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Talebi SS, Rezaie S, Hajmiri MS, Zamanirafe M, Ranjbar A, Moridi H, Mirjalili M, Mehrpooya M. Comparison of the effects of empagliflozin and sitagliptin, as add-on to metformin, on serum levels of asprosin and metabolic parameters in patients with type 2 diabetes mellitus. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9149-9165. [PMID: 38900252 DOI: 10.1007/s00210-024-03219-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024]
Abstract
The effect of sitagliptin and empagliflozin on serum levels of asprosin and metabolic parameters in patients with type 2 diabetes mellitus (T2DM) was assessed in a non-randomized, prospective observational study. Seventy-nine T2DM patients, without adequate glycemic control with metformin monotherapy, were included in the study. In addition to the ongoing metformin treatment, patients received sitagliptin 100 mg and empagliflozin 10 mg once daily for 12 weeks. Anthropometric parameters, lipid and glycemic profile, insulin resistance (homeostasis model assessment of insulin resistance index [HOMA-IR]), and asprosin serum levels were assessed at baseline and after 12 weeks of therapy. Both empagliflozin and sitagliptin treatments led to similar, significant improvement in fasting blood glucose (FBG) and hemoglobin A1C (HbA1C). Compared to baseline, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were improved with both treatments, but empagliflozin led to the more improvement. No significant change of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were observed in either group. Insulin resistance was significantly attenuated in both groups, but to a greater degree with empagliflozin treatment. The reduction in serum asprosin levels from baseline was significantly higher in patients taking empagliflozin compared to those receiving sitagliptin. Additionally, individuals on empagliflozin exhibited a more decrease in body mass index (BMI) and body weight compared to those on sitagliptin. According to our findings, the addition of empagliflozin to metformin appeared to offer greater benefits compared to the addition of sitagliptin in terms of decreasing asprosin levels and improving certain metabolic parameters in T2DM patients.
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Affiliation(s)
- Seyed Saman Talebi
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Shabnam Rezaie
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Shahid Fahmideh Ave, Hamadan, 6517838678, Iran
| | - Minoo Sadat Hajmiri
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Zamanirafe
- Medical Faculty, Hamadan University of Medical Science, Hamadan, Iran
| | - Akram Ranjbar
- Department of Pharmacology Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Heresh Moridi
- Department of Medical Laboratory Sciences, Faculty of Paramedical Sciences, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mahtabalsadat Mirjalili
- Department of Clinical Pharmacy, School of Pharmacy, Yazd University of Medical Sciences, Yazd, Iran
| | - Maryam Mehrpooya
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Shahid Fahmideh Ave, Hamadan, 6517838678, Iran.
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Sergi D, Melloni M, Passaro A, Neri LM. Influence of Type 2 Diabetes and Adipose Tissue Dysfunction on Breast Cancer and Potential Benefits from Nutraceuticals Inducible in Microalgae. Nutrients 2024; 16:3243. [PMID: 39408212 PMCID: PMC11478231 DOI: 10.3390/nu16193243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Breast cancer (BC) represents the most prevalent cancer in women at any age after puberty. From a pathogenetic prospective, despite a wide array of risk factors being identified thus far, poor metabolic health is emerging as a putative risk factor for BC. In particular, type 2 diabetes mellitus (T2DM) provides a perfect example bridging the gap between poor metabolic health and BC risk. Indeed, T2DM is preceded by a status of hyperinsulinemia and is characterised by hyperglycaemia, with both factors representing potential contributors to BC onset and progression. Additionally, the aberrant secretome of the dysfunctional, hypertrophic adipocytes, typical of obesity, characterised by pro-inflammatory mediators, is a shared pathogenetic factor between T2DM and BC. In this review, we provide an overview on the effects of hyperglycaemia and hyperinsulinemia, hallmarks of type 2 diabetes mellitus, on breast cancer risk, progression, treatment and prognosis. Furthermore, we dissect the role of the adipose-tissue-secreted adipokines as additional players in the pathogenesis of BC. Finally, we focus on microalgae as a novel superfood and a source of nutraceuticals able to mitigate BC risk by improving metabolic health and targeting cellular pathways, which are disrupted in the context of T2DM and obesity.
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Affiliation(s)
- Domenico Sergi
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (D.S.); (M.M.)
| | - Mattia Melloni
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (D.S.); (M.M.)
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (D.S.); (M.M.)
| | - Luca Maria Neri
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (D.S.); (M.M.)
- Laboratory for Technologies of Advanced Therapies (LTTA)—Electron Microscopy Center, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy
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Quispe R, Sweeney T, Martin SS, Jones SR, Allison MA, Budoff MJ, Ndumele CE, Elshazly MB, Michos ED. Associations of Adipokine Levels With Levels of Remnant Cholesterol: The Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc 2024; 13:e030548. [PMID: 39248264 PMCID: PMC11935629 DOI: 10.1161/jaha.123.030548] [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: 04/22/2023] [Accepted: 03/06/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. METHODS AND RESULTS We studied 1791 MESA (Multi-Ethnic Study of Atherosclerosis) participants who took part in an ancillary study on body composition with adipokine levels measured (leptin, adiponectin, and resistin) at either visit 2 or visit 3. RC was calculated as non-high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol, measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed-effects models were used to assess the cross-sectional and longitudinal associations between adipokines and log-transformed levels of RC. Mean±SD age was 64.5±9.6 years; mean±SD body mass index was 29.9±5.0 kg/m2; and 52.0% were women. In fully adjusted cross-sectional models that included body mass index, diabetes, low-density lipoprotein cholesterol, and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.6% (95% CI, 12.2-16.9) lower RC. With each 1-unit increment in leptin and resistin, there was 4.8% (95% CI, 2.7-7.0) and 4.0% (95% CI, 0.2-8.1) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5 (interquartile range, 4-8) years. CONCLUSIONS Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for body mass index and low-density lipoprotein cholesterol.
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Affiliation(s)
- Renato Quispe
- Ciccarone Center for the Prevention of Cardiovascular DiseaseJohns Hopkins University School of MedicineBaltimoreMD
| | - Ty Sweeney
- Ciccarone Center for the Prevention of Cardiovascular DiseaseJohns Hopkins University School of MedicineBaltimoreMD
| | - Seth S. Martin
- Ciccarone Center for the Prevention of Cardiovascular DiseaseJohns Hopkins University School of MedicineBaltimoreMD
| | - Steven R. Jones
- Ciccarone Center for the Prevention of Cardiovascular DiseaseJohns Hopkins University School of MedicineBaltimoreMD
| | - Matthew A. Allison
- Department of Family MedicineUniversity of California San DiegoSan DiegoCA
| | | | - Chiadi E. Ndumele
- Ciccarone Center for the Prevention of Cardiovascular DiseaseJohns Hopkins University School of MedicineBaltimoreMD
| | - Mohamed B. Elshazly
- Department of Cardiovascular MedicineHeart and Vascular Institute, Cleveland ClinicClevelandOH
| | - Erin D. Michos
- Ciccarone Center for the Prevention of Cardiovascular DiseaseJohns Hopkins University School of MedicineBaltimoreMD
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Barrera F, Uribe J, Olvares N, Huerta P, Cabrera D, Romero-Gómez M. The Janus of a disease: Diabetes and metabolic dysfunction-associated fatty liver disease. Ann Hepatol 2024; 29:101501. [PMID: 38631419 DOI: 10.1016/j.aohep.2024.101501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 04/19/2024]
Abstract
Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.
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Affiliation(s)
- Francisco Barrera
- Laboratorio Experimental de Hepatología, Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Javier Uribe
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nixa Olvares
- Laboratorio Experimental de Hepatología, Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Programa de Immunogenética e Inmunología traslacional, Instituto de Ciencias e Inovación en Medicina, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Paula Huerta
- Programa de Medicina Interna, Instituto de Ciencias e Inovación en Medicina, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile; Hospital Padre Hurtado, Santiago, Chile
| | - Daniel Cabrera
- Laboratorio Experimental de Hepatología, Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Escuela de Medicina, Facultad de Ciencias Médicas, Universidad Bernardo O Higgins, Santiago, Chile
| | - Manuel Romero-Gómez
- Enfermedades Digestivas y Ciberehd, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (CSIC/HUVR/US), Universidad de Sevilla, Sevilla, España.
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Berwal D, Branisteanu DD, Glickman M, Sagar A, Pilitsis JG. The sex-dependent impact of adipose tissue and inflammation on chronic pain - A cross-sectional study from the all of us research program. Cytokine 2024; 179:156614. [PMID: 38621331 DOI: 10.1016/j.cyto.2024.156614] [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: 02/04/2024] [Accepted: 04/09/2024] [Indexed: 04/17/2024]
Abstract
Emerging evidence suggests an association between chronic pain and elevated body fat. We sought to determine if individuals with higher body fat, measured by hip circumference (HC) and waist circumference (WC), are at risk for chronic pain when they demonstrate higher expression of inflammatory markers. We investigated the incidence and severity of pain in patients with varying WC/HC and inflammatory markers (C-Reactive Protein, IL-6, leptin) using the NIH-sponsored All of Us Database. For each inflammatory marker and sex, participants were divided into four groups based on combinations of normal/high marker levels and small/large WC/HC. We used statistical analysis to compare WC/HC and pain severity (mean NRS pain score) between groups of the same sex. In females, but not males, combinations of elevated CRP with large WC/HC exerted additive effects on the incidence of chronic pain (p < 0.01) and severe pain (p < 0.001), as well as on the severity of pain evaluated by the mean NRS pain score (p < 0.01). This relationship held true for females with high IL-6 or leptin and large WC or HC (p < 0.001 for chronic pain and severe pain incidence, and p < 0.05 for pain severity). Neither IL-6 nor leptin showed any significant impact on pain in males. Obesity status and CRP exert additive prognostic effects for chronic pain in females, but not in males. The concomitant evaluation of other inflammatory factors, such as IL-6 or leptin in females, may further augment the prediction of chronic pain. PERSPECTIVE: This article investigates the relationship between chronic pain, obesity, and inflammatory markers. It could help elucidating sex difference in pain mechanisms, as well as the risk factors for chronic pain, potentially improving patient diagnosis, follow-up and treatment.
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Affiliation(s)
- Deepak Berwal
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - Dumitru D Branisteanu
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA; Department of Endocrinology, University of Medicine and Pharmacy "Grigore T. Popa" Iasi, Romania
| | - Mia Glickman
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - Amit Sagar
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - Julie G Pilitsis
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA; Department of Neurosurgery, University of Arizona College of Medicine, Tucson, AZ, USA.
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Lima PHB, Goncalves CV, Ribeiro IS, Galantini MPL, Muniz IPR, Santos GS, Silva RAADA. Diabetes and hypertension in elderly women: interactions between severity and failure to control inflammation. AN ACAD BRAS CIENC 2024; 96:e20230844. [PMID: 38922257 DOI: 10.1590/0001-3765202420230844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 04/04/2024] [Indexed: 06/27/2024] Open
Abstract
Elderly women are more susceptible to the development of chronic non-communicable diseases. Among these, diabetes mellitus (DM) and systemic arterial hypertension (SAH) stand out. This work aimed to carry out an expanded study on the interactions of anthropometric, biochemical and inflammatory parameters associated with the risk of severity in elderly women with hypertension and diabetes. The study involved the evaluation of 126 elderly women with hypertension and diabetes mellitus. The women were divided according disease severity (low, moderate, high and very high). Anthropometric data were collected by bioimpedance analysis. The inflammatory and biochemical data were obtained from volunteer blood samples. Waist circumference, waist circumference/height ratio, and systolic and diastolic pressures increased with severity. Biochemical marker levels increased with risk of severity, except HDLc. In the very high risk group, there was a higher IL-1β, IFN-γ and TNF-α production, however, lower IL-10 levels were observed. The very high risk group showed change values for the IL-10/IL-1β, IL-10/IL-17 and IL-10/TNF-α ratios. The results showed to be extensively altered in the very high risk group, where the inflammatory profile loses its responsiveness. This is the first study that shows an expanded view of the different parameters evaluated in elderly women with hypertension and diabetes.
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Affiliation(s)
- Paulo Henrique B Lima
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira, Rua Rio de Contas, 58, Bloco 17, Lote 58, Candeias, 45029-094 Vitória da Conquista, BA, Brazil
| | - Caroline V Goncalves
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira, Rua Rio de Contas, 58, Bloco 17, Lote 58, Candeias, 45029-094 Vitória da Conquista, BA, Brazil
| | - Israel S Ribeiro
- Universidade Federal do Sul da Bahia, Centro de Formação em Ciências da Saúde, Praça Joana Angélica, 58, São José, 45988-058 Teixeira de Freitas, BA, Brazil
| | - Maria Poliana L Galantini
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira, Rua Rio de Contas, 58, Bloco 17, Lote 58, Candeias, 45029-094 Vitória da Conquista, BA, Brazil
| | - Igor P R Muniz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira, Rua Rio de Contas, 58, Bloco 17, Lote 58, Candeias, 45029-094 Vitória da Conquista, BA, Brazil
- Universidade Estadual do Sudoeste da Bahia/UESB, Departamento de Ciências da Saúde, Campus Vitória da Conquista, Estr. Bem Querer, Km 04, 45031-300 Vitória da Conquista, BA, Brazil
| | - Gilvanéia S Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira, Rua Rio de Contas, 58, Bloco 17, Lote 58, Candeias, 45029-094 Vitória da Conquista, BA, Brazil
| | - Robson A A DA Silva
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira, Rua Rio de Contas, 58, Bloco 17, Lote 58, Candeias, 45029-094 Vitória da Conquista, BA, Brazil
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Gao H, Wang Z, Zhu D, Zhao L, Xiao W. Dioscin: Therapeutic potential for diabetes and complications. Biomed Pharmacother 2024; 170:116051. [PMID: 38154275 DOI: 10.1016/j.biopha.2023.116051] [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: 10/15/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 12/30/2023] Open
Abstract
Diabetes mellitus is a widespread metabolic disorder with increasing incidence worldwide, posing a considerable threat to human health because of its complications. Therefore, cost-effective antidiabetic drugs with minimal side effects are urgently needed. Dioscin, a naturally occurring compound, helps to reduce the complications of diabetes mellitus by regulating glucose and lipid metabolism, protecting islet β cells, improving insulin resistance, and inhibiting oxidative stress and inflammatory response. Plant-derived dioscin reduces the risk of toxicity and side effects associated with chemically synthesized drugs. It is a promising option for treating diabetes mellitus because of its preventive and therapeutic effects, which may be attributed to a variety of underlying mechanisms. However, data compiled by current studies are preliminary. Information about the molecular mechanism of dioscin remains limited, and no high-quality human experiments and clinical trials for testing its safety and efficacy have been conducted. As a resource for research in this area, this review is expected to provide a systematic framework for the application of dioscin in the treatment of diabetes mellitus and its complications.
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Affiliation(s)
- Haoyang Gao
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
| | - Ze Wang
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
| | - Danlin Zhu
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
| | - Linlin Zhao
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; School of Physical Education, Shanghai Normal University, Shanghai 200234, China.
| | - Weihua Xiao
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
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Mahmoudi-Aznaveh A, Tavoosidana G, Najmabadi H, Azizi Z, Ardestani A. The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance. Front Endocrinol (Lausanne) 2023; 14:1303930. [PMID: 38027137 PMCID: PMC10661932 DOI: 10.3389/fendo.2023.1303930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction An insufficient functional beta cell mass is a core pathological hallmark of type 2 diabetes (T2D). Despite the availability of several effective pharmaceuticals for diabetes management, there is an urgent need for novel medications to protect pancreatic beta cells under diabetic conditions. Integrative organ cross-communication controls the energy balance and glucose homeostasis. The liver and pancreatic islets have dynamic cross-communications where the liver can trigger a compensatory beta cell mass expansion and enhanced hormonal secretion in insulin-resistant conditions. However, the indispensable element(s) that foster beta cell proliferation and insulin secretion have yet to be completely identified. Exosomes are important extracellular vehicles (EVs) released by most cell types that transfer biological signal(s), including metabolic messengers such as miRNA and peptides, between cells and organs. Methods We investigated whether beta cells can take up liver-derived exosomes and examined their impact on beta cell functional genes and insulin expression. Exosomes isolated from human liver HepG2 cells were characterized using various methods, including Transmission Electron Microscopy (TEM), dynamic light scattering (DLS), and Western blot analysis of exosomal markers. Exosome labeling and cell uptake were assessed using CM-Dil dye. The effect of liver cell-derived exosomes on Min6 beta cells was determined through gene expression analyses of beta cell markers and insulin using qPCR, as well as Akt signaling using Western blotting. Results Treatment of Min6 beta cells with exosomes isolated from human liver HepG2 cells treated with insulin receptor antagonist S961 significantly increased the expression of beta cell markers Pdx1, NeuroD1, and Ins1 compared to the exosomes isolated from untreated cells. In line with this, the activity of AKT kinase, an integral component of the insulin receptor pathway, is elevated in pancreatic beta cells, as represented by an increase in AKT's downstream substrate, FoxO1 phosphorylation. Discussions This study suggests that liver-derived exosomes may carry a specific molecular cargo that can affect insulin expression in pancreatic beta cells, ultimately affecting glucose homeostasis.
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Affiliation(s)
- Azam Mahmoudi-Aznaveh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Tavoosidana
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Najmabadi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amin Ardestani
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
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Faiz H, Heiston EM, Malin SK. β-Aminoisobutyric Acid Relates to Favorable Glucose Metabolism through Adiponectin in Adults with Obesity Independent of Prediabetes. J Diabetes Res 2023; 2023:4618215. [PMID: 37780967 PMCID: PMC10539091 DOI: 10.1155/2023/4618215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/09/2023] [Accepted: 09/01/2023] [Indexed: 10/03/2023] Open
Abstract
β-Aminoisobutyric acid (BAIBA) is secreted by skeletal muscle and promotes insulin sensitivity, fat oxidation, and anti-inflammation. While BAIBA is purportedly lower in individuals with obesity, no work has examined if prediabetes (PD) differentially impacts BAIBA concentrations in people with obesity. Methods. Adults were classified as normal glucose tolerant (NGT; n = 22 (20F); 48.0 ± 2.4 yrs; 36.9 ± 1.2 kg/m2) or PD (n = 23 (18F); 54.2 ± 1.6 yrs; 38.4 ± 1.2 kg/m2) based on ADA criteria. A 180-minute 75 g OGTT was used to estimate fasting (HOMA-IR (liver)) and postprandial (Matsuda index (muscle)) insulin sensitivity as well as β-cell function (disposition index (DI), glucose-stimulated insulin secretion adjusted for insulin sensitivity). Body composition and fasting measures of BAIBA, fat oxidation (indirect calorimetry), and adipokines were determined. Results. NGT and PD had similar BAIBA concentrations (1.4 ± 0.1 vs. 1.2 ± 0.1 μM, P = 0.23) and fat oxidation (P = 0.31), despite NGT having lower fasting (92.2 ± 1.2 vs. 104.1 ± 3.2 mg/dL, P = 0.002) and tAUC180min glucose (P < 0.001) compared to PD. Moreover, NGT had higher postprandial insulin sensitivity (P = 0.01) and higher total phase DIliver (P = 0.003) and DImuscle (P = 0.001). Increased BAIBA was associated with adiponectin (r = 0.37, P = 0.02), adiponectin/leptin ratio (r = 0.39, P = 0.01), and lower glucose and insulin at 180 minutes (r = -0.31, P = 0.03 and r = -0.39, P = 0.03, respectively). Adiponectin also correlated with lower glucose at 180 minutes (r = -0.45, P = 0.005), and mediation analysis showed that BAIBA was no longer a significant predictor of glucose at 180 minutes after controlling for adiponectin (P = 0.08). Conclusion. While BAIBA did not differ between NGT and PD, higher BAIBA is related to favorable glucose metabolism, possibly through an adiponectin-related mechanism. Additional work is required to understand how exercise and/or diet impact BAIBA in relation to type 2 diabetes risk.
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Affiliation(s)
| | - Emily M. Heiston
- University of Virginia, Charlottesville, VA, USA
- Virginia Commonwealth University, Richmond, VA, USA
| | - Steven K. Malin
- Rutgers University, New Brunswick, NJ, USA
- University of Virginia, Charlottesville, VA, USA
- Division of Endocrinology, Metabolism & Nutrition, Rutgers University, New Brunswick, NJ, USA
- New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
- Institute of Translational Medicine and Science, Rutgers University, New Brunswick, NJ, USA
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Liao J, Li Y, Gui X, Zhang Y, Hu X, Cheng L, Hu W, Bai F. Serum Isthmin-1 Was Increased in Type 2 Diabetic Patients but Not in Diabetic Sensorimotor Peripheral Neuropathy. Diabetes Metab Syndr Obes 2023; 16:2013-2024. [PMID: 37427082 PMCID: PMC10327676 DOI: 10.2147/dmso.s411127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 05/16/2023] [Indexed: 07/11/2023] Open
Abstract
Purpose This study aimed to investigate the relationship between serum isthmin-1 (ISM1) and type 2 diabetes mellitus (T2DM), and the alteration of serum ISM1 level in both diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic adults with obesity. Patients and Methods We recruited 180 participants (120 T2DM and 60 controls) in the cross-sectional study. First, we compared the serum ISM1 concentration in diabetic patients and non-diabetic controls. Secondly, according to DSPN, patients were divided into DSPN and non-DSPN groups. Last, patients were categorized as lean T2DM (15 males, 15 females), overweight T2DM (35 males, 19 females), and obese T2DM groups (23 males, 13 females) according to gender and body mass index (BMI). All participants were collected with clinical characteristics and biochemical profiles. Serum ISM1 was detected in all subjects by ELISA. Results Higher serum ISM1 [7.78 ng/mL (IQR: 6.33-9.06) vs 5.22 (3.86-6.04), P <0.001] was observed in diabetic patients compared to non-diabetic controls. Binary logistic regression analysis showed that serum ISM1 was a risk factor for type 2 diabetes after adjustment (OR=4.218, 95% CI: 1.843-9.653, P=0.001). Compared to the non-DSPN group, serum ISM1 level was not changed significantly in patients who suffered from DSPN. Diabetic females with obesity had lower level of serum ISM1 (7.10±1.29 ng/mL) when compared to the lean T2DM (8.42±1.36 ng/mL, P <0.05) and the overweight T2DM (8.33±1.27 ng/mL, P <0.05). However, serum ISM1 was not changed significantly in male groups or all patients together. Conclusion Serum ISM1 was a risk factor for type 2 diabetes, and it was associated with diabetic adults with obesity while there was sexual dimorphism. However, serum ISM1 levels were not correlated with DSPN.
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Affiliation(s)
- Jiaxin Liao
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
| | - Yuting Li
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
| | - Xiaoting Gui
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
| | - Yong Zhang
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
| | - Xu Hu
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
| | - Liang Cheng
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
| | - Wen Hu
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
| | - Feng Bai
- Department of Endocrinology, The Huai’an Hospital Affiliated to Xuzhou Medical University and The Second People’s Hospital of Huai’an, Xuzhou Medical University, Huai’an, People’s Republic of China
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11
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Li M, Zhang R, Ge Q, Yue L, Ma D, Khattab F, Xie W, Cui Y, Gilon P, Zhao X, Li X, Cheng R. Chemerin as an Inducer of β Cell Proliferation Mediates Mitochondrial Homeostasis and Promotes β Cell Mass Expansion. Int J Mol Sci 2023; 24:ijms24119136. [PMID: 37298086 DOI: 10.3390/ijms24119136] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Loss of the β cell population is a crucial feature of type 2 diabetes. Restoring the β cell mass by stimulating β cell proliferation and preventing its apoptosis was proposed as a therapeutic approach to treating diabetes. Therefore, researchers have been increasingly interested in identifying exogenous factors that can stimulate β cell proliferation in situ and in vitro. Adipokine chemerin, which is secreted from adipose tissue and the liver, has been identified as a chemokine that plays a critical role in the regulation of metabolism. In this study, we demonstrate that chemerin as a circulating adipokine promotes β cell proliferation in vivo and in vitro. Chemerin serum levels and the expression of the main receptors within islets are highly regulated under a variety of challenging conditions, including obesity and type 2 diabetes. As compared to their littermates, mice overexpressing chemerin had a larger islet area and increased β cell mass with both a normal and high-fat diet. Moreover, in chemerin-overexpressed mice, we observed improved mitochondrial homeostasis and increased insulin synthesis. In summary, our findings confirm the potential role of chemerin as an inducer of β cell proliferation, and they provide novel insights into the helpful strategy to expand β cell population.
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Affiliation(s)
- Min Li
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Ruifan Zhang
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Qian Ge
- The First Clinical College, Chongqing Medical University, Chongqing 400016, China
| | - Lingzhi Yue
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Dan Ma
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Firas Khattab
- Pôle d'Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Wenhua Xie
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yewei Cui
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Patrick Gilon
- Pôle d'Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Xueya Zhao
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xi Li
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Rui Cheng
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
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12
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Naz R, Saqib F, Awadallah S, Wahid M, Latif MF, Iqbal I, Mubarak MS. Food Polyphenols and Type II Diabetes Mellitus: Pharmacology and Mechanisms. Molecules 2023; 28:molecules28103996. [PMID: 37241737 DOI: 10.3390/molecules28103996] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/04/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
Type II diabetes mellitus and its related complications are growing public health problems. Many natural products present in our diet, including polyphenols, can be used in treating and managing type II diabetes mellitus and different diseases, owing to their numerous biological properties. Anthocyanins, flavonols, stilbenes, curcuminoids, hesperidin, hesperetin, naringenin, and phenolic acids are common polyphenols found in blueberries, chokeberries, sea-buckthorn, mulberries, turmeric, citrus fruits, and cereals. These compounds exhibit antidiabetic effects through different pathways. Accordingly, this review presents an overview of the most recent developments in using food polyphenols for managing and treating type II diabetes mellitus, along with various mechanisms. In addition, the present work summarizes the literature about the anti-diabetic effect of food polyphenols and evaluates their potential as complementary or alternative medicines to treat type II diabetes mellitus. Results obtained from this survey show that anthocyanins, flavonols, stilbenes, curcuminoids, and phenolic acids can manage diabetes mellitus by protecting pancreatic β-cells against glucose toxicity, promoting β-cell proliferation, reducing β-cell apoptosis, and inhibiting α-glucosidases or α-amylase. In addition, these phenolic compounds exhibit antioxidant anti-inflammatory activities, modulate carbohydrate and lipid metabolism, optimize oxidative stress, reduce insulin resistance, and stimulate the pancreas to secrete insulin. They also activate insulin signaling and inhibit digestive enzymes, regulate intestinal microbiota, improve adipose tissue metabolism, inhibit glucose absorption, and inhibit the formation of advanced glycation end products. However, insufficient data are available on the effective mechanisms necessary to manage diabetes.
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Affiliation(s)
- Rabia Naz
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Fatima Saqib
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Samir Awadallah
- Department of Medical Lab Sciences, Faculty of Allied Medical Sciences, Zarqa University, Zarqa 13110, Jordan
| | - Muqeet Wahid
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Muhammad Farhaj Latif
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Iram Iqbal
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
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13
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Quispe R, Sweeney T, Martin SS, Jones SR, Allison MA, Budoff MJ, Ndumele CE, Elshazly MB, Michos ED. Associations of Adipokine Levels with Levels of Remnant Cholesterol: the Multi-Ethnic Study of Atherosclerosis (MESA). MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.04.24.23289072. [PMID: 37162928 PMCID: PMC10168480 DOI: 10.1101/2023.04.24.23289072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Background The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. Methods We studied 1,791 MESA participants of an ancillary study on body composition who had adipokine levels measured (leptin, adiponectin, resistin) at either visit 2 or 3. RC was calculated as non-high density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDL-C), measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed effects models were used to assess the cross-sectional and longitudinal associations between adipokines and levels of RC. Results Mean (SD) age was 64.5±9.6 years and for body mass index (BMI) was 29.9±5.0 kg/m2; 52.0% were women. In fully adjusted models that included BMI, LDL-C and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.4% (12.0, 16.8) lower RC. With each 1-unit increment in leptin and resistin, there was 4.5% (2.3, 6.6) and 5.1% (1.2, 9.2) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5(4-8) years. Conclusions Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for BMI and LDL-C. CLINICAL PERSPECTIVE What is new?: - Among individuals without history of cardiovascular disease, adiponectin is inversely associated with cross-sectional levels of remnant cholesterol, whereas leptin and resistin are directly associated.- Adiponectin had an inverse association with progression of remnant cholesterol levels over time.What are the clinical implications?: - Adiponectin levels were not associated with LDL-C levels but with levels of triglyceride-rich lipoproteins, particularly remnant cholesterol.-Incrementing adiponectin via lifestyle modification and/or pharmacological therapies (i.e. GLP-1 agonists) could be a mechanism to reduce remnant cholesterol levels and ultimately cardiovascular risk.
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14
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Mukherjee S, Maheshwari D, Pal R, Sachdeva N. Pancreatic fat in type 2 diabetes: Causal or coincidental? World J Meta-Anal 2023; 11:68-78. [DOI: 10.13105/wjma.v11.i3.68] [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: 09/17/2022] [Revised: 12/27/2022] [Accepted: 02/15/2023] [Indexed: 03/01/2023] Open
Abstract
Type 2 diabetes (T2D) is a multifactorial metabolic disorder affecting more than 450 million people across the globe. With the increasing prevalence of T2D and obesity, the role of fat accumulation at sites other than subcutaneous adipose tissue has received significant attention in the pathophysiology of T2D. Over the past decade and a half, a pressing concern has emerged on investigating the association of pancreatic fat accumulation or pancreatic steatosis with the development of disease. While a few reports have suggested a possible association between pancreatic fat and T2D and/or impaired glucose metabolism, a few reports suggest a lack of such association. Pancreatic fat has also been linked with genetic risk of developing T2D, prediabetes, reduced insulin secretion, and beta cell dysfunction albeit some confounding factors such as age and ethnicity may affect the outcome. With the technological advancements in clinical imaging and progress in assessment of pancreatic beta cell function, our understanding of the role of pancreatic fat in causing insulin resistance and development of various etiologies of T2D has significantly improved. This review summarizes various findings on the possible association of pancreatic fat accumulation with the pathophysiology of T2D.
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Affiliation(s)
- Soham Mukherjee
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Deep Maheshwari
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rimesh Pal
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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15
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Sanches JM, Zhao LN, Salehi A, Wollheim CB, Kaldis P. Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. FEBS J 2023; 290:620-648. [PMID: 34847289 DOI: 10.1111/febs.16306] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/14/2021] [Accepted: 11/29/2021] [Indexed: 02/06/2023]
Abstract
Diabetes is a complex and multifactorial disease that affects millions of people worldwide, reducing the quality of life significantly, and results in grave consequences for our health care system. In type 2 diabetes (T2D), the lack of β-cell compensatory mechanisms overcoming peripherally developed insulin resistance is a paramount factor leading to disturbed blood glucose levels and lipid metabolism. Impaired β-cell functions and insulin resistance have been studied extensively resulting in a good understanding of these pathways but much less is known about interorgan crosstalk, which we define as signaling between tissues by secreted factors. Besides hormones and organokines, dysregulated blood glucose and long-lasting hyperglycemia in T2D is associated with changes in metabolism with metabolites from different tissues contributing to the development of this disease. Recent data suggest that metabolites, such as lipids including free fatty acids and amino acids, play important roles in the interorgan crosstalk during the development of T2D. In general, metabolic remodeling affects physiological homeostasis and impacts the development of T2D. Hence, we highlight the importance of metabolic interorgan crosstalk in this review to gain enhanced knowledge of the pathophysiology of T2D, which may lead to new therapeutic approaches to treat this disease.
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Affiliation(s)
| | - Li Na Zhao
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Albert Salehi
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Claes B Wollheim
- Department of Clinical Sciences, Lund University, Malmö, Sweden.,Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Philipp Kaldis
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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16
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Andreozzi F, Di Fatta C, Spiga R, Mannino GC, Mancuso E, Averta C, De Caro C, Tallarico M, Leo A, Citraro R, Russo E, De Sarro G, Sesti G. Glucagon induces the hepatic expression of inflammatory markers in vitro and in vivo. Diabetes Obes Metab 2023; 25:556-569. [PMID: 36305474 DOI: 10.1111/dom.14902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/12/2022] [Accepted: 10/24/2022] [Indexed: 02/02/2023]
Abstract
Glucagon exerts multiple hepatic actions, including stimulation of glycogenolysis/gluconeogenesis. The liver plays a crucial role in chronic inflammation by synthesizing proinflammatory molecules, which are thought to contribute to insulin resistance and hyperglycaemia. Whether glucagon affects hepatic expression of proinflammatory cytokines and acute-phase reactants is unknown. Herein, we report a positive relationship between fasting glucagon levels and circulating interleukin (IL)-1β (r = 0.252, p = .042), IL-6 (r = 0.230, p = .026), fibrinogen (r = 0.193, p = .031), complement component 3 (r = 0.227, p = .024) and high sensitivity C-reactive protein (r = 0.230, p = .012) in individuals without diabetes. In CD1 mice, 4-week continuous treatment with glucagon induced a significant increase in circulating IL-1β (p = .02), and IL-6 (p = .001), which was countered by the contingent administration of the glucagon receptor antagonist, GRA-II. Consistent with these results, we detected a significant increase in the hepatic activation of inflammatory pathways, such as expression of NLRP3 (p < .02), and the phosphorylation of nuclear factor kappaB (NF-κB; p < .02) and STAT3 (p < .01). In HepG2 cells, we found that glucagon dose-dependently stimulated the expression of IL-1β (p < .002), IL-6 (p < .002), fibrinogen (p < .01), complement component 3 (p < .01) and C-reactive protein (p < .01), stimulated the activation of NLRP3 inflammasome (p < .01) and caspase-1 (p < .05), induced the phosphorylation of TRAF2 (p < .01), NF-κB (p < .01) and STAT3 (p < .01). Preincubating cells with GRA-II inhibited the ability of glucagon to induce an inflammatory response. Using HepaRG cells, we confirmed the dose-dependent ability of glucagon to stimulate the expression of NLRP3, the phosphorylation of NF-κB and STAT3, in the absence of GRA-II. These results suggest that glucagon has proinflammatory effects that may participate in the pathogenesis of hyperglycaemia and unfavourable cardiometabolic risk profile.
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Affiliation(s)
- Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
- Research Center for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Concetta Di Fatta
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Rosangela Spiga
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Gaia Chiara Mannino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Elettra Mancuso
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Carolina Averta
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Carmen De Caro
- Department of Science of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Martina Tallarico
- Department of Science of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonio Leo
- Department of Science of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Rita Citraro
- Department of Science of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Emilio Russo
- Department of Science of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | | | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, University of Rome-Sapienza, Rome, Italy
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17
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Wang CJ, Noble PB, Elliot JG, James AL, Wang KCW. From Beneath the Skin to the Airway Wall: Understanding the Pathological Role of Adipose Tissue in Comorbid Asthma-Obesity. Compr Physiol 2023; 13:4321-4353. [PMID: 36715283 DOI: 10.1002/cphy.c220011] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
This article provides a contemporary report on the role of adipose tissue in respiratory dysfunction. Adipose tissue is distributed throughout the body, accumulating beneath the skin (subcutaneous), around organs (visceral), and importantly in the context of respiratory disease, has recently been shown to accumulate within the airway wall: "airway-associated adipose tissue." Excessive adipose tissue deposition compromises respiratory function and increases the severity of diseases such as asthma. The mechanisms of respiratory impairment are inflammatory, structural, and mechanical in nature, vary depending on the anatomical site of deposition and adipose tissue subtype, and likely contribute to different phenotypes of comorbid asthma-obesity. An understanding of adipose tissue-driven pathophysiology provides an opportunity for diagnostic advancement and patient-specific treatment. As an exemplar, the potential impact of airway-associated adipose tissue is highlighted, and how this may change the management of a patient with asthma who is also obese. © 2023 American Physiological Society. Compr Physiol 13:4321-4353, 2023.
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Affiliation(s)
- Carolyn J Wang
- School of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - Peter B Noble
- School of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - John G Elliot
- School of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia.,Department of Pulmonary Physiology and Sleep Medicine, West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Alan L James
- Department of Pulmonary Physiology and Sleep Medicine, West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.,Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Kimberley C W Wang
- School of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia.,Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia, Australia
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18
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Krystynik O, Karasek D, Kahle M, Kubickova V, Macakova D, Cibickova L, Mraz M, Haluzik M. Non-altered incretin secretion in women with impaired fasting plasma glucose in the early stage of pregnancy: a case control study. Diabetol Metab Syndr 2023; 15:12. [PMID: 36717953 PMCID: PMC9885569 DOI: 10.1186/s13098-023-00981-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/06/2023] [Indexed: 02/01/2023] Open
Abstract
BACKGROUNDS Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) may be involved in pathogenesis of gestational diabetes mellitus (GDM). The aim was to compare GLP-1 and GIP production in fasting state and during 3 h mixed meal tolerance test (MMTT) measured by mean area under the curve (AUC) between pregnant women with normal and impaired fasting glucose in an early phase of pregnancy, and healthy non-pregnant controls. METHODS This study was undertaken as a case-control study. Repeated measurement of fasting plasma glucose ≥ 5.1 mmol/L and < 7.0 mmol/L during the first trimester of pregnancy and exclusion of overt diabetes according to IADSPG criteria was used to find women with impaired fasting glucose (n = 22). Age-matched controls consisted of healthy pregnant (n = 25) and non-pregnant (n = 24) women. In addition to incretins, anthropometric parameters and markers of insulin resistance and beta-cell function were assessed. Variables were summarized as median (interquartile range). RESULTS Fasting GLP-1 and GIP concentration or their AUC during MMTT did not significantly differ between pregnant women with impaired fasting plasma glucose [GLP-1AUC 19.0 (53.1) and GIPAUC 302 (100) pg/mL/min] and healthy pregnant women [GLP-1AUC 16.7 (22.3) and GIPAUC 297 (142) pg/mL/min] or non-pregnant controls [GLP-1AUC 16.8 (9.8) and for GIPAUC 313 (98) pg/mL/min]. Although women with impaired fasting glucose were more obese and showed decreased beta-cell function, there were not significant correlations between incretin production and parameters of insulin secretion, insulin resistance, or obesity. CONCLUSIONS Women with impaired fasting plasma glucose did not show altered incretin production in the first trimester of pregnancy. In contrast to type 2 diabetes, impaired incretin secretion does not seem to play a major role in the early development of GDM.
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Affiliation(s)
- Ondrej Krystynik
- Third Department of Internal Medicine - Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, I. P. Pavlova 6, 77900, Olomouc, Czech Republic
| | - David Karasek
- Third Department of Internal Medicine - Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, I. P. Pavlova 6, 77900, Olomouc, Czech Republic.
| | - Michal Kahle
- Department of Data Science, Institute for Clinical and Experimental Medicine, Vídeňská 1958,140 21, Prague, Czech Republic
| | - Veronika Kubickova
- Department of Clinical Biochemistry, University Hospital Olomouc, I. P. Pavlova 6, 77900, Olomouc, Czech Republic
| | - Dominika Macakova
- Third Department of Internal Medicine - Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, I. P. Pavlova 6, 77900, Olomouc, Czech Republic
| | - Lubica Cibickova
- Third Department of Internal Medicine - Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, I. P. Pavlova 6, 77900, Olomouc, Czech Republic
| | - Milos Mraz
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Vídeňská 1958, 140 21, Prague, Czech Republic
| | - Martin Haluzik
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Vídeňská 1958, 140 21, Prague, Czech Republic
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19
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Mehlich A, Bolanowski M, Mehlich D, Witek P. Medical treatment of Cushing's disease with concurrent diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1174119. [PMID: 37139336 PMCID: PMC10150952 DOI: 10.3389/fendo.2023.1174119] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
Cushing's disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.
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Affiliation(s)
- Anna Mehlich
- Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw, Warsaw, Poland
| | - Marek Bolanowski
- Chair and Department of Endocrinology, Diabetes, and Isotope Treatment, Wroclaw Medical University, Wroclaw, Poland
| | - Dawid Mehlich
- Laboratory of Molecular OncoSignalling, International Institute of Molecular Mechanisms and Machines (IMol) Polish Academy of Sciences, Warsaw, Poland
- Doctoral School of Medical University of Warsaw, Medical University of Warsaw, Warsaw, Poland
- Laboratory of Experimental Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Przemysław Witek
- Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw, Warsaw, Poland
- *Correspondence: Przemysław Witek,
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Melena I, Hughes JW. Islet cilia and glucose homeostasis. Front Cell Dev Biol 2022; 10:1082193. [PMID: 36531945 PMCID: PMC9751591 DOI: 10.3389/fcell.2022.1082193] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/22/2022] [Indexed: 09/05/2023] Open
Abstract
Diabetes is a growing pandemic affecting over ten percent of the U.S. population. Individuals with all types of diabetes exhibit glucose dysregulation due to altered function and coordination of pancreatic islets. Within the critical intercellular space in pancreatic islets, the primary cilium emerges as an important physical structure mediating cell-cell crosstalk and signal transduction. Many events leading to hormone secretion, including GPCR and second-messenger signaling, are spatiotemporally regulated at the level of the cilium. In this review, we summarize current knowledge of cilia action in islet hormone regulation and glucose homeostasis, focusing on newly implicated ciliary pathways that regulate insulin exocytosis and intercellular communication. We present evidence of key signaling proteins on islet cilia and discuss ways in which cilia might functionally connect islet endocrine cells with the non-endocrine compartments. These discussions aim to stimulate conversations regarding the extent of cilia-controlled glucose homeostasis in health and in metabolic diseases.
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Affiliation(s)
| | - Jing W. Hughes
- Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
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Lyu Z, Zhao M, Atanes P, Persaud SJ. Quantification of changes in human islet G protein-coupled receptor mRNA expression in obesity. Diabet Med 2022; 39:e14974. [PMID: 36260369 DOI: 10.1111/dme.14974] [Citation(s) in RCA: 3] [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: 07/12/2022] [Accepted: 10/13/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND G protein-coupled receptors (GPCRs) play crucial roles in regulating islet function, with Gαs- and Gαq-coupled receptors being linked to the stimulation of insulin secretion. We have quantified the mRNA expression of 384 non-olfactory GPCRs in islets isolated from lean and obese organ donors to determine alterations in islet GPCR mRNA expression in obesity. METHODS RT-qPCR was used to quantify GPCR mRNAs relative to five reference genes (ACTB, GAPDH, PPIA, TBP, and TFRC) in human islets isolated from lean (BMI = 22.6 ± 0.5) and obese (BMI = 32.0 ± 0.8) donors. RESULTS Overall, 197 and 256 GPCR mRNAs were detected above trace level in islets from lean and obese donors, respectively, with 191 GPCR mRNAs being common to the lean and obese groups. 40.9% (n = 157) and 27.1% (n = 104) of the mRNAs were expressed at trace level whilst 7.8% and 6.3% were absent in islets from lean and obese donors, respectively. Hundred and seventeen GPCR mRNAs were upregulated at least twofold in islets from obese donors, and there was >twofold downregulation of 21 GPCR mRNAs. Of particular interest, several receptors signalling via Gαs or Gαq showed significant mRNA upregulation in islets from obese donors (fold increase: PTH2R: 54.0 ± 14.6; MC2R: 34.3 ± 11.5; RXFP1: 8.5 ± 2.1; HTR2B: 6.0 ± 2.0; GPR110: 3.9 ± 1.2; PROKR2: 3.9 ± 0.7). CONCLUSIONS Under conditions of obesity, human islets showed significant alterations in mRNAs encoding numerous GPCRs. The increased expression of Gαs- and Gαq-coupled receptors that have not previously been investigated in β-cells opens up possibilities of novel therapeutic candidates that may lead to the potentiation of insulin secretion and/or β-cell mass to regulate glucose homeostasis.
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Affiliation(s)
- Zekun Lyu
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
| | - Min Zhao
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
| | - Patricio Atanes
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
| | - Shanta Jean Persaud
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
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Investigation of the Global Trend of Thyroid Cancer Incidence and Its Relationship with the Prevalence of Type 2 Diabetes: An Application of Longitudinal Random Effects Regression Model. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2022. [DOI: 10.5812/ijcm-120720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: In recent years, the incidence of thyroid cancer has been increasing. On the other hand, those with insulin resistance often have higher thyroid volume and a risk of developing thyroid nodules. Objectives: The objective of this study was to investigate the global trend of thyroid cancer and its relationship with the prevalence of type 2 diabetes. Methods: The information in the present study is related to the prevalence of type 2 diabetes and the incidence of thyroid cancer in all countries of the world, which was extracted from the Global Burden of Disease site during 1990 - 2019. In order to investigate the relationship between the prevalence of type 2 diabetes and the incidence of thyroid cancer, a longitudinal random effects regression model was used with both random effects of intercept and the slope of the regression line. Results: The results showed that the risk of developing thyroid cancer associated with diabetes was 0.00024 (95% CI 0.00023 - 0.00025), 24 persons per 100000. This significance level was also evaluated separately in men and women, so that the relative risk in men was estimated to be 0.00018 (95% CI 0.00017 - 0.00019) and in women equal to 0.00033 (95% CI 0.00031 - 0.00035). Conclusions: Findings showed that type 2 diabetes can be a risk factor for thyroid cancer. So that this effect can be considered on both men and women and is more intense in women than men.
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Daily Treatment of Mice with Type 2 Diabetes with Adropin for Four Weeks Improves Glucolipid Profile, Reduces Hepatic Lipid Content and Restores Elevated Hepatic Enzymes in Serum. Int J Mol Sci 2022; 23:ijms23179807. [PMID: 36077198 PMCID: PMC9456344 DOI: 10.3390/ijms23179807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/22/2022] [Accepted: 08/26/2022] [Indexed: 12/04/2022] Open
Abstract
Adropin is a peptide hormone encoded by Energy Homeostasis Associated gene. Adropin modulates energy homeostasis and metabolism of lipids and carbohydrates. There is growing evidence demonstrating that adropin enhances insulin sensitivity and lowers hyperlipidemia in obese mice. The aim of this study was to investigate the effects of daily administration of adropin for four weeks in mice with experimentally induced type 2 diabetes (T2D). Adropin improved glucose control without modulating insulin sensitivity. Adropin reduced body weight, size of adipocytes, blood levels of triacylglycerol and cholesterol in T2D mice. T2D mice treated with adropin had lower liver mass, reduced hepatic content of triacylglycerol and cholesterol. Furthermore, adropin attenuated elevated blood levels of hepatic enzymes (ALT, AST, GGT and ALP) in T2D mice. In T2D mice, adropin increased the circulating adiponectin level. Adropin had no effects on circulating insulin and glucagon levels and did not alter pancreatic islets morphology. These results suggest that adropin improves glucose control, lipid metabolism and liver functions in T2D. In conjunction with reduced lipid content in hepatocytes, these results render adropin as an interesting candidate in therapy of T2D.
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Fernández-Felipe J, Plaza A, Domínguez G, Pérez-Castells J, Cano V, Cioni F, Del Olmo N, Ruiz-Gayo M, Merino B. Effect of Lauric vs. Oleic Acid-Enriched Diets on Leptin Autoparacrine Signalling in Male Mice. Biomedicines 2022; 10:biomedicines10081864. [PMID: 36009410 PMCID: PMC9405789 DOI: 10.3390/biomedicines10081864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/16/2022] Open
Abstract
High-fat diets enriched with lauric acid (SOLF) do not enhance leptin production despite expanding white adipose tissue (WAT). Our study aimed at identifying the influence of SOLF vs. oleic acid-enriched diets (UOLF) on the autoparacrine effect of leptin and was carried out on eight-week-old mice consuming control chow, UOLF or SOLF. Phosphorylation of kinases integral to leptin receptor (LepR) signalling pathways (705Tyr-STAT3, 473Ser-Akt, 172Thr-AMPK), adipocyte-size distribution, fatty acid content, and gene expression were analyzed in WAT. SOLF enhanced basal levels of phosphorylated proteins but reduced the ability of leptin to enhance kinase phosphorylation. In contrast, UOLF failed to increase basal levels of phosphorylated proteins and did not modify the effect of leptin. Both SOLF and UOLF similarly affected adipocyte-size distribution, and the expression of genes related with adipogenesis and inflammation. WAT composition was different between groups, with SOLF samples mostly containing palmitic, myristic and lauric acids (>48% w/w) and UOLF WAT containing more than 80% (w/w) of oleic acid. In conclusion, SOLF appears to be more detrimental than UOLF to the autoparacrine leptin actions, which may have an impact on WAT inflammation. The effect of SOLF and UOLF on WAT composition may affect WAT biophysical properties, which are able to condition LepR signaling.
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Affiliation(s)
- Jesús Fernández-Felipe
- Department of Health and Pharmaceutical Sciences, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain; (J.F.-F.); (A.P.); (V.C.); (F.C.)
| | - Adrián Plaza
- Department of Health and Pharmaceutical Sciences, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain; (J.F.-F.); (A.P.); (V.C.); (F.C.)
- Laboratory of Bioactive Products and Metabolic Syndrome (BIOPROMET), IMDEA Food Institute, 28049 Madrid, Spain
| | - Gema Domínguez
- Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU-San Pablo, CEU Universities, 28660 Madrid, Spain; (G.D.); (J.P.-C.)
| | - Javier Pérez-Castells
- Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU-San Pablo, CEU Universities, 28660 Madrid, Spain; (G.D.); (J.P.-C.)
| | - Victoria Cano
- Department of Health and Pharmaceutical Sciences, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain; (J.F.-F.); (A.P.); (V.C.); (F.C.)
| | - Francesco Cioni
- Department of Health and Pharmaceutical Sciences, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain; (J.F.-F.); (A.P.); (V.C.); (F.C.)
| | - Nuria Del Olmo
- Departament of Psychobiology, Facultad de Psicología, Universidad Nacional de Educación a Distancia, 28040 Madrid, Spain;
| | - Mariano Ruiz-Gayo
- Department of Health and Pharmaceutical Sciences, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain; (J.F.-F.); (A.P.); (V.C.); (F.C.)
- Correspondence: (M.R.-G.); (B.M.)
| | - Beatriz Merino
- Department of Health and Pharmaceutical Sciences, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain; (J.F.-F.); (A.P.); (V.C.); (F.C.)
- Correspondence: (M.R.-G.); (B.M.)
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Farkas GJ, Burton AM, McMillan DW, Sneij A, Gater DR. The Diagnosis and Management of Cardiometabolic Risk and Cardiometabolic Syndrome after Spinal Cord Injury. J Pers Med 2022; 12:1088. [PMID: 35887592 PMCID: PMC9320035 DOI: 10.3390/jpm12071088] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/19/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022] Open
Abstract
Individuals with spinal cord injuries (SCI) commonly present with component risk factors for cardiometabolic risk and combined risk factors for cardiometabolic syndrome (CMS). These primary risk factors include obesity, dyslipidemia, dysglycemia/insulin resistance, and hypertension. Commonly referred to as "silent killers", cardiometabolic risk and CMS increase the threat of cardiovascular disease, a leading cause of death after SCI. This narrative review will examine current data and the etiopathogenesis of cardiometabolic risk, CMS, and cardiovascular disease associated with SCI, focusing on pivotal research on cardiometabolic sequelae from the last five years. The review will also provide current diagnosis and surveillance criteria for cardiometabolic disorders after SCI, a novel obesity classification system based on percent total body fat, and lifestyle management strategies to improve cardiometabolic health.
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Affiliation(s)
- Gary J. Farkas
- Department of Physical Medicine and Rehabilitation, School of Medicine, University of Miami Miller, Miami, FL 33136, USA; (A.S.); (D.R.G.J.)
- Christine E. Lynn Rehabilitation Center for the Miami Project to Cure Paralysis, Miami, FL 33136, USA;
| | - Adam M. Burton
- School of Medicine, University of Miami Miller, Miami, FL 33136, USA;
| | - David W. McMillan
- Christine E. Lynn Rehabilitation Center for the Miami Project to Cure Paralysis, Miami, FL 33136, USA;
- The Miami Project to Cure Paralysis, School of Medicine, University of Miami Miller, Miami, FL 33136, USA
| | - Alicia Sneij
- Department of Physical Medicine and Rehabilitation, School of Medicine, University of Miami Miller, Miami, FL 33136, USA; (A.S.); (D.R.G.J.)
- Christine E. Lynn Rehabilitation Center for the Miami Project to Cure Paralysis, Miami, FL 33136, USA;
| | - David R. Gater
- Department of Physical Medicine and Rehabilitation, School of Medicine, University of Miami Miller, Miami, FL 33136, USA; (A.S.); (D.R.G.J.)
- Christine E. Lynn Rehabilitation Center for the Miami Project to Cure Paralysis, Miami, FL 33136, USA;
- School of Medicine, University of Miami Miller, Miami, FL 33136, USA;
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Biondi G, Marrano N, Borrelli A, Rella M, Palma G, Calderoni I, Siciliano E, Lops P, Giorgino F, Natalicchio A. Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes. Int J Mol Sci 2022; 23:ijms23105522. [PMID: 35628332 PMCID: PMC9143684 DOI: 10.3390/ijms23105522] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/10/2022] Open
Abstract
The dysregulation of the β-cell functional mass, which is a reduction in the number of β-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a leading cause of β-cell loss and dysfunction and a risk factor for T2D. The natural history of β-cell failure in obesity-induced T2D can be divided into three steps: (1) β-cell compensatory hyperplasia and insulin hypersecretion, (2) insulin secretory dysfunction, and (3) loss of β-cell mass. Adipose tissue (AT) secretes many hormones/cytokines (adipokines) and fatty acids that can directly influence β-cell function and viability. As this secretory pattern is altered in obese and diabetic patients, it is expected that the cross-talk between AT and pancreatic β-cells could drive the maintenance of the β-cell integrity under physiological conditions and contribute to the reduction in the β-cell functional mass in a dysmetabolic state. In the current review, we summarise the evidence of the ability of the AT secretome to influence each step of β-cell failure, and attempt to draw a timeline of the alterations in the adipokine secretion pattern in the transition from obesity to T2D that reflects the progressive deterioration of the β-cell functional mass.
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Babaei P, Hoseini R. Exercise training modulates adipokine dysregulations in metabolic syndrome. SPORTS MEDICINE AND HEALTH SCIENCE 2022; 4:18-28. [PMID: 35782776 PMCID: PMC9219261 DOI: 10.1016/j.smhs.2022.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/01/2022] [Accepted: 01/07/2022] [Indexed: 12/16/2022] Open
Abstract
Metabolic syndrome (MetS) is a cluster of risk factors for various metabolic diseases, and it is characterized by central obesity, dyslipidemia, hypertension, and insulin resistance. The core component for MetS is adipose tissue, which releases adipokines and influences physical health. Adipokines consist of pro and anti-inflammatory cytokines and contribute to various physiological functions. Generally, a sedentary lifestyle promotes fat accumulation and secretion of pro-inflammatory adipokines. However, regular exercise has been known to exert various beneficial effects on metabolic and cognitive disorders. Although the mechanisms underlying exercise beneficial effects in MetS are not fully understood, changes in energy expenditure, fat accumulation, circulatory level of myokines, and adipokines might be involved. This review article focuses on some of the selected adipokines in MetS, and their responses to exercise training considering possible mechanisms.
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Affiliation(s)
- Parvin Babaei
- Cellular & Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Rastegar Hoseini
- Department of Sports Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran
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Hu X, Liu Z, Lu Y, Chi X, Han K, Wang H, Wang Y, Ma L, Xu B. Glucose metabolism enhancement by 10-hydroxy-2-decenoic acid via the PI3K/AKT signaling pathway in high-fat-diet/streptozotocin induced type 2 diabetic mice. Food Funct 2022; 13:9931-9946. [DOI: 10.1039/d1fo03818d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Here, we used high fat diet (HFD) combined with streptozotocin (STZ) injection to establish a diabetes model, with the aim of exploring the hypoglycemic effects of 10-hydroxy-2-decenoic acid (10-HDA), and...
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Langlois A, Dumond A, Vion J, Pinget M, Bouzakri K. Crosstalk Communications Between Islets Cells and Insulin Target Tissue: The Hidden Face of Iceberg. Front Endocrinol (Lausanne) 2022; 13:836344. [PMID: 35185804 PMCID: PMC8851682 DOI: 10.3389/fendo.2022.836344] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/06/2022] [Indexed: 12/11/2022] Open
Abstract
The regulation of insulin secretion is under control of a complex inter-organ/cells crosstalk involving various metabolites and/or physical connections. In this review, we try to illustrate with current knowledge how β-cells communicate with other cell types and organs in physiological and pathological contexts. Moreover, this review will provide a better understanding of the microenvironment and of the context in which β-cells exist and how this can influence their survival and function. Recent studies showed that β-cell insulin secretion is regulated also by a direct and indirect inter-organ/inter-cellular communication involving various factors, illustrating the idea of "the hidden face of the iceberg". Moreover, any disruption on the physiological communication between β-cells and other cells or organs can participate on diabetes onset. Therefore, for new anti-diabetic treatments' development, it is necessary to consider the entire network of cells and organs involved in the regulation of β-cellular function and no longer just β-cell or pancreatic islet alone. In this context, we discuss here the intra-islet communication, the β-cell/skeletal muscle, β-cell/adipose tissue and β-cell/liver cross talk.
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Nash MS, Farkas GJ, Tiozzo E, Gater DR. Exercise to mitigate cardiometabolic disorders after spinal cord injury. Curr Opin Pharmacol 2021; 62:4-11. [PMID: 34864560 DOI: 10.1016/j.coph.2021.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 10/21/2021] [Indexed: 01/14/2023]
Abstract
The cardiometabolic disorder (CMD) is a syndrome caused by coalescing of cardiovascular, endocrine, pro-thrombotic, and inflammatory health risks. Together, these risks confer a hazard as health-threatening as coronary artery disease or type2 diabetes, whether an individual has a diagnosis of coronary disease or diabetes, or not. CMD is most often defined by three or more of five clinically assessed risk components, notably obesity, insulin resistance, hypertension, hypertriglyceridemia, and depressed high-density lipoprotein cholesterol. Evidence currently suggests that worldwide CMD is expanding at a pandemic rate, and it is known that people living with spinal cord injuries (SCI) qualify for the diagnosis at more than 50% of the prevalence of a non-disabled cohort. A recent evidence-based guideline warned of the current state of CMD following SCI and recommended early lifestyle intervention incorporating exercise and prudent nutrition as a first-line disease countermeasure. This monograph will define the CMD following SCI, explore its underlying pathophysiology, and provide evidence that recommends exercise for CMD health hazards after SCI.
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Affiliation(s)
- Mark S Nash
- Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Physical Medicine & Rehabilitation, The University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Physical Therapy, The University of Miami Miller School of Medicine, Miami, FL 33136, USA; The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Gary J Farkas
- Department of Physical Medicine & Rehabilitation, The University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Eduard Tiozzo
- Department of Physical Medicine & Rehabilitation, The University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - David R Gater
- Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Physical Medicine & Rehabilitation, The University of Miami Miller School of Medicine, Miami, FL 33136, USA; The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Lien YC, Lu XM, Won KJ, Wang PZ, Osei-Bonsu W, Simmons RA. The Transcriptome and Epigenome Reveal Novel Changes in Transcription Regulation During Pancreatic Rat Islet Maturation. Endocrinology 2021; 162:6360893. [PMID: 34467975 PMCID: PMC8455347 DOI: 10.1210/endocr/bqab181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Indexed: 01/03/2023]
Abstract
Islet function is critical for normal glucose homeostasis. Unlike adult β cells, fetal and neonatal islets are more proliferative and have decreased insulin secretion in response to stimuli. However, the underlying mechanisms governing functional maturity of islets have not been completely elucidated. Pancreatic islets comprise different cell types. The microenvironment of islets and interactions between these cell types are critical for β-cell development and maturation. Thus, the study of intact islets is optimal to identify novel molecular mechanisms controlling islet functional development. Transcriptomes and genome-wide histone landscapes of H3K4me3, H3K27me3, and H3K27Ac from intact islets isolated from 2- and 10-week-old Sprague-Dawley rats were integrated to elucidate genes and pathways modulating islet development, as well as the contribution of epigenetic regulation. A total of 4489 differentially expressed genes were identified; 2289 and 2200 of them were up- and down-regulated in 10-week islets, respectively. Ingenuity Pathway Analysis revealed critical pathways regulating functional maturation of islets, including nutrient sensing, neuronal function, immune function, cell replication, and extracellular matrix. Furthermore, we identified significant changes in enrichment of H3K4me3, H3K27me3, and H3K27Ac marks, which correlated with expression changes of genes critical for islet function. These histone marks were enriched at critical transcription factor-binding motifs, such as Hoxa9, C/EBP-β, Gata1, Foxo1, E2f1, E2f3, and Mafb. In addition, our chromatin immunoprecipitation sequencing data revealed multiple potential bivalent genes whose poised states changed with maturation. Collectively, our current study identified critical novel pathways for mature islet function and suggested a role for histone modifications in regulating islet development and maturation.
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Affiliation(s)
- Yu-Chin Lien
- Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Xueqing Maggie Lu
- Institute for Biomedical Informatics, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kyoung-Jae Won
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Paul Zhiping Wang
- Institute for Biomedical Informatics, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Wendy Osei-Bonsu
- Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rebecca A Simmons
- Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Correspondence: Rebecca A. Simmons, MD, BRB II/III, 13th Floor, Rm 1308, 421 Curie Blvd, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA.
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Luís C, Baylina P, Soares R, Fernandes R. Metabolic Dysfunction Biomarkers as Predictors of Early Diabetes. Biomolecules 2021; 11:1589. [PMID: 34827587 PMCID: PMC8615896 DOI: 10.3390/biom11111589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022] Open
Abstract
During the pathophysiological course of type 2 diabetes (T2D), several metabolic imbalances occur. There is increasing evidence that metabolic dysfunction far precedes clinical manifestations. Thus, knowing and understanding metabolic imbalances is crucial to unraveling new strategies and molecules (biomarkers) for the early-stage prediction of the disease's non-clinical phase. Lifestyle interventions must be made with considerable involvement of clinicians, and it should be considered that not all patients will respond in the same manner. Individuals with a high risk of diabetic progression will present compensatory metabolic mechanisms, translated into metabolic biomarkers that will therefore show potential predictive value to differentiate between progressors/non-progressors in T2D. Specific novel biomarkers are being proposed to entrap prediabetes and target progressors to achieve better outcomes. This study provides a review of the latest relevant biomarkers in prediabetes. A search for articles published between 2011 and 2021 was conducted; duplicates were removed, and inclusion criteria were applied. From the 29 studies considered, a survey of the most cited (relevant) biomarkers was conducted and further discussed in the two main identified fields: metabolomics, and miRNA studies.
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Affiliation(s)
- Carla Luís
- FMUP–Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal;
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- LABMI-PORTIC, Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology and Innovation Center, Porto Polytechnic, 4200-375 Porto, Portugal;
| | - Pilar Baylina
- LABMI-PORTIC, Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology and Innovation Center, Porto Polytechnic, 4200-375 Porto, Portugal;
- IPP–Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal
| | - Raquel Soares
- FMUP–Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal;
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- Biochemistry Unit, Department of Biochemistry, FMUP, Faculty of Medicine, University of Porto, Al Prof Hernani Monteiro, 4200-319 Porto, Portugal
| | - Rúben Fernandes
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- LABMI-PORTIC, Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology and Innovation Center, Porto Polytechnic, 4200-375 Porto, Portugal;
- IPP–Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal
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Zipris D. Visceral Adipose Tissue: A New Target Organ in Virus-Induced Type 1 Diabetes. Front Immunol 2021; 12:702506. [PMID: 34421908 PMCID: PMC8371384 DOI: 10.3389/fimmu.2021.702506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/19/2021] [Indexed: 12/14/2022] Open
Abstract
Type 1 diabetes (T1D) is a proinflammatory pathology that leads to the specific destruction of insulin producing β-cells and hyperglycaemia. Much of the knowledge about type 1 diabetes (T1D) has focused on mechanisms of disease progression such as adaptive immune cells and the cytokines that control their function, whereas mechanisms linked with the initiation of the disease remain unknown. It has been hypothesized that in addition to genetics, environmental factors play a pivotal role in triggering β-cell autoimmunity. The BioBreeding Diabetes Resistant (BBDR) and LEW1.WR1 rats have been used to decipher the mechanisms that lead to virus-induced T1D. Both animals develop β-cell inflammation and hyperglycemia upon infection with the parvovirus Kilham Rat Virus (KRV). Our earlier in vitro and in vivo studies indicated that KRV-induced innate immune upregulation early in the disease course plays a causal role in triggering β-cell inflammation and destruction. Furthermore, we recently found for the first time that infection with KRV induces inflammation in visceral adipose tissue (VAT) detectable as early as day 1 post-infection prior to insulitis and hyperglycemia. The proinflammatory response in VAT is associated with macrophage recruitment, proinflammatory cytokine and chemokine upregulation, endoplasmic reticulum (ER) and oxidative stress responses, apoptosis, and downregulation of adipokines and molecules that mediate insulin signaling. Downregulation of inflammation suppresses VAT inflammation and T1D development. These observations are strikingly reminiscent of data from obesity and type 2 diabetes (T2D) in which VAT inflammation is believed to play a causal role in disease mechanisms. We propose that VAT inflammation and dysfunction may be linked with the mechanism of T1D progression.
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Affiliation(s)
- Danny Zipris
- Innate Biotechnologies LLC, Denver, CO, United States
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Lee H, Gao Y, Ko E, Lee J, Lee HK, Lee S, Choi M, Shin S, Park YH, Moon HB, Uppal K, Kim KT. Nonmonotonic response of type 2 diabetes by low concentration organochlorine pesticide mixture: Findings from multi-omics in zebrafish. JOURNAL OF HAZARDOUS MATERIALS 2021; 416:125956. [PMID: 34492873 DOI: 10.1016/j.jhazmat.2021.125956] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 04/03/2021] [Accepted: 04/21/2021] [Indexed: 06/13/2023]
Abstract
Exposure to a single organochlorine pesticide (OCP) at high concentration and over a short period of exposure constrain our understanding of the contribution of chemical exposure to type 2 diabetes (T2D). A total of 450 male and female zebrafish was exposed to mixtures of five OCPs at 0, 0.05, 0.25, 2.5, and 25 μg/L for 12 weeks. T2D-related hematological parameters (i.e., glucose, insulin, free fatty acid, and triglycerides) and mitochondrial complex I to IV activities were assessed. Metabolomics, proteomics, and transcriptomics were analyzed in female livers, and their data-driven integration was performed. High fasting glucose and low insulin levels were observed only at 0.05 μg/L of the OCP mixture in females, indicating a nonlinear and sexually dependent response. We found that exposure to the OCP mixture inhibited the activities of mitochondrial complexes, especially III and IV. Combining individual and integrated omics analysis, T2D-linked metabolic pathways that regulate mitochondrial function, insulin signaling, and energy homeostasis were altered by the OCP mixture, which explains the observed phenotypic hematological effects. We demonstrated the cause-and-effect relationship between exposures to OCP mixture and T2D using zebrafish model. This study gives an insight into mechanistic research of metabolic diseases caused by chemical exposure using zebrafish.
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Affiliation(s)
- Hyojin Lee
- Department of Environmental Energy Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea
| | - Yan Gao
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Eun Ko
- Department of Biotechnology and Bioengineering, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Jihye Lee
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong City 30019, Republic of Korea
| | - Hyun-Kyung Lee
- Department of Marine Science and Convergent Technology, Hanyang University, Ansan 15588, Republic of Korea
| | - Sangkyu Lee
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Moonsung Choi
- Department of Optometry, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea; Convergence Institute of Biomedical Engineering and Biomaterials, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea
| | - Sooim Shin
- Department of Biotechnology and Bioengineering, Chonnam National University, Gwangju 61186, Republic of Korea; Interdisciplinary Program of Bioenergy and Biomaterials Graduate School, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Youngja Hwang Park
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong City 30019, Republic of Korea
| | - Hyo-Bang Moon
- Department of Marine Science and Convergent Technology, Hanyang University, Ansan 15588, Republic of Korea
| | - Karan Uppal
- Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Ki-Tae Kim
- Department of Environmental Energy Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea; Department of Environmental Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
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Circulating C1q/TNF-related protein-12 levels are associated with the severity of coronary artery disease. Cytokine 2021; 144:155545. [PMID: 33965313 DOI: 10.1016/j.cyto.2021.155545] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Coronary artery disease (CAD) is the world's largest cause of death. The association of CAD with inflammation is well established. Recently, it has been confirmed that the C1q/TNF-related protein 12 (CTRP12) has a great anti-inflammatory effect. However, few data are available regarding the serum CTRP12 concentration levels in CAD patients. OBJECTIVE The study was performed to evaluate the correlation between the serum levels of CTRP12 and the CAD severity regarding to the number of affected vessels. METHODS About 200 suspected CAD patients and 50 healthy ones as a control, were evaluated based on case-control study. According to the results of angiography, patients were divided into CAD+ (n = 150) with any major coronary artery stenosis ≥50% and CAD- (n = 50) with <50% stenosis of the arteries. The CAD+patients were categorized into one- (1VD), two- (2VD) and three-vessel disease (3VD) based on the number of stenotic vessels. In the current study, different parameters such as CTRP12, tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), total oxidant status (TOS), total antioxidant capacity (TAC), and malondialdehyde (MDA) levels were evaluated, and also lipid profiles, hs-CRP and demographic factors were investigated as well. RESULTS Data revealed that CTRP12 and TAC levels in CAD + group were significantly lower than control subjects (P < 0.05). CTRP12 levels were found to be significantly lower in the 3VD compared with 1VD and 2VD subgroups (p < 0.01 and p < 0.05, respectively). CONCLUSION Our results confirmed that serum CTRP12 level is inversely associated with CAD severity. Therefore, it may be used as a prediction marker for CAD.
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Gravina G, Ferrari F, Nebbiai G. The obesity paradox and diabetes. Eat Weight Disord 2021; 26:1057-1068. [PMID: 32954485 DOI: 10.1007/s40519-020-01015-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Obesity has been proven to be a risk factor for type 2 diabetes mellitus (T2DM) through numerous pathogenetic mechanisms. Unexpectedly, some studies suggest that subjects with overweight/obesity and T2DM have better clinical outcome than their normal weight peers. This finding is described as "obesity paradox" and calls into question the importance of weight loss in this specific population. OBJECTIVE This article is a narrative overview on the obesity and type 2 diabetes mellitus, particularly regarding the obesity paradox in T2DM patients. METHODS We used as sources MEDLINE/PubMed, CINAHL, EMBASE, and Cochrane Library, from inception to March 2020; we chose 30 relevant papers regarding the association of obesity with clinical outcome and mortality of patients affected by T2DM. RESULTS Many studies report that in patients with T2DM, overweight and obesity are associated with a better prognosis than underweight or normal weight, suggesting the presence of an obesity paradox. However, these studies have numerous limitations due to their mainly retrospective nature and to numerous confounding factors, such as associated pathologies, antidiabetic treatments, smoking habit, lack of data about distribution of body fat or weight history. CONCLUSION Literature data regarding the phenomenon of obesity paradox in T2DM patients are controversial due to the several limitations of the studies; therefore in the management of patients with overweight/obesity and T2DM is recommended referring to the established guidelines, which indicate diet and physical activity as the cornerstone of the treatment. LEVEL OF EVIDENCE Level V: narrative review.
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Affiliation(s)
- Giovanni Gravina
- Center for Eating Behaviour and Metabolism Disorders, Casa di Cura San Rossore, Pisa, Italy.
| | - Federica Ferrari
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - Grazia Nebbiai
- Center for Eating Behaviour and Metabolism Disorders, Casa di Cura San Rossore, Pisa, Italy
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Elzinga SE, Savelieff MG, O'Brien PD, Mendelson FE, Hayes JM, Feldman EL. Sex differences in insulin resistance, but not peripheral neuropathy, in a diet-induced prediabetes mouse model. Dis Model Mech 2021; 14:dmm048909. [PMID: 33692086 PMCID: PMC8077554 DOI: 10.1242/dmm.048909] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/02/2021] [Indexed: 12/25/2022] Open
Abstract
Peripheral neuropathy (PN) is a common complication of prediabetes and diabetes and is an increasing problem worldwide. Existing PN treatments rely solely on glycemic control, which is effective in type 1 but not type 2 diabetes. Sex differences in response to anti-diabetic drugs further complicate the identification of effective PN therapies. Preclinical research has been primarily carried out in males, highlighting the need for increased sex consideration in PN models. We previously reported PN sex dimorphism in obese leptin-deficient ob/ob mice. This genetic model is inherently limited, however, owing to leptin's role in metabolism. Therefore, the current study goal was to examine PN and insulin resistance in male and female C57BL6/J mice fed a high-fat diet (HFD), an established murine model of human prediabetes lacking genetic mutations. HFD mice of both sexes underwent longitudinal phenotyping and exhibited expected metabolic and PN dysfunction compared to standard diet (SD)-fed animals. Hindpaw thermal latencies to heat were shorter in HFD females versus HFD males, as well as SD females versus males. Compared to HFD males, female HFD mice exhibited delayed insulin resistance, yet still developed the same trajectory of nerve conduction deficits and intraepidermal nerve fiber density loss. Subtle differences in adipokine levels were also noted by sex and obesity status. Collectively, our results indicate that although females retain early insulin sensitivity upon HFD challenge, this does not protect them from developing the same degree of PN as their male counterparts. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Sarah E. Elzinga
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
| | - Masha G. Savelieff
- NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
| | - Phillipe D. O'Brien
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
| | - Faye E. Mendelson
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
| | - John M. Hayes
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
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Abstract
OBJECTIVE The aim of this study was to evaluate the resistin concentrations in saliva; which is a noninvasive and stress-free diagnostic sample, and to investigate the significance of salivary resistin concentrations in screening GDM. METHODS This cross-sectional case-control study included 41 newly diagnosed GDM patients and 40 healthy pregnant. The participants were consecutively included in the study among eligible pregnant women; who were in the age range from 18 to 40 years of age and at the gestational age between 24 and 28 weeks. The levels of serum and salivary resistin were determined using an enzyme-linked immunosorbent assay method. RESULTS Maternal serum resistin and salivary resistin concentrations were significantly higher in the patients with GDM compared to the individuals in the control group. The data were evaluated by the receiver-operator curve analysis; which revealed that serum and saliva resistin concentrations were moderately successful markers to differentiate subjects with GDM from healthy pregnant women. CONCLUSIONS The results indicate that the determination of saliva resistin levels at the gestational age between 24 to 28 weeks may be used as an alternative, stress-free, and noninvasive technique that may be used in GDM screening.
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Affiliation(s)
- Beril Gürlek
- Department of Obstetrics and Gynecology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - Sabri Çolak
- Department of Obstetrics and Gynecology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
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Benáková Š, Holendová B, Plecitá-Hlavatá L. Redox Homeostasis in Pancreatic β-Cells: From Development to Failure. Antioxidants (Basel) 2021; 10:antiox10040526. [PMID: 33801681 PMCID: PMC8065646 DOI: 10.3390/antiox10040526] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.
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Affiliation(s)
- Štěpánka Benáková
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
- First Faculty of Medicine, Charles University, Katerinska 1660/32, 121 08 Prague, Czech Republic
| | - Blanka Holendová
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
- Department of Mitochondrial Physiology, Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
- Correspondence: ; Tel.: +420-296-442-285
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Daniel B, Livne A, Cohen G, Kahremany S, Sasson S. Endothelial Cell-Derived Triosephosphate Isomerase Attenuates Insulin Secretion From Pancreatic Beta Cells of Male Rats. Endocrinology 2021; 162:6042346. [PMID: 33341896 DOI: 10.1210/endocr/bqaa234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Indexed: 12/14/2022]
Abstract
Insulin secretion from pancreatic beta cells is tightly regulated by glucose and paracrine signals within the microenvironment of islets of Langerhans. Extracellular matrix from islet microcapillary endothelial cells (IMEC) affect beta-cell spreading and amplify insulin secretion. This study was aimed at investigating the hypothesis that contact-independent paracrine signals generated from IMEC may also modulate beta-cell insulin secretory functions. For this purpose, conditioned medium (CMp) preparations were prepared from primary cultures of rat IMEC and were used to simulate contact-independent beta cell-endothelial cell communication. Glucose-stimulated insulin secretion (GSIS) assays were then performed on freshly isolated rat islets and the INS-1E insulinoma cell line, followed by fractionation of the CMp, mass spectroscopic identification of the factor, and characterization of the mechanism of action. The IMEC-derived CMp markedly attenuated first- and second-phase GSIS in a time- and dose-dependent manner without altering cellular insulin content and cell viability. Size exclusion fractionation, chromatographic and mass-spectroscopic analyses of the CMp identified the attenuating factor as the enzyme triosephosphate isomerase (TPI). An antibody against TPI abrogated the attenuating activity of the CMp while recombinant human TPI (hTPI) attenuated GSIS from beta cells. This effect was reversed in the presence of tolbutamide in the GSIS assay. In silico docking simulation identified regions on the TPI dimer that were important for potential interactions with the extracellular epitopes of the sulfonylurea receptor in the complex. This study supports the hypothesis that an effective paracrine interaction exists between IMEC and beta cells and modulates glucose-induced insulin secretion via TPI-sulfonylurea receptor-KATP channel (SUR1-Kir6.2) complex attenuating interactions.
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Affiliation(s)
- Bareket Daniel
- Institute for Drug Research, Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel
| | - Ariela Livne
- Institute for Drug Research, Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel
| | - Guy Cohen
- Institute for Drug Research, Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel
- The Skin Research Institute, The Dead-Sea and Arava Science Center, Masada, Israel
| | - Shirin Kahremany
- The Skin Research Institute, The Dead-Sea and Arava Science Center, Masada, Israel
- Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat Gan, Israel
| | - Shlomo Sasson
- Institute for Drug Research, Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel
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Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance. Int J Mol Sci 2021; 22:ijms22020623. [PMID: 33435513 PMCID: PMC7827500 DOI: 10.3390/ijms22020623] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/29/2020] [Accepted: 01/02/2021] [Indexed: 12/12/2022] Open
Abstract
Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.
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Gater DR, Farkas GJ, Tiozzo E. Pathophysiology of Neurogenic Obesity After Spinal Cord Injury. Top Spinal Cord Inj Rehabil 2021; 27:1-10. [PMID: 33814879 PMCID: PMC7983633 DOI: 10.46292/sci20-00067] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Individuals with a spinal cord injury (SCI) have a unique physiology characterized by sarcopenia, neurogenic osteoporosis, neurogenic anabolic deficiency, sympathetic dysfunction, and blunted satiety associated with their SCI, all of which alter energy balance and subsequently body composition. The distinct properties of "neurogenic obesity" place this population at great risk for metabolic dysfunction, including systemic inflammation, hyperglycemia, dyslipidemia, and hypertension. The purpose of this article is to demonstrate the relationship between neurogenic obesity and the metabolic syndrome after SCI, highlighting the mechanisms associated with adipose tissue pathology and those respective comorbidities. Additionally, representative studies of persons with SCI will be provided to elucidate the severity of the problem and to prompt greater vigilance among SCI specialists as well as primary care providers in order to better manage the epidemic from a public health perspective.
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Affiliation(s)
- David R. Gater
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida
| | - Gary J. Farkas
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida
| | - Eduard Tiozzo
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida
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Jain J, Gupta N, Mathur R, Nimesh S, Mathur SK. A Study on Impact of BPA in the Adipose Tissue Dysfunction (Adiposopathy) in Asian Indian Type 2 Diabetes Mellitus Subjects. Indian J Clin Biochem 2020; 35:451-457. [PMID: 33013015 DOI: 10.1007/s12291-019-00843-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 07/10/2019] [Indexed: 12/01/2022]
Abstract
A surge to increase the production via usage of chemicals at both industrial and agricultural arena has forced humans to be routinely and imprudently exposed to a wide variety of endocrine disrupting chemicals. The overall aim of the study was to evaluate possible relation that might exist between bisphenol-A (BPA) and the adipose tissue hormones, and further impact on adiposopathy. In the present study, the role of BPA, an "endocrine disruptor" with respect to adiposopathy was evaluated in type 2 diabetes mellitus patients. For the study, 150 healthy control subjects and 150 newly diagnosed diabetes patients were recruited. Fasting venous blood samples was analyzed for several biochemical parameters such as serum glucose, lipid profile, insulin, adiponectin, leptin, TNF-α, IL-6, IL-1, free fatty acid. Concentrations of BPA were also measured both in control and diabetic subjects. Serum BPA concentration was found to be significantly higher in diabetic subjects in comparison to the control subjects. Levels of BPA were found to be positively correlated with BMI and WC in diabetic subjects. Also, it was found to be positively correlated with leptin and negatively correlated with adiponectin in diabetic subjects. Therefore, the current study suggested more deleterious effect of BPA on diabetes and its pathophysiology.
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Affiliation(s)
- Jyoti Jain
- Department of Biochemistry, SMS Medical College and Hospital, Jaipur, Rajasthan India
| | - Nidhi Gupta
- Research and Development Cell, Department of Biotechnology, IIS (Deemed to be University), Jaipur, Rajasthan India
| | - Rati Mathur
- Department of Biochemistry, SMS Medical College and Hospital, Jaipur, Rajasthan India
| | - Surendra Nimesh
- Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandar Sindri, N.H. 8, Kishangarh, Ajmer, Rajasthan India
| | - Sandeep K Mathur
- Department of Endocrinology, SMS Medical College and Hospital, Jaipur, Rajasthan 302004 India
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Kapustin RV, Chepanov SV, Babakov VN, Rogovskaya NY, Kopteeva EV, Alekseenkova EN, Arzhanova ON. Maternal serum leptin, adiponectin, resistin and monocyte chemoattractant protein-1 levels in different types of diabetes mellitus. Eur J Obstet Gynecol Reprod Biol 2020; 254:284-291. [PMID: 33039836 DOI: 10.1016/j.ejogrb.2020.09.050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/23/2020] [Accepted: 09/28/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Evaluation of serum concentration of leptin, adiponectin, resistin, and MCP-1 in pregnant patients with different types of diabetes mellitus (DM) considering preconception planning and method of DM correction in 11-14th and 30-34th weeks of pregnancy. STUDY DESIGN Longitudinal, prospective study included 130 pregnant women divided into the following comparison groups: type 1 DM (T1DM, n = 40), type 2 DM (T2DM, n = 35), GDM (n = 40), and the control group (n = 15). The ELISA method defined the levels of leptin, resistin, adiponectin, and MCP-1 concentration in serum, which was assessed in 11-14th and 30-34th weeks of pregnancy. Statistical analysis was accomplished using SPSS 23.0 and "Prism 8-GraphPad" software. RESULTS The leptin level in the 1st trimester was the highest in T2DM insulin group compared to the control due to gestational age, hence in the 3rd trimester in all groups its serum concentrations appeared higher than in healthy patients (p = 0.0001). In the 1st trimester leptin levels directly correlated with women's BMI, newborns' weight and macrosomia rate, in the 3rd trimester - with OGTT levels, HbA1c, gestational hypertension, and preeclampsia rates. Resistin levels in the 1st and 3rd trimesters were increased in almost all DM groups compared to the control group (p = 0.0001). The study established direct positive correlation between resistin and HbA1c, birth weight, and preeclampsia. In the 1st trimester, adiponectin demonstrated the lowest levels in T2DM insulin compared to T1DM and the control group (p = 0.0001) while in the 3rd trimester, adiponectin levels declined alongside gestational age in DM patients and all the groups compared to the control group (p < 0.05). Adiponectin negatively correlated with BMI, OGTT levels, and preeclampsia rate. MCP-1 levels in T2DM appeared higher than in T1DM patients and the control group in the 1st trimester, whereas in the 3rd trimester MCP-1 declined, correlating with BMI, preeclampsia and OGTT levels. CONCLUSION High rate of adverse perinatal outcomes in diabetic pregnancy might be developed due to more severe metabolic failures and further disturbances of adipokines expression.
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Affiliation(s)
- Roman V Kapustin
- Department of Obstetrics, Division of Maternal-Fetal Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, 3 Mendeleevskaya Line, St. Petersburg, 199034, Russia; Department of Obstetrics, Gynecology and Reproduction, Faculty of Medicine, St. Petersburg State University, 7-9 Universitetskaya Emb., St. Petersburg, 199034, Russia.
| | - Sergey V Chepanov
- Department of Immunology and Intercellular Interactions, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, 3 Mendeleevskaya Line, St. Petersburg, 199034, Russia
| | - Vladimir N Babakov
- Research Institute of Hygiene, Occupational Pathology and Human Ecology FMBA, Kuzmolovsky, Vsevolozhsky District, Leningrad Reg., 188663, Russia
| | - Nadezhda Y Rogovskaya
- Research Institute of Hygiene, Occupational Pathology and Human Ecology FMBA, Kuzmolovsky, Vsevolozhsky District, Leningrad Reg., 188663, Russia
| | - Ekaterina V Kopteeva
- Department of Obstetrics, Gynecology and Reproduction, Faculty of Medicine, St. Petersburg State University, 7-9 Universitetskaya Emb., St. Petersburg, 199034, Russia
| | - Elena N Alekseenkova
- Department of Obstetrics, Gynecology and Reproduction, Faculty of Medicine, St. Petersburg State University, 7-9 Universitetskaya Emb., St. Petersburg, 199034, Russia
| | - Olga N Arzhanova
- Department of Obstetrics, Division of Maternal-Fetal Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, 3 Mendeleevskaya Line, St. Petersburg, 199034, Russia; Department of Obstetrics, Gynecology and Reproduction, Faculty of Medicine, St. Petersburg State University, 7-9 Universitetskaya Emb., St. Petersburg, 199034, Russia
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Khalil AS, Jaenisch R, Mooney DJ. Engineered tissues and strategies to overcome challenges in drug development. Adv Drug Deliv Rev 2020; 158:116-139. [PMID: 32987094 PMCID: PMC7518978 DOI: 10.1016/j.addr.2020.09.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/29/2020] [Accepted: 09/23/2020] [Indexed: 12/16/2022]
Abstract
Current preclinical studies in drug development utilize high-throughput in vitro screens to identify drug leads, followed by both in vitro and in vivo models to predict lead candidates' pharmacokinetic and pharmacodynamic properties. The goal of these studies is to reduce the number of lead drug candidates down to the most likely to succeed in later human clinical trials. However, only 1 in 10 drug candidates that emerge from preclinical studies will succeed and become an approved therapeutic. Lack of efficacy or undetected toxicity represents roughly 75% of the causes for these failures, despite these parameters being the primary exclusion criteria in preclinical studies. Recently, advances in both biology and engineering have created new tools for constructing new preclinical models. These models can complement those used in current preclinical studies by helping to create more realistic representations of human tissues in vitro and in vivo. In this review, we describe current preclinical models to identify their value and limitations and then discuss select areas of research where improvements in preclinical models are particularly needed to advance drug development. Following this, we discuss design considerations for constructing preclinical models and then highlight recent advances in these efforts. Taken together, we aim to review the advances as of 2020 surrounding the prospect of biological and engineering tools for adding enhanced biological relevance to preclinical studies to aid in the challenges of failed drug candidates and the burden this poses on the drug development enterprise and thus healthcare.
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Affiliation(s)
- Andrew S Khalil
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02115, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
| | - David J Mooney
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02115, USA.
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Feyzi M, Tabandeh MR, Shariati M, Edalatmanesh MA. Age Associated Changes in Transcription of Adiponectin, AdipoR1 and AdipoR2 Genes in Pancreas of Rats. CELL JOURNAL 2020; 22:61-67. [PMID: 32779434 PMCID: PMC7481892 DOI: 10.22074/cellj.2020.6921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 09/02/2019] [Indexed: 12/04/2022]
Abstract
Objective Adiponectin has a crucial role in the function, proliferation and viability of β-cell via action of two receptors:
AdipoR1 and AdipoR2. Nevertheless, age related change of Adiponectin system genes in pancreas is unclear or
controversial. This study sought to investigate the effects of aging process on serum Adiponectin levels, Adiponectin
and its receptor expression in the rat pancreas.
Materials and Methods In this experimental study, insulin resistance markers including serum insulin and glucose
concentrations, homeostatic model assessment of insulin resistance (HOMA-IR), oral glucose tolerance test (OGTT),
glucose induced insulin secretion (GIIS), serum Adiponectin levels, pancreatic expression of Adiponectin and its
receptors were studied in male Sprague-Dawley rats at the age of 2, 5, 10, 18, 52 and 72 weeks of age.
Results We found that aging triggered signs of insulin resistance characteristics in rats at 72 age weeks including
marked insulin reduction, hyperglycemia and increased HOMA-IR. Circulating Adiponectin as well as pancreatic
expression of Adiponectin and AdipoR1 was gradually decreased with age, while the opposite expression pattern of
AdipoR2 was observed in the old rats.
Conclusion Because Adiponectin and Adiponectin signaling have crucial role in β-cell function and viability, we
concluded that reduction of Adiponectin signaling may be involved in aging induced β-cell dysfunction. As a result,
manipulation of Adiponectin signaling may be a beneficial approach for improvement of β-cell function in the old people.
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Affiliation(s)
- Marziyeh Feyzi
- Department of Biology, Fars Science and Research Branch, Islamic Azad University, Fars, Iran.,Department of Biology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Mohammad Reza Tabandeh
- Department of Basic Sciences, Division of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran. Electronic Address: .,Stem Cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mehrdad Shariati
- Department of Biology, Kazerun Branch, Islamic Azad University, Kazerun, Iran
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Pratap AA, Holsinger RMD. Altered Brain Adiponectin Receptor Expression in the 5XFAD Mouse Model of Alzheimer's Disease. Pharmaceuticals (Basel) 2020; 13:E150. [PMID: 32664663 PMCID: PMC7407895 DOI: 10.3390/ph13070150] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/25/2020] [Accepted: 07/08/2020] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndromes share common pathologies with Alzheimer's disease (AD). Adiponectin, an adipocyte-derived protein, regulates energy metabolism via its receptors, AdipoR1 and AdipoR2. To investigate the distribution of adiponectin receptors (AdipoRs) in Alzheimer's, we examined their expression in the aged 5XFAD mouse model of AD. In age-matched wild-type mice, we observed neuronal expression of both ARs throughout the brain as well as endothelial expression of AdipoR1. The pattern of receptor expression in the aged 5XFAD brain was significantly perturbed. Here, we observed decreased neuronal expression of both ARs and decreased endothelial expression of AdipoR1, but robust expression of AdipoR2 in activated astrocytes. We also observed AdipoR2-expressing astrocytes in the dorsomedial hypothalamic and thalamic mediodorsal nuclei, suggesting the possibility that astrocytes utilise AdipoR2 signalling to fuel their activated state in the AD brain. These findings provide further evidence of a metabolic disturbance and demonstrate a potential shift in energy utilisation in the AD brain, supporting imaging studies performed in AD patients.
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Affiliation(s)
- Anishchal A. Pratap
- Laboratory of Molecular Neuroscience and Dementia, Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia;
- Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - R. M. Damian Holsinger
- Laboratory of Molecular Neuroscience and Dementia, Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia;
- Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
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Huang R, Yin S, Ye Y, Chen N, Luo S, Xia M, Zhao L. Circulating Retinol-Binding Protein 4 Is Inversely Associated With Pancreatic β-Cell Function Across the Spectrum of Glycemia. Diabetes Care 2020; 43:1258-1265. [PMID: 32265192 DOI: 10.2337/dc19-2432] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/14/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The aim of this study was to examine the association of circulating retinol-binding protein 4 (RBP4) levels with β-cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 291 subjects aged 35-60 years with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT), or type 2 diabetes were screened by a standard 2-h oral glucose tolerance test (OGTT) with the use of traditional measures to evaluate β-cell function. From these participants, 74 subjects were recruited for an oral minimal model test, and β-cell function was assessed with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS Circulating RBP4 levels were significantly and inversely correlated with β-cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indices, but not with HOMA of β-cell function, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β-cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion. CONCLUSIONS Circulating RBP4 levels are inversely and independently correlated with β-cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.
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Affiliation(s)
- Rong Huang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, People's Republic of China.,Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Songping Yin
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, People's Republic of China.,Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Yongxin Ye
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, People's Republic of China.,Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Nixuan Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, People's Republic of China.,Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Shiyun Luo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, People's Republic of China.,Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Min Xia
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, People's Republic of China .,Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Lina Zhao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, People's Republic of China .,Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
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Adipokines as key players in β cell function and failure. Clin Sci (Lond) 2020; 133:2317-2327. [PMID: 31769478 DOI: 10.1042/cs20190523] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/11/2019] [Accepted: 11/13/2019] [Indexed: 12/13/2022]
Abstract
The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the "classic" adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose-pancreatic β cell axis.
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Functional Interactomes of Genes Showing Association with Type-2 Diabetes and Its Intermediate Phenotypic Traits Point towards Adipo-Centric Mechanisms in Its Pathophysiology. Biomolecules 2020; 10:biom10040601. [PMID: 32294959 PMCID: PMC7226597 DOI: 10.3390/biom10040601] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/20/2020] [Accepted: 03/23/2020] [Indexed: 11/23/2022] Open
Abstract
The pathogenic mechanisms causing type 2 diabetes (T2D) are still poorly understood; a greater awareness of its causation can lead to the development of newer and better antidiabetic drugs. In this study, we used a network-based approach to assess the cellular processes associated with protein–protein interaction subnetworks of glycemic traits—HOMA-β and HOMA-IR. Their subnetworks were further analyzed in terms of their overlap with the differentially expressed genes (DEGs) in pancreatic, muscle, and adipose tissue in diabetics. We found several DEGs in these tissues showing an overlap with the HOMA-β subnetwork, suggesting a role of these tissues in β-cell failure. Many genes in the HOMA-IR subnetwork too showed an overlap with the HOMA-β subnetwork. For understanding the functional theme of these subnetworks, a pathway-to-pathway complementary network analysis was done, which identified various adipose biology-related pathways, containing genes involved in both insulin secretion and action. In conclusion, network analysis of genes showing an association between T2D and its intermediate phenotypic traits suggests their potential role in beta cell failure. These genes enriched the adipo-centric pathways and were expressed in both pancreatic and adipose tissue and, therefore, might be one of the potential targets for future antidiabetic treatment.
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