- Exercise Biological Center, China Institute of Sport Science, Beijing, China; Physical Education College, Shanghai Normal University, Shanghai, China
| | - Han Li
- Exercise Biological Center, China Institute of Sport Science, Beijing, China
| | - Jincheng Xu
- Exercise Biological Center, China Institute of Sport Science, Beijing, China; Winter Sports Management Center of the General Administration of Sport of China, Beijing, China
| | - Shuqiang Cui
- Exercise Biological Center, China Institute of Sport Science, Beijing, China; Beijing Institute of Sports Science, Beijing, China
| | - Lili Lai
- Exercise Biological Center, China Institute of Sport Science, Beijing, China; Nanchang Normal University, Jiangxi, China
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12
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Simchoni M, Derazne E, Pinhas-Hamiel O, Cukierman-Yaffe T, Bendor CD, Bardugo A, Chodick G, Tzur D, Endevelt R, Gerstein HC, Afek A, Twig G. Adolescent body mass index and cognitive performance: a nationwide study of 2.48 million Israeli adolescents. Eur J Endocrinol 2023; 188:630-640. [PMID: 37406222 DOI: 10.1093/ejendo/lvad075] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/13/2023] [Accepted: 05/10/2023] [Indexed: 07/07/2023]
Abstract
IMPORTANCE The increased incidence of adolescent obesity over recent decades may be associated with lower cognitive performance than the expected potential. OBJECTIVE We aimed to assess the association between adolescent body mass index (BMI) and cognitive function. DESIGN A nationwide, cross-sectional, population-based study. SETTING Pre-recruitment evaluation for military service during 1967-2018. PARTICIPANTS All Israeli-born adolescents, 1 459 522 males and 1 027 953 females aged 16 to ≤20 years. EXPOSURES Weight and height were measured to calculate BMI. MAIN OUTCOME Cognitive performance was assessed by using a validated intelligence-quotient-equivalent test and was standardized to the year- and sex-Z-score. For 445 385 persons, parental cognitive scores could be identified. Multinomial logistic regression models were applied. RESULTS Among male adolescents with severe obesity, 29.4% achieved a cognitive score below the 25th percentile, compared with 17.7% among their normal-weight (50th-84th percentile) counterparts. A J-shaped relation was observed between BMI and the odds ratio (OR) for a low cognitive score among male adolescents: underweight, 1.45 (1.43-1.48); overweight, 1.13 (1.12-1.15); mild obesity, 1.36 (1.33-1.39); and severe obesity, 1.58 (1.52-1.64). Similar findings were observed in females. For both sexes, point estimates were overall consistent in models adjusted for sociodemographic confounders, coexisting morbidities, and parental cognitive scores. Examinees with abnormal BMI had higher ORs for a lower-than-expected cognitive score, based on their parents' data as adolescents, in a manner that depends on obesity severity. CONCLUSION AND RELEVANCE Obesity, is associated with increased odds for a lower cognitive performance, and the inability to fully achieve cognitive potential, regardless of sociodemographic background.
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Affiliation(s)
- Maya Simchoni
- Department of Military Medicine, Faculty of Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan 9112102, Israel
| | - Estela Derazne
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Orit Pinhas-Hamiel
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Pediatric Endocrinology and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan 5262000, Israel
| | - Tali Cukierman-Yaffe
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Ramat Gan 5262000, Israel
| | - Cole D Bendor
- Department of Military Medicine, Faculty of Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan 9112102, Israel
| | - Aya Bardugo
- Department of Military Medicine, Faculty of Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan 9112102, Israel
| | - Gabriel Chodick
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Maccabitech Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv 6801296, Israel
| | - Dorit Tzur
- Department of Military Medicine, Faculty of Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan 9112102, Israel
| | - Ronit Endevelt
- Nutrition Division, Public Health Services, Israel Ministry of Health and School of Public Health, University of Haifa, Haifa 3103301, Israel
| | - Herzel C Gerstein
- Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton L8L 2X2, Canada
| | - Arnon Afek
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Central Management, Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel
| | - Gilad Twig
- Department of Military Medicine, Faculty of Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan 9112102, Israel
- Department of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan 52621, Israel
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13
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Bisht MK, Dahiya P, Ghosh S, Mukhopadhyay S. The cause-effect relation of tuberculosis on incidence of diabetes mellitus. Front Cell Infect Microbiol 2023; 13:1134036. [PMID: 37434784 PMCID: PMC10330781 DOI: 10.3389/fcimb.2023.1134036] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/25/2023] [Indexed: 07/13/2023] Open
Abstract
Tuberculosis (TB) is one of the oldest human diseases and is one of the major causes of mortality and morbidity across the Globe. Mycobacterium tuberculosis (Mtb), the causal agent of TB is one of the most successful pathogens known to mankind. Malnutrition, smoking, co-infection with other pathogens like human immunodeficiency virus (HIV), or conditions like diabetes further aggravate the tuberculosis pathogenesis. The association between type 2 diabetes mellitus (DM) and tuberculosis is well known and the immune-metabolic changes during diabetes are known to cause increased susceptibility to tuberculosis. Many epidemiological studies suggest the occurrence of hyperglycemia during active TB leading to impaired glucose tolerance and insulin resistance. However, the mechanisms underlying these effects is not well understood. In this review, we have described possible causal factors like inflammation, host metabolic changes triggered by tuberculosis that could contribute to the development of insulin resistance and type 2 diabetes. We have also discussed therapeutic management of type 2 diabetes during TB, which may help in designing future strategies to cope with TB-DM cases.
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Affiliation(s)
- Manoj Kumar Bisht
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Priyanka Dahiya
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Sudip Ghosh
- Molecular Biology Unit, Indian Council of Medical Research (ICMR)-National Institute of Nutrition, Jamai Osmania PO, Hyderabad, India
| | - Sangita Mukhopadhyay
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
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14
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Haderlie SA, Hieber JK, Boles JA, Berardinelli JG, Thomson JM. Molecular Pathways for Muscle and Adipose Tissue Are Altered between Beef Steers Classed as Choice or Standard. Animals (Basel) 2023; 13:1947. [PMID: 37370457 PMCID: PMC10294903 DOI: 10.3390/ani13121947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Targets for finished livestock are often determined by expected fat, either subcutaneous or intramuscular. These targets are used frequently to improve eating quality. Lower intramuscular fat, lack of product uniformity, and insufficient tenderness can negatively impact beef acceptability. This study aimed to investigate the differences in gene expression that alter metabolism and intercellular signaling in the muscle and adipose tissue in beef carcasses at different fat endpoints. In this study, longissimus thoracis muscle samples and adipose tissue were collected at harvest, and RNA was extracted and then sequenced using RNAseq. Differential expression was determined using edgeR, and p-values were adjusted using the Benjamini-Hochberg method. A corrected p-value of 0.005 and log2 (fold change) of >1 were the threshold to identify differential expression. Comparison between intermuscular and subcutaneous fat showed no differences in the genes activated in the two adipose tissue depots, suggesting that subcutaneous fat was an adequate sample. Carcass data allowed the classification of carcasses by USDA quality grades (marbling targets). In comparing muscle from Standard and Choice carcasses, 15 genes were downregulated, and 20 were upregulated. There were 49 downregulated and 113 upregulated genes comparing adipose tissue from Standard and Choice carcasses. These genes are related to the metabolism of fat and energy. This indicates that muscle transcript expression varies less than adipose. In addition, subcutaneous fat can be used to evaluate transcript changes in fat. However, it is unclear whether these fat tissues can be used as surrogates for marbling.
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Affiliation(s)
| | | | | | | | - Jennifer M. Thomson
- Department of Animal and Range Sciences, Montana State University, Bozeman, MT 59717, USA
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15
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Torosian K, Lal E, Kavanaugh A, Loomba R, Ajmera V, Guma M. Psoriatic disease and non-alcoholic fatty liver disease shared pathogenesis review. Semin Arthritis Rheum 2023; 59:152165. [PMID: 36716599 PMCID: PMC9992353 DOI: 10.1016/j.semarthrit.2023.152165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/03/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023]
Abstract
Psoriatic disease (PD) and non-alcoholic fatty liver disease (NAFLD) potentially share disease pathways given the numerous inflammatory pathways involved in both diseases and a higher prevalence of NAFLD in PD patients. Metabolic syndrome and obesity are a key link between the two diseases, but even when controlling for this, associations between both diseases are still seen. Therapeutics that impact metabolic or inflammatory pathways may be impactful in both PD and NAFLD. In this review, we describe common inflammatory pathways contributing to both PD and NAFLD and critically review the potential impact of treatments for and on both diseases.
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Affiliation(s)
- Kelly Torosian
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Esha Lal
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Arthur Kavanaugh
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA; Division of Epidemiology, Department of Family and Preventative Medicine, University of California at San Diego, La Jolla, USA
| | - Veeral Ajmera
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA.
| | - Monica Guma
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain; San Diego VA Healthcare Service, San Diego, CA, 92161, USA.
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16
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De la Cruz-Concepción B, Flores-Cortez YA, Barragán-Bonilla MI, Mendoza-Bello JM, Espinoza-Rojo M. Insulin: A connection between pancreatic β cells and the hypothalamus. World J Diabetes 2023; 14:76-91. [PMID: 36926659 PMCID: PMC10011898 DOI: 10.4239/wjd.v14.i2.76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/13/2022] [Accepted: 01/17/2023] [Indexed: 02/14/2023] Open
Abstract
Insulin is a hormone secreted by pancreatic β cells. The concentration of glucose in circulation is proportional to the secretion of insulin by these cells. In target cells, insulin binds to its receptors and activates phosphatidylinositol-3-kinase/protein kinase B, inducing different mechanisms depending on the cell type. In the liver it activates the synthesis of glycogen, in adipose tissue and muscle it allows the capture of glucose, and in the hypothalamus, it regulates thermogenesis and appetite. Defects in insulin function [insulin resistance (IR)] are related to the development of neurodegenerative diseases in obese people. Furthermore, in obesity and diabetes, its role as an anorexigenic hormone in the hypothalamus is diminished during IR. Therefore, hyperphagia prevails, which aggravates hyper-glycemia and IR further, becoming a vicious circle in which the patient cannot regulate their need to eat. Uncontrolled calorie intake induces an increase in reactive oxygen species, overcoming cellular antioxidant defenses (oxidative stress). Reactive oxygen species activate stress-sensitive kinases, such as c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, that induce phos-phorylation in serine residues in the insulin receptor, which blocks the insulin signaling pathway, continuing the mechanism of IR. The brain and pancreas are organs mainly affected by oxidative stress. The use of drugs that regulate food intake and improve glucose metabolism is the conventional therapy to improve the quality of life of these patients. Currently, the use of antioxidants that regulate oxidative stress has given good results because they reduce oxidative stress and inflammatory processes, and they also have fewer side effects than synthetic drugs.
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Affiliation(s)
- Brenda De la Cruz-Concepción
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Yaccil Adilene Flores-Cortez
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Martha Isela Barragán-Bonilla
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Juan Miguel Mendoza-Bello
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Monica Espinoza-Rojo
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
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17
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Liu J, Liu Z, Sun W, Luo L, An X, Yu D, Wang W. Role of sex hormones in diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:1135530. [PMID: 37143724 PMCID: PMC10151816 DOI: 10.3389/fendo.2023.1135530] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 03/22/2023] [Indexed: 05/06/2023] Open
Abstract
Diabetic nephropathy (DN) is the most common microvascular complication in diabetes and one of the leading causes of end-stage renal disease. The standard treatments for patients with classic DN focus on blood glucose and blood pressure control, but these treatments can only slow the progression of DN instead of stopping or reversing the disease. In recent years, new drugs targeting the pathological mechanisms of DN (e.g., blocking oxidative stress or inflammation) have emerged, and new therapeutic strategies targeting pathological mechanisms are gaining increasing attention. A growing number of epidemiological and clinical studies suggest that sex hormones play an important role in the onset and progression of DN. Testosterone is the main sex hormone in males and is thought to accelerate the occurrence and progression of DN. Estrogen is the main sex hormone in females and is thought to have renoprotective effects. However, the underlying molecular mechanism by which sex hormones regulate DN has not been fully elucidated and summarized. This review aims to summarize the correlation between sex hormones and DN and evaluate the value of hormonotherapy in DN.
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Affiliation(s)
- Jiahui Liu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhe Liu
- College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Weixia Sun
- Nephrology Department, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ling Luo
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xingna An
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Dehai Yu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
- *Correspondence: Dehai Yu, ; Wanning Wang,
| | - Wanning Wang
- Nephrology Department, First Hospital of Jilin University, Changchun, Jilin, China
- *Correspondence: Dehai Yu, ; Wanning Wang,
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18
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Madhu SV, Aslam M, Mishra BK, Gupta A, Jhamb R. Association of 25 (OH) Vitamin D and Leptin in Individuals with Insulin Resistance. Indian J Endocrinol Metab 2022; 26:435-438. [PMID: 36618517 PMCID: PMC9815200 DOI: 10.4103/ijem.ijem_141_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 07/17/2022] [Accepted: 09/05/2022] [Indexed: 11/19/2022] Open
Abstract
Introduction Asian-Indian individuals with diabetes have been shown to have low vitamin D levels. Whether this hypovitamonisis D is associated with hyperleptinaemia is unclear. Also, whether this association is different in those with and without insulin resistance has not been ascertained. The present study aimed to investigate the association of 25-hydroxy vitamin D [25(OH) vitamin D] and leptin in individuals with and without insulin resistance. Methods Ninety two individuals were recruited in two study groups (n = 46 each group). First group included individuals with insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] ≥2.0). Second group included those without insulin resistance (HOMA-IR <2.0). Comparison of 25(OH) vitamin D, leptin, anthropometry, and biochemical parameters was done between two groups and correlations between 25(OH) vitamin D, leptin, and HOMA-IR were studied. Results Individuals with insulin resistance were of simiar age (39.6 ± 5.3 years) and body mass index (24.4 ± 3.2 kg/m2) as those without (39.5 ± 5.2 years and 23.6 ± 3.2 kg/m2). Individuals with insulin resistance showed significantly lower 25(OH) vitamin D (17.8 ± 7.1 vs. 22.3 ± 11.6 ng/mL, P = .03) and significantly higher leptin levels (16.9 ± 15.8 vs. 9.6 ± 9.3 ng/mL, P = .09) compared to those without. Significant negative correlation was observed between 25(OH) vitamin D and leptin levels overall (r = -0.3, P = .008). HOMA-IR showed significantly negative correlation with 25(OH) vitamin D levels in individuals with insulin resistance (r = -0.33, P = .027). Conclusion The present study found higher circulating leptin levels and lower 25(OH) vitamin D levels in individuals with insulin resistance. 25(OH) vitamin D levels were inversely associated with leptin levels particularly in women.
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Affiliation(s)
- S. V. Madhu
- Department of Endocrinology, Centre for Diabetes Endocrinology and Metabolism, University College of Medical Sciences (University of Delhi), and GTB Hospital, Dilshad Garden, Delhi, India
| | - M. Aslam
- Department of Endocrinology, Centre for Diabetes Endocrinology and Metabolism, University College of Medical Sciences (University of Delhi), and GTB Hospital, Dilshad Garden, Delhi, India
| | - B. K. Mishra
- Department of Endocrinology, Centre for Diabetes Endocrinology and Metabolism, University College of Medical Sciences (University of Delhi), and GTB Hospital, Dilshad Garden, Delhi, India
| | - A. Gupta
- Department of Endocrinology, Centre for Diabetes Endocrinology and Metabolism, University College of Medical Sciences (University of Delhi), and GTB Hospital, Dilshad Garden, Delhi, India
| | - Rajat Jhamb
- Department of Endocrinology, Centre for Diabetes Endocrinology and Metabolism, University College of Medical Sciences (University of Delhi), and GTB Hospital, Dilshad Garden, Delhi, India
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Khan MM. Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia. World J Psychiatry 2022; 12:827-842. [PMID: 35978970 PMCID: PMC9258274 DOI: 10.5498/wjp.v12.i6.827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/03/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia. AIM To determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ. METHODS In this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m2). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient (r) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA). RESULTS In patients with FEP, plasma leptin not BMI was significantly lower (P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher (P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA (r = -0.4972, P = 0.001), PANSS-PSS (r = -0.4034, P = 0.028), and PANSS-NSS (r = -0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS (r = 0.5844, P = 0.0034) and PANSS-NSS (r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher (P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI (r = 0.312, P = 0.032) but not with PANSS scores or erythrocyte membrane SFAs-PA. However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only (r = 0.4729, P = 0.031). Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultra-high risk of developing psychosis; therefore, the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia. CONCLUSION Disrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia. Large-scale studies are warranted to validate the above findings.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era's Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States
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20
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Agius R, Pace NP, Fava S. Sex differences in cardiometabolic abnormalities in a middle-aged Maltese population. CANADIAN JOURNAL OF PUBLIC HEALTH = REVUE CANADIENNE DE SANTE PUBLIQUE 2022; 113:484-500. [PMID: 35006592 PMCID: PMC9043060 DOI: 10.17269/s41997-021-00592-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 10/25/2021] [Indexed: 01/12/2023]
Abstract
OBJECTIVES There are sex differences in distribution of fat and in the prevalence of overweight and obesity. We therefore sought to explore sex differences in the prevalence of adiposity-metabolic health phenotypes, in anthropometric and cardio-metabolic parameters, and in the relationship between body mass index (BMI) categories and metabolic health. METHODS We conducted a cross-sectional study carried out between January 2018 and June 2019, of a nationally representative sample of the Maltese Caucasian population aged 41 ± 5 years. Metabolic health was defined as presence of ≤ 1 parameter of the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III criteria. RESULTS Males exhibited the unhealthy metabolic phenotype more frequently than women (41.3% vs 27.8%). In total, 10.3% of normal weight men and 6.3% of normal weight women were metabolically unhealthy. Males had a higher median BMI, but a lower proportion of males exhibited an abnormally high waist circumference as compared with females. A significant difference in sex distribution was noted for each body composition phenotype. CONCLUSION In a contemporary sample of middle-aged individuals, males were more metabolically unhealthy and more insulin resistant than their female counterparts in spite of exhibiting an abnormal waist circumference less frequently and having similar waist index. This suggests that the currently used cut-offs for normal waist circumference should be revised downwards in men. Since even normal weight men were more often metabolically unhealthy than normal weight women, BMI cut-offs may also need to be lowered in men.
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Affiliation(s)
- Rachel Agius
- University of Malta Medical School, Msida, Malta ,Mater Dei Hospital, Msida, Malta
| | | | - Stephen Fava
- University of Malta Medical School, Msida, Malta ,Mater Dei Hospital, Msida, Malta
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Zak K, Popova V, Orlenko V, Furmanova O, Tronko N. Cytokines in the blood of patients with type 2 diabetes mellitus depending on the level of overweight/obesity (literature review and own data). INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2021; 17:534-551. [DOI: 10.22141/2224-0721.17.7.2021.244969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The paper analyzes the current literature data and the results of our own researches concerning the state of the cytokine network: pro- and anti-inflammatory cytokines (interleukin (IL)1α, IL-1β, IL-4, IL-6, IL-10, IL-17 and tumor necrosis factor (TNF) α), α- and β-chemokines, including IL-8 and IL-16, as well as adipokines (leptin and adiponectin) in the peripheral blood of patients with type 2 diabetes (T2D) with normal and increased body weight/obesity. It has been shown that patients with T2D are characterized by an increased content of proinflammatory cytokines (IL-1, IL-6, IL-17, TNFα), α- and β-chemokines in the peripheral blood, including IL-8 and IL-16, as well as leptin with a decrease in adiponectin content. In lean patients (with body mass index (BMI)<25.5 kg/m2) compared to lean normoglycemic individuals from the control group (BMI<25.5kg/m2), there is a small but significant increase in IL-1β, IL-6, IL-17, TNFα and leptin, which, as BMI increases, significantly increases in severe obesity (BMI>30.0kg/m2), especially in obese women (BMI>35.0kg/m2). Similarly, an increase in proinflammatory cytokines is observed in normoglycemic people, but not as significant as in T2D. Less clear data were obtained when during determination of the anti-inflammatory cytokines IL-4 and IL-10, which is explained by a significant polymorphism of their genes, and both protective and compensatory effects on pro-inflammatory cytokine rise. In T2D patients, especially those with obesity, there is an increase in the leptin level and a decrease in the adiponectin content. The severity of the course and the percentage of mortality are closely associated with the BMI of patients. The effectiveness of the fight against an increase in the incidence of T2D should be primarily aimed at preventing obesity, and in case of already developed T2D— at reducing concomitant obesity. The analysis of the data presented also suggests that a sharp increase in the content of pro-inflammatory cytokines (so called cytokine storm) observed in patients with T2D and obesity infected with COVID-19, is a consequence of the summation and potentiation of already existing inflammatory process.
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Zhang ZT, Guo N, Zhuang GD, Deng SM, He WJ, Chen ZQ, Xu YH, Tang D, Wang SM. Metabolic Profiling of Carbonyl Compounds for Unveiling Protective Mechanisms of Pueraria lobata against Diabetic Nephropathy by UPLC-Q-Orbitrap HRMS/MS Analysis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:10943-10951. [PMID: 34514791 DOI: 10.1021/acs.jafc.1c03582] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Carbonyl compounds play a critical role in the pathogenesis of diabetic nephropathy (DN). Pueraria lobata (PL), also known as "Kudzu", is a widely consumed functional food or nutraceutical and has shown promise in the prevention of diabetes and complications such as DN. To explore the beneficial effects and the underlying mechanisms of PL against DN, a new strategy for in-depth metabolic profiling of carbonyl compounds in DN mice plasma by chemical derivatization combined with UPLC-Q-Orbitrap high-resolution mass spectrometry (HRMS)/MS analysis was developed for the first time. Pharmacological evaluation revealed that PL extracts containing a total of 73 identified compounds could ameliorate kidney injury and regulate abnormal glycolipid metabolism. In metabolomics analysis, 19 carbonyl compounds with significant differences were identified between DN mice and normal mice. Moreover, 12 metabolites had a tendency to return to normal levels after PL treatment. Overall, PL exerts beneficial effects on DN by regulating abnormal glycolipid metabolism and carbonyl stress, and endogenous carbonyl compounds might serve as potential biomarkers for DN.
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Affiliation(s)
- Zhi-Tong Zhang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ning Guo
- School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Guo-Dong Zhuang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Si-Min Deng
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Wen-Jiao He
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhi-Quan Chen
- Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - You-Hua Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Dan Tang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Shu-Mei Wang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Wei X, Lu Z, Li L, Zhang H, Sun F, Ma H, Wang L, Hu Y, Yan Z, Zheng H, Yang G, Liu D, Tepel M, Gao P, Zhu Z. Reducing NADPH Synthesis Counteracts Diabetic Nephropathy through Restoration of AMPK Activity in Type 1 Diabetic Rats. Cell Rep 2021; 32:108207. [PMID: 32997989 DOI: 10.1016/j.celrep.2020.108207] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 07/11/2020] [Accepted: 09/09/2020] [Indexed: 01/14/2023] Open
Abstract
Diabetic nephropathy (DN) is a major complication of diabetes mellitus and a primary cause of end-stage renal failure. Clinical studies indicate that metabolic surgery improves DN; however, the mechanism remains unclear. Here, we report that Roux-en-Y Gastric Bypass (RYGB) surgery significantly blocked and reversed DN without affecting the insulin signaling pathway. This protective role of RYGB surgery is almost blocked by either inhibition or knockout of 5'AMP-activated protein kinase (AMPK) in podocytes. Furthermore, mRNA microarray data reveal that RYGB surgery obviously reduced the gene expression involved in nicotinamide adenine dinucleotide phosphate (NAPDH) synthesis. The expression of a key NADPH synthase, hexose-6-phosphate dehydrogenase (H6PD), was inhibited by the low plasma corticosterone level after surgery. In addition, blocking NAPDH synthesis by knocking down H6PD mimicked the beneficial role of RYGB surgery through activation of AMPK in podocytes. Therefore, this study demonstrates that reducing NADPH production is critical for renal AMPK activation in response to RYGB surgery.
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Affiliation(s)
- Xiao Wei
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Zongshi Lu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Li Li
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Hexuan Zhang
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Fang Sun
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Huan Ma
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Lijuan Wang
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Yingru Hu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Zhencheng Yan
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Hongting Zheng
- Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Gangyi Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, Chongqing 400010, China
| | - Daoyan Liu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Martin Tepel
- Odense University Hospital, Department of Nephrology, University of Southern Denmark, Institute for Molecular Medicine, Cardiovascular and Renal Research, Institute of Clinical Research, Odense, Denmark
| | - Peng Gao
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
| | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
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24
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Wei X, Bai Y, Wang Z, Zheng X, Jin Z, Liu X. Association between dipeptidyl peptidase-4 inhibitors use and leptin in type 2 diabetes mellitus. Diabetol Metab Syndr 2021; 13:88. [PMID: 34446063 PMCID: PMC8390252 DOI: 10.1186/s13098-021-00703-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 08/02/2021] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Dipeptidyl peptidase-4 inhibitors (DPP-4i) provide a unique antihyperglycemic effect by regulating incretin peptides in type 2 diabetes mellitus (T2DM) patients who are inadequately controlled with insulin therapy. The aim of this study was to investigate the impact of DPP-4i on leptin concentrations in subjects with T2DM. METHODS Randomized controlled trials (RCTs) with comparators were systematically searched through PubMed, Embase, and the Cochrane Library. Quantitative analysis was performed with a fixed or random-effects model according to heterogeneity. Publication bias was evaluated by using the standard methods for sensitivity analysis. RESULTS Ten trials with 698 patients with T2DM were included. Pooled analysis demonstrated that DPP-4i did not significantly change leptin concentrations (1.31 ng/mL, 95 % CI - 0.48 to 3.10). DPP-4i exerted effects on modulating leptin levels compared to active comparators (0.21 ng/mL, 95 % CI - 1.37 to 1.78). Meta-analysis was powerful and stable after sensitivity analysis. CONCLUSIONS DPP-4i did not modulate leptin concentrations in T2DM and exerted no stronger effects than traditional antidiabetic agents.
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Affiliation(s)
- Xin Wei
- Department of Cardiology and Macrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yu Bai
- Department of Otolaryngology, Beijing Haidian Hospital, Beijing, China
| | - Zhuo Wang
- Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaohong Zheng
- Department of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zening Jin
- Department of Cardiology and Macrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Xin Liu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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25
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Rzepa Ł, Peller M, Eyileten C, Rosiak M, Kondracka A, Mirowska-Guzel D, Opolski G, Filipiak KJ, Postuła M, Kapłon-Cieslicka A. Resistin is Associated with Inflammation and Renal Function, but not with Insulin Resistance in Type 2 Diabetes. Horm Metab Res 2021; 53:478-484. [PMID: 34169498 DOI: 10.1055/a-1492-3077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The aim of the study was to investigate the association of adipokines (resistin, leptin and adiponectin) with obesity, insulin resistance (IR) and inflammation in type 2 diabetes mellitus (T2DM). A total of 284 patients with T2DM were included. Concentrations of resistin, leptin, adiponectin, and inflammatory markers [high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6)] were measured and homeostatic model assessment for IR (HOMA-IR) index was calculated. Resistin correlated negatively with estimated glomerular filtration rate (eGFR) and positively with hsCRP, TNF-α, IL-6, and white blood cell count (WBC). Leptin correlated positively with HOMA-IR, whereas adiponectin correlated negatively. Leptin also correlated positively with body mass index (BMI), waist circumference, IL-6, WBC and negatively with eGFR. Adiponectin correlated negatively with waist circumference, WBC, and eGFR. Multivariate logistic regression indicated lower eGFR and higher WBC and IL-6 as independent predictive factors of resistin concentration above the upper quartile (CAQ3), whereas female sex and higher BMI and HOMA-IR of leptin CAQ3, and lower HOMA-IR and older age of adiponectin CAQ3. In conclusion, in contrast to leptin and adiponectin, in T2DM patients, resistin is not associated with BMI and IR, but with inflammation and worse kidney function.
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Affiliation(s)
- Łukasz Rzepa
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Michał Peller
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
| | - Marek Rosiak
- Department of Cardiology and Hypertension, Central Clinical Hospital, Warsaw, Poland
| | - Agnieszka Kondracka
- Department of Internal Diseases and Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Dagmara Mirowska-Guzel
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
| | - Grzegorz Opolski
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof J Filipiak
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Marek Postuła
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
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Rojas M, Chávez-Castillo M, Bautista J, Ortega Á, Nava M, Salazar J, Díaz-Camargo E, Medina O, Rojas-Quintero J, Bermúdez V. Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. World J Diabetes 2021; 12:745-766. [PMID: 34168725 PMCID: PMC8192246 DOI: 10.4239/wjd.v12.i6.745] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/20/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
At present, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD.
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Affiliation(s)
- Milagros Rojas
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Mervin Chávez-Castillo
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Jordan Bautista
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Ángel Ortega
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Manuel Nava
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Edgar Díaz-Camargo
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Oscar Medina
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Joselyn Rojas-Quintero
- Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02155, United States
| | - Valmore Bermúdez
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia
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27
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Myers MG, Affinati AH, Richardson N, Schwartz MW. Central nervous system regulation of organismal energy and glucose homeostasis. Nat Metab 2021; 3:737-750. [PMID: 34158655 DOI: 10.1038/s42255-021-00408-5] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/12/2021] [Indexed: 02/05/2023]
Abstract
Growing evidence implicates the brain in the regulation of both immediate fuel availability (for example, circulating glucose) and long-term energy stores (that is, adipose tissue mass). Rather than viewing the adipose tissue and glucose control systems separately, we suggest that the brain systems that control them are components of a larger, highly integrated, 'fuel homeostasis' control system. This conceptual framework, along with new insights into the organization and function of distinct neuronal systems, provides a context within which to understand how metabolic homeostasis is achieved in both basal and postprandial states. We also review evidence that dysfunction of the central fuel homeostasis system contributes to the close association between obesity and type 2 diabetes, with the goal of identifying more effective treatment options for these common metabolic disorders.
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Affiliation(s)
- Martin G Myers
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Alison H Affinati
- Departments of Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Nicole Richardson
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Michael W Schwartz
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA.
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28
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Fan S, Xu Y, Lu Y, Jiang Z, Li H, Morrill JC, Cai J, Wu Q, Xu Y, Xue M, Arenkiel BR, Huang C, Tong Q. A neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia. Nat Commun 2021; 12:2662. [PMID: 33976218 PMCID: PMC8113586 DOI: 10.1038/s41467-021-22940-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/07/2021] [Indexed: 02/07/2023] Open
Abstract
Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepRArc) are selectively activated in T1D. Activation of LepRArc neurons, Arc GABAergic (GABAArc) neurons, or arcuate AgRP neurons, is able to reverse the leptin's rescuing effect. Conversely, inhibition of GABAArc neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin's rescuing effects. Finally, T1D LepRArc neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Our results identify aberrant activation of LepRArc neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepRArc neurons through reversing energy deprivation.
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Affiliation(s)
- Shengjie Fan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yuanzhong Xu
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yungang Lu
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zhiying Jiang
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Hongli Li
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jessie C Morrill
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- MD Anderson Cancer Center & UT Health Graduate School for Biomedical Sciences, University of Texas Health Science at Houston, Houston, TX, USA
| | - Jing Cai
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- MD Anderson Cancer Center & UT Health Graduate School for Biomedical Sciences, University of Texas Health Science at Houston, Houston, TX, USA
| | - Qi Wu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
| | - Yong Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
| | - Mingshan Xue
- Department of Neuroscience and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA
| | - Benjamin R Arenkiel
- Department of Molecular and Human Genetics and Department of Neuroscience, Baylor College of Medicine, and Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Qingchun Tong
- Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
- MD Anderson Cancer Center & UT Health Graduate School for Biomedical Sciences, University of Texas Health Science at Houston, Houston, TX, USA.
- Department of Neurobiology and Anatomy of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
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29
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Fujikawa T. Central regulation of glucose metabolism in an insulin-dependent and -independent manner. J Neuroendocrinol 2021; 33:e12941. [PMID: 33599044 DOI: 10.1111/jne.12941] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 12/17/2022]
Abstract
The central nervous system (CNS) contributes significantly to glucose homeostasis. The available evidence indicates that insulin directly acts on the CNS, in particular the hypothalamus, to regulate hepatic glucose production, thereby controlling whole-body glucose metabolism. Additionally, insulin also acts on the brain to regulate food intake and fat metabolism, which may indirectly regulate glucose metabolism. Studies conducted over the last decade have found that the CNS can regulate glucose metabolism in an insulin-independent manner. Enhancement of central leptin signalling reverses hyperglycaemia in insulin-deficient rodents. Here, I review the mechanisms by which central insulin and leptin actions regulate glucose metabolism. Although clinical studies have shown that insulin treatment is currently indispensable for managing diabetes, unravelling the neuronal mechanisms underlying the central regulation of glucose metabolism will pave the way for the design of novel therapeutic drugs for diabetes.
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Affiliation(s)
- Teppei Fujikawa
- Center for Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA
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30
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Binayi F, Zardooz H, Ghasemi R, Hedayati M, Askari S, Pouriran R, Sahraei M. The chemical chaperon 4-phenyl butyric acid restored high-fat diet- induced hippocampal insulin content and insulin receptor level reduction along with spatial learning and memory deficits in male rats. Physiol Behav 2021; 231:113312. [PMID: 33412188 DOI: 10.1016/j.physbeh.2021.113312] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/01/2021] [Accepted: 01/02/2021] [Indexed: 12/18/2022]
Abstract
This study assessed the effect of a chronic high-fat diet (HFD) on plasma and hippocampal insulin and corticosterone levels, the hippocampus insulin receptor amount, and spatial learning and memory with or without receiving 4-phenyl butyric acid (4-PBA) in male rats. Rats were divided into high-fat and normal diet groups, then each group was subdivided into dimethyl sulfoxide (DMSO) and 4-PBA groups. After weaning, the rats were fed with HFD for 20 weeks. Then, 4-PBA or DMSO were injected for 3 days. Subsequently, oral glucose tolerance test was done. On the following day, spatial memory tests were performed. Then the hippocampus Bip, Chop, insulin, corticosterone, and insulin receptor levels were determined. HFD increased plasma glucose, leptin and corticosterone concentrations, hippocampus Bip, Chop and corticosterone levels, food intake, abdominal fat weight and body weight along with impaired glucose tolerance. It decreased plasma insulin, and insulin content, and its receptor amount in hippocampus. HFD lengthened escape latency and shortened the duration spent in target zone. 4-PBA administration improved the HFD- induced adverse changes. Chronic HFD possibly through the induction of endoplasmic reticulum (ER) stress and subsequent changes in the levels of hippocampal corticosterone, insulin and insulin receptor along with possible leptin resistance caused spatial learning and memory deficits.
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Affiliation(s)
- Fateme Binayi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Homeira Zardooz
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Rasoul Ghasemi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Askari
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramin Pouriran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Sahraei
- School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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31
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Pereira S, Cline DL, Glavas MM, Covey SD, Kieffer TJ. Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism. Endocr Rev 2021; 42:1-28. [PMID: 33150398 PMCID: PMC7846142 DOI: 10.1210/endrev/bnaa027] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Indexed: 12/18/2022]
Abstract
The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin's regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. To fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored.
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Affiliation(s)
- Sandra Pereira
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Daemon L Cline
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Maria M Glavas
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Scott D Covey
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.,Department of Surgery, University of British Columbia, Vancouver, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, Canada
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32
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Crouch M, Al-Shaer A, Shaikh SR. Hormonal Dysregulation and Unbalanced Specialized Pro-Resolving Mediator Biosynthesis Contribute toward Impaired B Cell Outcomes in Obesity. Mol Nutr Food Res 2021; 65:e1900924. [PMID: 32112513 PMCID: PMC8627245 DOI: 10.1002/mnfr.201900924] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 02/09/2020] [Indexed: 12/16/2022]
Abstract
Diet-induced obesity is associated with impaired B-cell-driven humoral immunity, which coincides with chronic inflammation and has consequences for responses to infections and vaccinations. Key nutritional, cellular, and molecular mechanisms by which obesity may impair aspects of humoral immunity such as B cell development, class switch recombination, and formation of long-lived antibody secreting cells are reviewed. A key theme to emerge is the central role of white adipose tissue on the formation and function of pro-inflammatory B cell subsets that exacerbate insulin resistance. The underlying role of select hormones such as leptin is highlighted, which may be driving the formation of pro-inflammatory B cells in the absence of antigen stimulation. This review also extensively covers the regulatory role of lipid metabolites such as prostaglandins and specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. Notably, SPM biosynthesis is impaired in obesity and contributes toward impaired antibody production. Future directions for research, including avenues for therapeutic intervention, are included.
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Affiliation(s)
- Miranda Crouch
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Abrar Al-Shaer
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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33
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de Jesus AA, Hou Y, Brooks S, Malle L, Biancotto A, Huang Y, Calvo KR, Marrero B, Moir S, Oler AJ, Deng Z, Montealegre Sanchez GA, Ahmed A, Allenspach E, Arabshahi B, Behrens E, Benseler S, Bezrodnik L, Bout-Tabaku S, Brescia AC, Brown D, Burnham JM, Caldirola MS, Carrasco R, Chan AY, Cimaz R, Dancey P, Dare J, DeGuzman M, Dimitriades V, Ferguson I, Ferguson P, Finn L, Gattorno M, Grom AA, Hanson EP, Hashkes PJ, Hedrich CM, Herzog R, Horneff G, Jerath R, Kessler E, Kim H, Kingsbury DJ, Laxer RM, Lee PY, Lee-Kirsch MA, Lewandowski L, Li S, Lilleby V, Mammadova V, Moorthy LN, Nasrullayeva G, O'Neil KM, Onel K, Ozen S, Pan N, Pillet P, Piotto DG, Punaro MG, Reiff A, Reinhardt A, Rider LG, Rivas-Chacon R, Ronis T, Rösen-Wolff A, Roth J, Ruth NM, Rygg M, Schmeling H, Schulert G, Scott C, Seminario G, Shulman A, Sivaraman V, Son MB, Stepanovskiy Y, Stringer E, Taber S, Terreri MT, Tifft C, Torgerson T, Tosi L, Van Royen-Kerkhof A, Wampler Muskardin T, Canna SW, Goldbach-Mansky R. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J Clin Invest 2020; 130:1669-1682. [PMID: 31874111 DOI: 10.1172/jci129301] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 12/18/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
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Affiliation(s)
- Adriana A de Jesus
- Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USA
| | - Yangfeng Hou
- Department of Rheumatology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong, China
| | - Stephen Brooks
- Biomining and Discovery Section, NIAMS/NIH, Bethesda, Maryland, USA
| | - Louise Malle
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Angelique Biancotto
- Immunology & Inflammation Research Therapeutic Area, Sanofi, Boston, Massachusetts, USA
| | - Yan Huang
- Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USA
| | - Katherine R Calvo
- Department of Laboratory Medicine (DLM), Clinical Center/NIH, Bethesda, Maryland, USA
| | | | | | - Andrew J Oler
- Bioinformatics and Computational Biosciences Branch (BCBB), Office of Cyber Infrastructure and Computational Biology (OCICB), NIAID/NIH, Bethesda, Maryland, USA
| | - Zuoming Deng
- Biomining and Discovery Section, NIAMS/NIH, Bethesda, Maryland, USA
| | | | - Amina Ahmed
- The Autoinflammatory Diseases Consortium.,Levine Children's Hospital, Charlotte, North Carolina, USA
| | - Eric Allenspach
- The Autoinflammatory Diseases Consortium.,Divisions of Immunology & Rheumatology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA
| | - Bita Arabshahi
- The Autoinflammatory Diseases Consortium.,Virginia Commonwealth University & Pediatric Specialists of Virginia, Fairfax, Virginia, USA
| | - Edward Behrens
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Susanne Benseler
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics, Pediatric Rheumatology Section, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | - Liliana Bezrodnik
- The Autoinflammatory Diseases Consortium.,Immunology Unit, Pediatric Hospital R. Gutierrez, Buenos Aires, Argentina
| | - Sharon Bout-Tabaku
- The Autoinflammatory Diseases Consortium.,Department of Pediatric Medicine, Sidra Medicine, Qatar Foundation, Doha, Qatar
| | - AnneMarie C Brescia
- The Autoinflammatory Diseases Consortium.,Nemours/Alfred I. DuPont Hospital for Children, Wilmington, Delaware, USA
| | - Diane Brown
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Children's Hospital Los Angeles & USC, Los Angeles, California, USA
| | - Jon M Burnham
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Maria Soledad Caldirola
- The Autoinflammatory Diseases Consortium.,Immunology Unit, Pediatric Hospital R. Gutierrez, Buenos Aires, Argentina
| | - Ruy Carrasco
- The Autoinflammatory Diseases Consortium.,Pediatric Rheumatology, Dell Children's Medical Center of Central Texas, Austin, Texas, USA
| | - Alice Y Chan
- The Autoinflammatory Diseases Consortium.,Divisions of Pediatric AIBMT & Rheumatology, UCSF, San Francisco, California, USA
| | - Rolando Cimaz
- The Autoinflammatory Diseases Consortium.,Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
| | - Paul Dancey
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Janeway Children's Hospital & Rehabilitation Centre, Saint John's, Newfoundland and Labrador, Canada
| | - Jason Dare
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Rheumatology, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, Arkansas, USA
| | - Marietta DeGuzman
- The Autoinflammatory Diseases Consortium.,Department of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, Texas, USA
| | - Victoria Dimitriades
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Allergy, Immunology & Rheumatology, UC Davis Health, Sacramento, California, USA
| | - Ian Ferguson
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics/Pediatric Rheumatology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Polly Ferguson
- The Autoinflammatory Diseases Consortium.,Pediatrics Department, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Laura Finn
- The Autoinflammatory Diseases Consortium.,Pathology Department, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA
| | - Marco Gattorno
- The Autoinflammatory Diseases Consortium.,Center for Autoinflammatory Diseases and Immunedeficiencies, IRCCS Giannina Gaslini, Genoa, Italy
| | - Alexei A Grom
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Eric P Hanson
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, Indiana, USA
| | - Philip J Hashkes
- The Autoinflammatory Diseases Consortium.,Pediatric Rheumatology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Christian M Hedrich
- The Autoinflammatory Diseases Consortium.,Department of Women's & Children's Health, Institute of Translational Medicine, University of Liverpool & Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom
| | - Ronit Herzog
- The Autoinflammatory Diseases Consortium.,Department of Otolaryngology, Division of Allergy and Immunology, New York University, New York, New York, USA
| | - Gerd Horneff
- The Autoinflammatory Diseases Consortium.,Asklepios Klinik Sankt, Augustin GmbH, St. Augustin, Germany and Department of Pediatric and Adolescents Medicine, University of Cologne, Cologne, Germany
| | - Rita Jerath
- The Autoinflammatory Diseases Consortium.,Augusta University Medical Center, Augusta, Georgia, USA
| | - Elizabeth Kessler
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Children's Mercy, Kansas City and University of Missouri, Kansas City, Missouri, USA
| | - Hanna Kim
- The Autoinflammatory Diseases Consortium.,Pediatric Translational Research Branch, NIAMS/NIH, Bethesda, Maryland, USA
| | - Daniel J Kingsbury
- The Autoinflammatory Diseases Consortium.,Randall Children's Hospital at Legacy Emanuel, Portland, Oregon, USA
| | - Ronald M Laxer
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Rheumatology, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Pui Y Lee
- The Autoinflammatory Diseases Consortium.,Division of Allergy, Immunology and Rheumatology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Min Ae Lee-Kirsch
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Laura Lewandowski
- The Autoinflammatory Diseases Consortium.,Systemic Autoimmunity Branch, NIAMS/NIH, Bethesda, Maryland, USA
| | - Suzanne Li
- The Autoinflammatory Diseases Consortium.,Hackensack University Medical Center, Hackensack Meridian School of Medicine at Seton Hall University, Hackensack, New Jersey, USA
| | - Vibke Lilleby
- The Autoinflammatory Diseases Consortium.,Department of Rheumatology, Pediatric Section, Oslo University Hospital, Oslo, Norway
| | - Vafa Mammadova
- The Autoinflammatory Diseases Consortium.,Azerbaijan Medical University, Baku, Azerbaijan
| | - Lakshmi N Moorthy
- The Autoinflammatory Diseases Consortium.,Rutgers - Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
| | - Gulnara Nasrullayeva
- The Autoinflammatory Diseases Consortium.,Azerbaijan Medical University, Baku, Azerbaijan
| | - Kathleen M O'Neil
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, Indiana, USA
| | - Karen Onel
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Rheumatology, Weill Cornell Medicine & Hospital for Special Surgery, New York, New York, USA
| | - Seza Ozen
- The Autoinflammatory Diseases Consortium.,Hacettepe University, Department of Pediatrics, Ankara, Turkey
| | - Nancy Pan
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Rheumatology, Weill Cornell Medicine & Hospital for Special Surgery, New York, New York, USA
| | - Pascal Pillet
- The Autoinflammatory Diseases Consortium.,Children Hospital Pellegrin-Enfants, Bordeaux, France
| | - Daniela Gp Piotto
- The Autoinflammatory Diseases Consortium.,Department of Pediatric Rheumatology, Federal University of Sao Paulo, Sao Paulo, Brazil
| | - Marilynn G Punaro
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Andreas Reiff
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine, USC, Los Angeles, California, USA
| | - Adam Reinhardt
- The Autoinflammatory Diseases Consortium.,University of Nebraska Medical Center/Children's Hospital and Medical Center, Omaha, Nebraska, USA
| | - Lisa G Rider
- The Autoinflammatory Diseases Consortium.,Environmental Autoimmunity Group, NIEHS/NIH, Bethesda, Maryland, USA
| | - Rafael Rivas-Chacon
- The Autoinflammatory Diseases Consortium.,Department of Pediatric Rheumatology, Nicklaus Children's Hospital, Miami, Florida, USA
| | - Tova Ronis
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Rheumatology, Children's National Health System, Washington, DC, USA
| | - Angela Rösen-Wolff
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Johannes Roth
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Dermatology and Rheumatology, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Natasha Mckerran Ruth
- The Autoinflammatory Diseases Consortium.,Medical University of South Carolina, Charleston, South Carolina, USA
| | - Marite Rygg
- The Autoinflammatory Diseases Consortium.,Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, and Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway
| | - Heinrike Schmeling
- The Autoinflammatory Diseases Consortium.,Department of Pediatrics, Pediatric Rheumatology Section, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | - Grant Schulert
- The Autoinflammatory Diseases Consortium.,Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Christiaan Scott
- The Autoinflammatory Diseases Consortium.,University of Cape Town, Red Cross War Memorial Children's Hospital, Cape Town, South Africa
| | - Gisella Seminario
- The Autoinflammatory Diseases Consortium.,Immunology Unit, Pediatric Hospital R. Gutierrez, Buenos Aires, Argentina
| | - Andrew Shulman
- The Autoinflammatory Diseases Consortium.,Pediatric Rheumatology, Children's Hospital of Orange County, UC Irvine, Irvine, California, USA
| | - Vidya Sivaraman
- The Autoinflammatory Diseases Consortium.,Section of Rheumatology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Mary Beth Son
- The Autoinflammatory Diseases Consortium.,Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Yuriy Stepanovskiy
- The Autoinflammatory Diseases Consortium.,Department of Pediatric Infectious Diseases and Immunology, Shupyk National Medical Academy for Postgraduate Education, Kiev, Ukraine
| | - Elizabeth Stringer
- The Autoinflammatory Diseases Consortium.,IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Sara Taber
- The Autoinflammatory Diseases Consortium.,Division of Pediatric Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA
| | - Maria Teresa Terreri
- The Autoinflammatory Diseases Consortium.,Department of Pediatric Rheumatology, Federal University of Sao Paulo, Sao Paulo, Brazil
| | - Cynthia Tifft
- The Autoinflammatory Diseases Consortium.,Undiagnosed Diseases Program, NHGRI/NIH, Bethesda, Maryland, USA
| | - Troy Torgerson
- The Autoinflammatory Diseases Consortium.,Divisions of Immunology & Rheumatology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA
| | - Laura Tosi
- The Autoinflammatory Diseases Consortium.,Bone Health Program, Children's National Health System, Washington, DC, USA
| | - Annet Van Royen-Kerkhof
- The Autoinflammatory Diseases Consortium.,Department of Pediatric Immunology and Rheumatology, Wilhelmina Children's Hospital Utrecht, Utrecht, Netherlands
| | - Theresa Wampler Muskardin
- The Autoinflammatory Diseases Consortium.,New York University School of Medicine, New York, New York, USA
| | - Scott W Canna
- Children's Hospital Pittsburgh, Pittsburgh, Pennsylvania, USA
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Park JM, Shin SP, Cho SK, Lee JH, Kim JW, Kang CD, Huh JH, Lee KJ. Triglyceride and glucose (TyG) index is an effective biomarker to identify severe acute pancreatitis. Pancreatology 2020; 20:1587-1591. [PMID: 33008750 DOI: 10.1016/j.pan.2020.09.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 09/19/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Early diagnosis of severe acute pancreatitis (AP) is important to reduce morbidity and mortality. We investigated the association between the triglyceride and glucose index (TyG index) and the prognosis of severe AP (SAP). METHODS The TyG index was calculated as: ln [fasting triglycerides (mg/dL) x fasting plasma glucose (mg/dL)]/2. Multivariable logistic regression analyses were used to investigate the independent association between the TyG index and the severity of AP. RESULTS In this study, 373 patients with AP were recruited from three hospitals. The TyG index was higher in the SAP group than in the non-SAP group. Further, the TyG index was higher than in patients admitted to an intensive care unit and those who died of AP. The TyG index was an independent predictive factor for SAP (odds ratio 7.14, 95% confidence interval 2.80-18.19). The area under the curve increased significantly, from 0.738 to 0.830, after adding the TyG index to a predictive SAP model. CONCLUSIONS Our findings suggest that the TyG index is an independent prognostic factor in patients with AP and could be used as a simple prognostic indicator for SAP.
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Affiliation(s)
- Jin Myung Park
- Department of Internal Medicine, Kangwon National University School of Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea
| | - Suk Pyo Shin
- Division of Gastroenterology and Hepatology, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Seung Kook Cho
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Jun Hyeok Lee
- Center of Biomedical Data Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Jae Woo Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Chang Don Kang
- Department of Internal Medicine, Kangwon National University School of Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea
| | - Ji Hye Huh
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea.
| | - Kyong Joo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
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35
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Zheng J, Ding J, Liao M, Qiu Z, Yuan Q, Mai W, Dai Y, Zhang H, Wu H, Wang Y, Liao Y, Chen X, Cheng X. Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner. FASEB J 2020; 35:e21157. [PMID: 33155736 DOI: 10.1096/fj.202000300r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 10/15/2020] [Accepted: 10/19/2020] [Indexed: 12/13/2022]
Abstract
The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQβ-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQβ-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQβ-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQβ-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.
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Affiliation(s)
- Jiayu Zheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaxing Ding
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengyang Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihua Qiu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingchen Yuan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wuqian Mai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Dai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongrong Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hailang Wu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingxuan Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhua Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao Chen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
PURPOSE OF REVIEW Obesity and diabetes have already become the second largest risk factor for cardiovascular disease. During the last decade, remarkable advances have been made in understanding the human genome's contribution to glucose homeostasis disorders and obesity. A few studies on rare mutations of candidate genes provide potential genetic targets for the treatment of diabetes and obesity. In this review, we discussed the detailed findings of these studies and the possible causalities between specific genetic variations and dysfunctions in energy or glucose homeostasis. We are optimistic that novel therapeutic strategies targeting these specific mutants for treating and preventing diabetes and obesity will be developed in the near future. RECENT FINDINGS Studies on rare genetic mutation-caused obesity or diabetes have identified potential genetic targets to decrease body weight or reduce the risk of diabetes. Rare mutations observed in lipodystrophy, obese, or diabetic human patients are promising targets in the treatment of diabetes and obesity.
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Affiliation(s)
- Bing Feng
- Pennington Biomedical Research Center, Brain Glycemic And Metabolism Control Department, Louisiana State University, 6400 Perkins Rd, Basic Science Building L2024, Baton Rouge, LA, 70808, USA
| | - Pingwen Xu
- The Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Yanlin He
- Pennington Biomedical Research Center, Brain Glycemic And Metabolism Control Department, Louisiana State University, 6400 Perkins Rd, Basic Science Building L2024, Baton Rouge, LA, 70808, USA.
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Singha A, Palavicini JP, Pan M, Farmer S, Sandoval D, Han X, Fujikawa T. Leptin Receptors in RIP-Cre 25Mgn Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice. Front Endocrinol (Lausanne) 2020; 11:588447. [PMID: 33071988 PMCID: PMC7538546 DOI: 10.3389/fendo.2020.588447] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 08/25/2020] [Indexed: 12/13/2022] Open
Abstract
Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of Ins2 gene (RIP-Cre25Mgn neurons) are required for central leptin signaling to reverse dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgn neurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgn neurons (RIP-CreΔLEPR mice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-CreΔLEPR mice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-CreΔLEPR mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in these mice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgn neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by improving dyslipidemia.
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Affiliation(s)
- Ashish Singha
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Juan Pablo Palavicini
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Meixia Pan
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Scotlynn Farmer
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Darleen Sandoval
- Department of Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Xianlin Han
- Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Teppei Fujikawa
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
- Center for Biomedical Neuroscience, University of Texas Health San Antonio, San Antonio, TX, United States
- Division of Hypothalamic Research Center, Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, TX, United States
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38
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Barkabi-Zanjani S, Ghorbanzadeh V, Aslani M, Ghalibafsabbaghi A, Chodari L. Diabetes mellitus and the impairment of male reproductive function: Possible signaling pathways. Diabetes Metab Syndr 2020; 14:1307-1314. [PMID: 32755827 DOI: 10.1016/j.dsx.2020.07.031] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/04/2020] [Accepted: 07/17/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Today, it has been shown that diabetes mellitus (DM) can affect male fertility. Glucose metabolism is a vital process in spermatogenesis that is impacted by diabetes condition. But the mechanisms by which DM causes male infertility are not wholly clarified. The aim of this review is to provide brief information about the influence of hyperglycemia on male fertility and specific emphasis on the molecular signaling pathway that is involved. METHODS Broad literature search in the electronic database "Pubmed", "Google Scholar", the website of "World Health Organization" (WHO) and Control Disease and Prevention (CDC) took place. There was no time restriction. A key criterion for the selection of articles was English and language. Finally, one hundred thirty seven articles were included in the review. RESULTS Diabetes mellitus affects many signaling pathways that involved in the spermatogenesis. It seems that increased ROS and oxidative stress in the diabetes is the beginning of all fertility problems and affects all of involved signaling pathways in the spermatogenesis. CONCLUSIONS It seems that there was strong interconnected between oxidative stress and all of involved signaling pathways in the reproductive problems in diabetes. So, approaches that diminish oxidative stress in the testis can be effective in improving diabetes related infertility complications.
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Affiliation(s)
- Sona Barkabi-Zanjani
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vajihe Ghorbanzadeh
- Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Mohamadreza Aslani
- Lung Inflammatory Diseases Research Center, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran; Neurogenetic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Leila Chodari
- Neurophysiology Research Center, Cellular and Molecular Medicine Institute,Urmia University of Medical Sciences, Urmia, Iran; Department of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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39
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Li Q, Zhao C, Zhang Y, Du H, Xu T, Xu X, Zhang J, Kuang T, Lai X, Fan G, Zhang Y. 1H NMR-Based Metabolomics Coupled With Molecular Docking Reveal the Anti-Diabetic Effects and Potential Active Components of Berberis vernae on Type 2 Diabetic Rats. Front Pharmacol 2020; 11:932. [PMID: 32636751 PMCID: PMC7317004 DOI: 10.3389/fphar.2020.00932] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022] Open
Abstract
The dried stem bark of Berberis vernae C.K.Schneid., known as “Xiao-bo-pi” in Chinese, is a representative anti-diabetic herb in traditional Tibetan medical system. However, its anti-diabetic mechanisms and active components remain unclear. In this study, 1H NMR-based metabolomics, biochemistry assay, molecular docking, and network analysis were integrated to evaluate the anti-diabetic effects of B. vernae extract on type 2 diabetic rats, and to explore its active components and underlying mechanisms. Diabetes was induced by high-fat diet and streptozotocin. After 30 days of treatment, B. vernae extract significantly decreased the serum levels of fasting blood glucose, insulin, insulin resistance index, glycated serum protein, TNF-α, IL-1β, and IL-6, whereas significantly increased the serum levels of insulin sensitivity index in type 2 diabetic rats. A total of 28 endogenous metabolites were identified by 1H NMR-based metabolomics, of which 9 metabolites that were changed by diabetes were significantly reversed by B. vernae extract. The constructed compound-protein-metabolite-disease (CPMD) interaction network revealed the correlation between chemical constituents, target proteins, differential metabolites, and type 2 diabetes. Ferulic acid 4-O-β-D-glucopyranoside, bufotenidine, jatrorrhizine, and berberine showed good hit rates for both the 30 disease-related proteins and 14 differential metabolites-related proteins, indicating that these four compounds might be the active ingredients of B. vernae against type 2 diabetes. Moreover, pathway analysis revealed that the anti-diabetic mechanisms of B. vernae might be related to its regulation of several metabolic pathways (e.g., butanoate metabolism) and disease-related signal pathways (e.g., adipocytokine signaling pathway). In summary, B. vernae exerts a significant anti-diabetic effect and has potential as a drug candidate for the treatment of type 2 diabetes.
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Affiliation(s)
- Qi Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chengcheng Zhao
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunsen Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Huan Du
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tong Xu
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinmei Xu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tingting Kuang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xianrong Lai
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Gang Fan
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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40
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Abstract
PURPOSE OF REVIEW In this brief review, we highlight studies that have contributed to our current understanding of glucose homeostasis by the central nervous system (CNS) leptin-melanocortin system, particularly proopiomelanocortin neurons and melanocortin-4 receptors (MC4R). RECENT FINDINGS Leptin deficiency is associated with insulin resistance and impaired glucose metabolism whereas leptin administration improves tissue glucose uptake/oxidation and reduces hepatic glucose output. These antidiabetic effects of leptin have been demonstrated in experimental animals and humans, even when circulating insulin levels are barely detectable. Recent evidence suggests that these antidiabetic actions of leptin are mediated, in large part, by stimulation of leptin receptors (LRs) in the CNS and require activation of proopiomelanocortin (POMC) neurons and MC4R. These chronic antidiabetic effects of the CNS leptin-melanocortin system appear to be independent of autonomic nervous system and pituitary-thyroid-adrenal (PTA) axis mechanisms. The powerful antidiabetic actions of the CNS leptin-melanocortin system are capable of normalizing plasma glucose even in the absence of insulin and involve interactions of multiple neuronal populations and intracellular signaling pathways. Although the links between the CNS leptin-melanocortin system and its chronic effects on peripheral tissue glucose metabolism are still uncertain, they are independent of insulin action, activation of the autonomic nervous system, or the PTA axis. Unraveling the pathways that contribute to the powerful antidiabetic effects of the CNS leptin-melanocortin system may provide novel therapeutic approaches for diabetes mellitus.
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Affiliation(s)
- Alexandre A da Silva
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA.
| | - Jussara M do Carmo
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA
| | - John E Hall
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA
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41
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Zouhar P, Rakipovski G, Bokhari MH, Busby O, Paulsson JF, Conde-Frieboes KW, Fels JJ, Raun K, Andersen B, Cannon B, Nedergaard J. UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia. Am J Physiol Endocrinol Metab 2020; 318:E72-E86. [PMID: 31743040 PMCID: PMC6985793 DOI: 10.1152/ajpendo.00253.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
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Affiliation(s)
- Petr Zouhar
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- Department of Adipose Tissue Biology, Institute of Physiology CAS, Prague, the Czech Republic
| | | | - Muhammad Hamza Bokhari
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Oliver Busby
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | | | | | | | - Kirsten Raun
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Barbara Cannon
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Jan Nedergaard
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
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42
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Su KZ, Li YR, Zhang D, Yuan JH, Zhang CS, Liu Y, Song LM, Lin Q, Li MW, Dong J. Relation of Circulating Resistin to Insulin Resistance in Type 2 Diabetes and Obesity: A Systematic Review and Meta-Analysis. Front Physiol 2019; 10:1399. [PMID: 31803062 PMCID: PMC6877503 DOI: 10.3389/fphys.2019.01399] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/30/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Resistin, a cysteine-rich polypeptide encoded by the RETN gene, which plays an important role in many mechanisms in rodent studies, including lipid metabolism, inflammation and insulin resistance. Nevertheless, the relationship between resistin and insulin resistance in humans is under debate. The present study was designed to clarify the correlation between resistin and insulin resistance. Methods: A systematic literature search was performed using PubMed, Embase and Cochrane Library until March 3, 2019 with the keywords "resistin" and "insulin resistance." Funnel plots and Egger's test were used to detect publication bias. A random-effects model was used to calculate the pooled effect size. Subgroup analysis and meta regression was performed to identify the sources of heterogeneity. Results: Fifteen studies were included in our systematic review. Among them, 10 studies with Pearson coefficients were used for meta-analysis. We found resistin levels were weakly correlated with insulin resistance in those with T2DM and obesity (r = 0.21, 95% CI: 0.06-0.35, I 2 = 59.7%, P = 0.003). Nevertheless, subgroup analysis suggested that circulating resistin levels were significantly positively correlated with insulin resistance in individuals with hyperresistinemia (≥14.8 ng/ml) (r = 0.52, 95% CI: 0.35-0.68, I 2 = 0.0%, P = 0.513). And there was no relationship between circulating resistin and insulin resistance in those with normal circulating resistin levels (<14.8 ng/ml) (r = 0.08, 95% CI: -0.01-0.18, I 2 = 0.0%, P = 0.455). Publication bias was insignificant (Egger's test P = 0.592). Conclusion: In T2DM and obese individuals, resistin levels were positively correlated with insulin resistance in those with hyperresistinemia, but not in those with normal circulating resistin levels.
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Affiliation(s)
- Kai-zhen Su
- Clinical Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Yan-run Li
- Clinical Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Di Zhang
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Jun-hua Yuan
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Cai-shun Zhang
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Yuan Liu
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Li-min Song
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Qian Lin
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Man-wen Li
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Jing Dong
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
- Physiology Department, Medical College, Qingdao University, Qingdao, China
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43
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Khanal P, Patil BM, Mandar BK, Dey YN, Duyu T. Network pharmacology-based assessment to elucidate the molecular mechanism of anti-diabetic action of Tinospora cordifolia. CLINICAL PHYTOSCIENCE 2019. [DOI: 10.1186/s40816-019-0131-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Tinospora cordifolia is used traditionally for the treatment of diabetes and is used in various formulations. Scientific evidence is also available for its anti-diabetic potency under various animal models. However, the probable molecular mechanism of Tinospora cordifolia in the treatment of diabetes has not been illuminated yet. Hence, the present study dealt to elucidate the probable molecular mechanism of anti-diabetic effect of Tinospora cordifolia using network pharmacology approach.
Methods
The structural information of bioactive phytoconstituents was retrieved from different open source databases. Compounds were then predicted for their hits with the probable targets involved in the diabetes mellitus. Phytoconstituents were also predicted for their druglikeness score, probable side effects, and ADMET profile. The modulated protein pathways were identified by using the Kyoto Encyclopedia of Genes and Genomes pathway analysis. The interaction between the compounds, proteins, and pathways was interpreted based on the edge count. The docking study was performed using Autodock4.0.
Results
Nine phytoconstituents from Tinospora cordifolia were identified to modulate the pathogenic protein molecules involved in diabetes mellitus. Among them, tembetarine scored highest druglikeness hit and had the maximum interaction with proteins involved in diabetes. Further, neuroactive ligand-receptor interaction was predicted as majorly modulated pathway.
Conclusion
The current study identified an important antidiabetic constituent, tembetarine which modulated the majority of diabetic proteins majorly modulating neuroactive ligand-receptor interaction.
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HOMA-estimated insulin resistance as an independent prognostic factor in patients with acute pancreatitis. Sci Rep 2019; 9:14894. [PMID: 31624312 PMCID: PMC6797758 DOI: 10.1038/s41598-019-51466-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 10/01/2019] [Indexed: 12/17/2022] Open
Abstract
This prospective study investigated the relationship between insulin resistance assessed using the homeostatic model assessment of insulin resistance (HOMA-IR) and the prognosis of acute pancreatitis (AP). A total of 269 patients with AP were recruited in this study. HOMA-IR scores were calculated using fasting insulin and plasma glucose levels. Patients were then categorized into the non-insulin-resistant group (HOMA-IR <2.5) and the insulin-resistant group (HOMA-IR ≥2.5). We performed multivariable logistic regression analysis to investigate the independent association between IR assessed using HOMA-IR and the severity of AP. We also conducted receiver operating characteristic analysis to investigate the predictive ability of HOMA-IR for severe AP. The proportion of patients with severe AP (according to the Atlanta classification) and the percentage of ICU admissions and mortality were higher in patients with insulin resistance than in those without insulin resistance. The area under the curve (AUC) of HOMA-IR for predicting severe AP was 0.719 (95% CI 0.59–0.85, P = 0.003). This value was not significantly different from the AUCs of other AP scoring systems such as CTSI, Ranson, and BISAP. Insulin resistance was the only independent factor for either ICU admission (OR 5.95, 95% CI 1.95–18.15, P = 0.002) or severe AP (OR 6.72, 95% CI 1.34–33.62, P = 0.020). Our findings suggest that the HOMA-IR score is an independent prognostic factor in patients with acute pancreatitis. This finding indicates that insulin resistance is potentially involved in the mechanism for severe AP.
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Chatmethakul T, Roghair RD. Risk of hypertension following perinatal adversity: IUGR and prematurity. J Endocrinol 2019; 242:T21-T32. [PMID: 30657741 PMCID: PMC6594910 DOI: 10.1530/joe-18-0687] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 01/18/2019] [Indexed: 12/12/2022]
Abstract
Consistent with the paradigm shifting observations of David Barker and colleagues that revealed a powerful relationship between decreased weight through 2 years of age and adult disease, intrauterine growth restriction (IUGR) and preterm birth are independent risk factors for the development of subsequent hypertension. Animal models have been indispensable in defining the mechanisms responsible for these associations and the potential targets for therapeutic intervention. Among the modifiable risk factors, micronutrient deficiency, physical immobility, exaggerated stress hormone exposure and deficient trophic hormone production are leading candidates for targeted therapies. With the strong inverse relationship seen between gestational age at delivery and the risk of hypertension in adulthood trumping all other major cardiovascular risk factors, improvements in neonatal care are required. Unfortunately, therapeutic breakthroughs have not kept pace with rapidly improving perinatal survival, and groundbreaking bench-to-bedside studies are urgently needed to mitigate and ultimately prevent the tsunami of prematurity-related adult cardiovascular disease that may be on the horizon. This review highlights our current understanding of the developmental origins of hypertension and draws attention to the importance of increasing the availability of lactation consultants, nutritionists, pharmacists and physical therapists as critical allies in the battle that IUGR or premature infants are waging not just for survival but also for their future cardiometabolic health.
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Affiliation(s)
- Trassanee Chatmethakul
- Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Robert D Roghair
- Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
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Hölscher C. Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer's Disease. Front Aging Neurosci 2019; 11:88. [PMID: 31068799 PMCID: PMC6491455 DOI: 10.3389/fnagi.2019.00088] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 04/03/2019] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes is a risk factor for developing Alzheimer’s disease (AD). The underlying mechanism that links up the two conditions seems to be the de-sensitization of insulin signaling. In patients with AD, insulin signaling was found to be de-sensitized in the brain, even if they did not have diabetes. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common – they induce a chronic inflammation response in the brain. Pro-inflammatory cytokines block growth factor signaling and enhance oxidative stress. The underlying molecular processes for this are described in the review. Treatments to re-sensitize insulin signaling in the brain are also described, such as nasal insulin tests in AD patients, or treatments with re-sensitizing hormones, such as leptin, ghrelin, glucagon-like peptide 1 (GLP-1),and glucose-dependent insulinotropic polypeptide (GIP). The first clinical trials show promising results and are a proof of concept that utilizing such treatments is valid.
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Affiliation(s)
- Christian Hölscher
- Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, China
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A hindbrain inhibitory microcircuit mediates vagally-coordinated glucose regulation. Sci Rep 2019; 9:2722. [PMID: 30804396 PMCID: PMC6389891 DOI: 10.1038/s41598-019-39490-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
Neurons in the brainstem dorsal vagal complex integrate neural and humoral signals to coordinate autonomic output to viscera that regulate a variety of physiological functions, but how this circuitry regulates metabolism is murky. We tested the hypothesis that premotor, GABAergic neurons in the nucleus tractus solitarius (NTS) form a hindbrain micro-circuit with preganglionic parasympathetic motorneurons of the dorsal motor nucleus of the vagus (DMV) that is capable of modulating systemic blood glucose concentration. In vitro, neuronal activation or inhibition using either excitatory or inhibitory designer receptor exclusively activated by designer drugs (DREADDs) constructs expressed in GABAergic NTS neurons increased or decreased, respectively, action potential firing of GABAergic NTS neurons and downstream synaptic inhibition of the DMV. In vivo, DREADD-mediated activation of GABAergic NTS neurons increased systemic blood glucose concentration, whereas DREADD-mediated silencing of these neurons was without effect. The DREADD-induced hyperglycemia was abolished by blocking peripheral muscarinic receptors, consistent with the hypothesis that altered parasympathetic drive mediated the response. This effect was paralleled by elevated serum glucagon and hepatic phosphoenolpyruvate carboxykinase 1 (PEPCK1) expression, without affecting insulin levels or muscle metabolism. Activity in a hindbrain inhibitory microcircuit is sufficient to modulate systemic glucose concentration, independent of insulin secretion or utilization.
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Clemmensen C, Finan B, Müller TD, DiMarchi RD, Tschöp MH, Hofmann SM. Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases. Nat Rev Endocrinol 2019; 15:90-104. [PMID: 30446744 DOI: 10.1038/s41574-018-0118-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Obesity and its comorbidities, such as type 2 diabetes mellitus and cardiovascular disease, constitute growing challenges for public health and economies globally. The available treatment options for these metabolic disorders cannot reverse the disease in most individuals and have not substantially reduced disease prevalence, which underscores the unmet need for more efficacious interventions. Neurobiological resilience to energy homeostatic perturbations, combined with the heterogeneous pathophysiology of human metabolic disorders, has limited the sustainability and efficacy of current pharmacological options. Emerging insights into the molecular origins of eating behaviour, energy expenditure, dyslipidaemia and insulin resistance suggest that coordinated targeting of multiple signalling pathways is probably necessary for sizeable improvements to reverse the progression of these diseases. Accordingly, a broad set of combinatorial approaches targeting feeding circuits, energy expenditure and glucose metabolism in concert are currently being explored and developed. Notably, several classes of peptide-based multi-agonists and peptide-small molecule conjugates with superior preclinical efficacy have emerged and are currently undergoing clinical evaluation. Here, we summarize advances over the past decade in combination pharmacotherapy for the management of obesity and type 2 diabetes mellitus, exclusively focusing on large-molecule formats (notably enteroendocrine peptides and proteins) and discuss the associated therapeutic opportunities and challenges.
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Affiliation(s)
- Christoffer Clemmensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
| | - Brian Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | | | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität, Munich, Germany
| | - Susanna M Hofmann
- Institute for Diabetes and Regeneration, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
- Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany.
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Neumann UH, Kwon MM, Baker RK, Kieffer TJ. Leptin contributes to the beneficial effects of insulin treatment in streptozotocin-diabetic male mice. Am J Physiol Endocrinol Metab 2018; 315:E1264-E1273. [PMID: 30300012 DOI: 10.1152/ajpendo.00159.2018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It was long thought that the only hormone capable of reversing the catabolic consequences of diabetes was insulin. However, various studies have demonstrated that the adipocyte-derived hormone leptin can robustly lower blood glucose levels in rodent models of insulin-deficient diabetes. In addition, it has been suggested that some of the metabolic manifestations of insulin-deficient diabetes are due to hypoleptinemia as opposed to hypoinsulinemia. Because insulin therapy increases leptin levels, we sought to investigate the contribution of leptin to the beneficial effects of insulin therapy. To do this, we tested insulin therapy in streptozotocin (STZ) diabetic mice that were either on an ob/ ob background or that were given a leptin antagonist to determine if blocking leptin action would blunt the glucose-lowering effects of insulin therapy. We found that STZ diabetic ob/ ob mice have a diminished blood glucose-lowering effect in response to insulin therapy compared with STZ diabetic controls and exhibited more severe weight loss post-STZ injection. In addition, STZ diabetic mice administered a leptin antagonist through daily injection or plasmid expression respond less robustly to insulin therapy as assessed by both fasting blood glucose levels and blood glucose levels during an oral glucose tolerance test. However, leptin antagonism did not prevent the insulin-induced reduction in β-hydroxybutyrate and triglyceride levels. Therefore, we conclude that elevated leptin levels can contribute to the glucose-lowering effect of insulin therapy in insulin-deficient diabetes.
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Affiliation(s)
- Ursula H Neumann
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia , Vancouver, British Columbia , Canada
| | - Michelle M Kwon
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia , Vancouver, British Columbia , Canada
| | - Robert K Baker
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia , Vancouver, British Columbia , Canada
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia , Vancouver, British Columbia , Canada
- Department of Surgery, Life Sciences Institute, University of British Columbia , Vancouver, British Columbia , Canada
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Kadota R, Sugita K, Uchida K, Yamada H, Yamashita M, Kimura H. A mathematical model of type 1 diabetes involving leptin effects on glucose metabolism. J Theor Biol 2018; 456:213-223. [PMID: 30098320 DOI: 10.1016/j.jtbi.2018.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 08/03/2018] [Accepted: 08/06/2018] [Indexed: 12/14/2022]
Abstract
Leptin, a hormone released from fat cells in adipose tissues, was recently found to be capable of normalizing glucose metabolism in animals. Clinical data on patients with lipodystrophy indicates that leptin may have a positive effect on glucose metabolism in individuals with diabetes. There are growing expectations that leptin can improve the current insulin treatment for patients with type 1 diabetes. We investigated this possibility through in silico experiments based on a mathematical model of diabetes, which is currently the only mode of research that eliminates human risk. A model of the brain-centered glucoregulatory system, in which leptin plays a central role, was constructed and integrated within a conventional model of insulin/glucose dynamics. The model has been validated using experimental data from animal studies. The in silico combination experiments showed excellent therapeutic performance over insulin monotherapy.
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Affiliation(s)
- Rei Kadota
- Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo, Japan
| | - Kazuma Sugita
- Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo, Japan
| | - Kenko Uchida
- Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo, Japan
| | - Hitoshi Yamada
- TOYOTA MOTOR CORPORATION, 1, Toyota-cho, Toyota, Aichi, Japan
| | | | - Hidenori Kimura
- Faculty of Science and Engineering, Waseda University, Building 55S, Room 706A, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan.
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