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Kang F, Zhang Z, Fu H, Sun J, Zhang J, Wang Q. β-Cell Dedifferentiation in HOMA-βlow and HOMA-βhigh Subjects. J Clin Endocrinol Metab 2025; 110:e1430-e1438. [PMID: 39133811 PMCID: PMC12012814 DOI: 10.1210/clinem/dgae538] [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: 04/07/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 09/12/2024]
Abstract
CONTEXT β-Cell dedifferentiation ratio is increased in type 2 diabetes; but its direct link to in vivo β-cell function in human remains unclear. OBJECTIVE The present study was designed to investigate whether β-cell dedifferentiation in situ was closely associated with β-cell function in vivo and to identify targets crucial for β-cell dedifferentiation/function in human. METHODS We acquired homeostasis model assessment of β-cell function (HOMA-β) values, calculated the number of hormone-negative endocrine cells, and evaluated important markers and novel candidates for β-cell dedifferentiation/function on paraneoplastic pancreatic tissues from 13 patients with benign pancreatic cystic neoplasm or intrapancreatic accessory spleen. RESULTS Both the β-cell dedifferentiation ratio and the dedifferentiation marker (Aldh1a3) were inversely related to in vivo β-cell function (HOMA-β) and in situ β-cell functional markers Glut2 and Ucn3 in humans. Moreover, the islets from HOMA-βlow subjects were manifested as (1) increased β-cell dedifferentiation ratio, (2) enriched dedifferentiation maker Aldh1a3, and (3) lower expression of Glut2 and Ucn3 compared with those from HOMA-βhigh subjects. We found that basic leucine zipper transcription factor 2 (Bach2) expression was significantly induced in islets from HOMA-βlow patients and was positively correlated with the ratio of β-cell dedifferentiation in humans. CONCLUSION Our findings emphasize the contribution of β-cell dedifferentiation to β-cell dysfunction in humans. Bach2 induction in β-cells with higher frequency of dedifferentiation observed in HOMA-βlow subjects reinforces its distinctive role as a pharmaceutical target of β-cell dedifferentiation for the treatment of people with diabetes.
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Affiliation(s)
- Fuyun Kang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhuo Zhang
- Department of Surgery, Shanghai United Family Hospital, Shanghai 200021, China
| | - Hui Fu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jiajun Sun
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Zhang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qidi Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Montalvo Landivar AP, Gao Z, Liu M, Gruskin ZL, Leduc A, Preza S, Xie Y, Rozo AV, Ahn JH, Straubhaar JR, Doliba N, Stoffers DA, Slavov N, Alvarez-Dominguez JR. An adult clock regulator links circadian rhythms to pancreatic β-cell maturation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.08.11.552890. [PMID: 37609178 PMCID: PMC10441398 DOI: 10.1101/2023.08.11.552890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
The circadian clock attunes metabolism to daily energy cycles, but how it regulates maturation of metabolic tissues is poorly understood. Here we show that DEC1, a clock transcription factor induced in adult islet β cells, coordinates their glucose responsiveness by synchronizing energetic and secretory rhythms. DEC1 binds and regulates maturity-linked genes to integrate insulin exocytosis with energy metabolism, and β-cell Dec1 ablation disrupts their transcription synchrony. Dec1-disrupted mice develop lifelong glucose intolerance and insulin deficiency, despite normal islet formation and intact Clock/Bmal1 genes. Metabolic dysfunction upon β-cell Dec1 loss stems from poor coupling of insulin secretion to glucose metabolism, reminiscent of fetal/neonatal immaturity. We link stunted maturation to a deficit in circadian bioenergetics, prompted by compromised glucose utilization, mitochondrial dynamics, and respiratory metabolism, which is rescued by increased metabolic flux. Thus, DEC1 links circadian clockwork to β-cell metabolic maturation, revealing a hierarchy for how the clock programs metabolic tissue specialization.
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Affiliation(s)
- Ana P. Montalvo Landivar
- Department of Neurosurgery, Brigham and Women’s Hospital; Boston, MA 02115, USA
- These authors contributed equally to this work
| | - Zihan Gao
- Chronobiology and Sleep Institute, and Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Department of Bioengineering, University of Pennsylvania; Philadelphia, PA 19104, USA
- These authors contributed equally to this work
| | - Mai Liu
- Chronobiology and Sleep Institute, and Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Department of Bioengineering, University of Pennsylvania; Philadelphia, PA 19104, USA
- These authors contributed equally to this work
| | - Zoe L. Gruskin
- Chronobiology and Sleep Institute, and Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
| | - Andrew Leduc
- Departments of Bioengineering and Biology, Single-Cell Proteomics Center and Barnett Institute, Northeastern University; Boston, MA 02115, USA
| | - Sam Preza
- Chronobiology and Sleep Institute, and Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Department of Bioengineering, University of Pennsylvania; Philadelphia, PA 19104, USA
| | - Yu Xie
- Chronobiology and Sleep Institute, and Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Department of Bioengineering, University of Pennsylvania; Philadelphia, PA 19104, USA
| | - Andrea V. Rozo
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
| | - June H. Ahn
- Chronobiology and Sleep Institute, and Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
| | - Juerg R. Straubhaar
- Bioinformatics Center, Massachusetts Eye and Ear Infirmary; Boston, MA 02114, USA
| | - Nicolai Doliba
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
| | - Doris A. Stoffers
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
| | - Nikolai Slavov
- Departments of Bioengineering and Biology, Single-Cell Proteomics Center and Barnett Institute, Northeastern University; Boston, MA 02115, USA
| | - Juan R. Alvarez-Dominguez
- Chronobiology and Sleep Institute, and Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104, USA
- Lead contact
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3
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Dolfini D, Imbriano C, Mantovani R. The role(s) of NF-Y in development and differentiation. Cell Death Differ 2025; 32:195-206. [PMID: 39327506 PMCID: PMC11802806 DOI: 10.1038/s41418-024-01388-1] [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: 05/27/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
NF-Y is a conserved sequence-specific trimeric Transcription Factor -TF- binding to the CCAAT element. We review here the role(s) in development, from pre-implantation embryo to terminally differentiated tissues, by rationalizing and commenting on genetic, genomic, epigenetic and biochemical studies. This effort brings to light the impact of NF-YA isoforms on stemness and differentiation, as well as binding to distal vs promoter proximal sites and connections with selected TFs.
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Affiliation(s)
- Diletta Dolfini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Carol Imbriano
- Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Modena, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy.
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4
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Li H, Lin L, Huang X, Lu Y, Su X. 2-Hydroxylation is a chemical switch linking fatty acids to glucose-stimulated insulin secretion. J Biol Chem 2024; 300:107912. [PMID: 39442620 PMCID: PMC11742320 DOI: 10.1016/j.jbc.2024.107912] [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: 04/28/2024] [Revised: 09/07/2024] [Accepted: 10/08/2024] [Indexed: 10/25/2024] Open
Abstract
Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is metabolically regulated and progressively diminished during the development of type 2 diabetes (T2D). This dynamic process is tightly coupled with fatty acid metabolism, but the underlying mechanisms remain poorly understood. Fatty acid 2-hydroxylase (FA2H) catalyzes the conversion of fatty acids to chiral specific (R)-2-hydroxy fatty acids ((R)-2-OHFAs), which influences cell metabolism. However, little is known about its potential coupling with GSIS in pancreatic β cells. Here, we showed that Fa2h knockout decreases plasma membrane localization and protein level of glucose transporter 2 (GLUT2), which is essential for GSIS, thereby controlling blood glucose homeostasis. Conversely, FA2H overexpression increases GLUT2 on the plasma membrane and enhances GSIS. Mechanistically, FA2H suppresses the internalization and trafficking of GLUT2 to the lysosomes for degradation. Overexpression of wild-type FA2H, but not its mutant with impaired hydroxylase activity in the pancreatic β-cells, improves glucose tolerance by promoting insulin secretion. Levels of 2-OHFAs and Fa2h gene expression are lower in high-fat diet-induced obese mouse islets with impaired GSIS. Moreover, lower gene expression of FA2H is observed in a set of human T2D islets when the insulin secretion index is significantly suppressed, indicating the potential involvement of FA2H in regulating mouse and human GSIS. Collectively, our results identified an FA chemical switch to maintain the proper response of GSIS in pancreatic β cells and provided a new perspective on the β-cell failure that triggers T2D.
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Affiliation(s)
- Hong Li
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Lin Lin
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Xiaoheng Huang
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yang Lu
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Xiong Su
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China; Suzhou Key Laboratory of Systems Biomedicine, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
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5
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Spellman MJ, Assaf T, Nangia S, Fernandez J, Nicholson KC, Shepard BD. Handling the sugar rush: the role of the renal proximal tubule. Am J Physiol Renal Physiol 2024; 327:F1013-F1025. [PMID: 39447117 PMCID: PMC11687834 DOI: 10.1152/ajprenal.00265.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 10/26/2024] Open
Abstract
Blood glucose homeostasis is critical to ensure the proper functioning of the human body. Through the processes of filtration, reabsorption, secretion, and metabolism, much of this task falls to the kidneys. With a rise in glucose and other added sugars, there is an increased burden on this organ, mainly the proximal tubule, which is responsible for all glucose reabsorption. In this review, we focus on the current physiological and cell biological functions of the renal proximal tubule as it works to reabsorb and metabolize glucose and fructose. We also highlight the physiological adaptations that occur within the proximal tubule as sugar levels rise under pathophysiological conditions including diabetes. This includes the detrimental impacts of an excess glucose load that leads to glucotoxicity. Finally, we explore some of the emerging therapeutics that modulate renal glucose handling and the systemic protection that can be realized by targeting the reabsorptive properties of the kidney.
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Affiliation(s)
- Michael J Spellman
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Tala Assaf
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Shivani Nangia
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Joel Fernandez
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Kyle C Nicholson
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Blythe D Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
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6
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Michaels TM, Essop MF, Joseph DE. Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells. Viruses 2024; 16:1243. [PMID: 39205219 PMCID: PMC11358987 DOI: 10.3390/v16081243] [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: 07/15/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024] Open
Abstract
The COVID-19 pandemic has revealed a bidirectional relationship between SARS-CoV-2 infection and diabetes mellitus. Existing evidence strongly suggests hyperglycemia as an independent risk factor for severe COVID-19, resulting in increased morbidity and mortality. Conversely, recent studies have reported new-onset diabetes following SARS-CoV-2 infection, hinting at a potential direct viral attack on pancreatic beta cells. In this review, we explore how hyperglycemia, a hallmark of diabetes, might influence SARS-CoV-2 entry and accessory proteins in pancreatic β-cells. We examine how the virus may enter and manipulate such cells, focusing on the role of the spike protein and its interaction with host receptors. Additionally, we analyze potential effects on endosomal processing and accessory proteins involved in viral infection. Our analysis suggests a complex interplay between hyperglycemia and SARS-CoV-2 in pancreatic β-cells. Understanding these mechanisms may help unlock urgent therapeutic strategies to mitigate the detrimental effects of COVID-19 in diabetic patients and unveil if the virus itself can trigger diabetes onset.
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Affiliation(s)
- Tara M. Michaels
- Centre for Cardio-Metabolic Research in Africa, Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, South Africa;
| | - M. Faadiel Essop
- Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, South Africa;
| | - Danzil E. Joseph
- Centre for Cardio-Metabolic Research in Africa, Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, South Africa;
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7
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Baghestani S, Haldin C, Kosijer P, Alam CM, Toivola DM. β-Cell keratin 8 maintains islet mechanical integrity, mitochondrial ultrastructure, and β-cell glucose transporter 2 plasma membrane targeting. Am J Physiol Cell Physiol 2024; 327:C462-C476. [PMID: 38912736 DOI: 10.1152/ajpcell.00123.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/31/2024] [Accepted: 06/12/2024] [Indexed: 06/25/2024]
Abstract
Islet β-cell dysfunction is an underlying factor for type I diabetes (T1D) development. Insulin sensing and secretion are tightly regulated in β-cells at multiple subcellular levels. The epithelial intermediate filament (IF) protein keratin (K) 8 is the main β-cell keratin, constituting the filament network with K18. To identify the cell-autonomous functions of K8 in β-cells, mice with targeted deletion of β-cell K8 (K8flox/flox; Ins-Cre) were analyzed for islet morphology, ultrastructure, and integrity, as well as blood glucose regulation and streptozotocin (STZ)-induced diabetes development. Glucose transporter 2 (GLUT2) localization was studied in β-cells in vivo and in MIN6 cells with intact or disrupted K8/K18 filaments. Loss of β-cell K8 leads to a major reduction in K18. Islets without β-cell K8 are more fragile, and these β-cells display disjointed plasma membrane organization with less membranous E-cadherin and smaller mitochondria with diffuse cristae. Lack of β-cell K8 also leads to a reduced glucose-stimulated insulin secretion (GSIS) response in vivo, despite undisturbed systemic blood glucose regulation. K8flox/flox, Ins-Cre mice have a decreased sensitivity to STZ compared with K8 wild-type mice, which is in line with decreased membranous GLUT2 expression observed in vivo, as GLUT2 is required for STZ uptake in β-cells. In vitro, MIN6 cell plasma membrane GLUT2 is rescued in cells overexpressing K8/K18 filaments but mistargeted in cells with disrupted K8/K18 filaments. β-Cell K8 is required for islet and β-cell structural integrity, normal mitochondrial morphology, and GLUT2 plasma membrane targeting, and has implications on STZ sensitivity as well as systemic insulin responses.NEW & NOTEWORTHY Keratin 8 is the main cytoskeletal protein in the cytoplasmic intermediate filament network in β-cells. Here for the first time, we assessed the β-cell autonomous mechanical and nonmechanical roles of keratin 8 in β-cell function. We demonstrated the importance of keratin 8 in islet and β-cell structural integrity, maintaining mitochondrial morphology and GLUT2 plasma membrane targeting.
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Affiliation(s)
- Sarah Baghestani
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship, Åbo Akademi University, Turku, Finland
| | - Caroline Haldin
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship, Åbo Akademi University, Turku, Finland
| | - Petar Kosijer
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship, Åbo Akademi University, Turku, Finland
| | - Catharina M Alam
- School of Applied Sciences, Edinburgh Napier University, Edinburg, United Kingdom
| | - Diana M Toivola
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship, Åbo Akademi University, Turku, Finland
- Turku Center for Disease Modeling, University of Turku, Turku, Finland
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8
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Samario-Román J, Velasco M, Larqué C, Cárdenas-Vázquez R, Ortiz-Huidobro RI, Hiriart M. NGF effects promote the maturation of rat pancreatic beta cells by regulating GLUT2 levels and distribution, and glucokinase activity. PLoS One 2024; 19:e0303934. [PMID: 38875221 PMCID: PMC11178159 DOI: 10.1371/journal.pone.0303934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 05/02/2024] [Indexed: 06/16/2024] Open
Abstract
The nerve growth factor (NGF) participates in cell survival and glucose-stimulated insulin secretion (GSIS) processes in rat adult beta cells. GSIS is a complex process in which metabolic events and ionic channel activity are finely coupled. GLUT2 and glucokinase (GK) play central roles in GSIS by regulating the rate of the glycolytic pathway. The biphasic release of insulin upon glucose stimulation characterizes mature adult beta cells. On the other hand, beta cells obtained from neonatal, suckling, and weaning rats are considered immature because they secrete low levels of insulin and do not increase insulin secretion in response to high glucose. The weaning of rats (at postnatal day 20 in laboratory conditions) involves a dietary transition from maternal milk to standard chow. It is characterized by increased basal plasma glucose levels and insulin levels, which we consider physiological insulin resistance. On the other hand, we have observed that incubating rat beta cells with NGF increases GSIS by increasing calcium currents in neonatal cells. In this work, we studied the effects of NGF on the regulation of cellular distribution and activity of GLUT2 and GK to explore its potential role in the maturation of GSIS in beta cells from P20 rats. Pancreatic islet cells from both adult and P20 rats were isolated and incubated with 5.6 mM or 15.6 mM glucose with and without NGF for 4 hours. Specific immunofluorescence assays were conducted following the incubation period to detect insulin and GLUT2. Additionally, we measured glucose uptake, glucokinase activity, and insulin secretion assays at 5.6 mM or 15.6 mM glucose concentrations. We observed an age-dependent variation in the distribution of GLUT2 in pancreatic beta cells and found that glucose plays a regulatory role in GLUT2 distribution independently of age. Moreover, NGF increases GLUT2 abundance, glucose uptake, and GSIS in P20 beta cells and GK activity in adult beta cells. Our results suggest that besides increasing calcium currents, NGF regulates metabolic components of the GSIS, thereby contributing to the maturation process of pancreatic beta cells.
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Affiliation(s)
- Jazmín Samario-Román
- Neuroscience Division, Cognitive Neuroscience Department, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Myrian Velasco
- Neuroscience Division, Cognitive Neuroscience Department, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Carlos Larqué
- Department of Embryology and Genetics, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - René Cárdenas-Vázquez
- Laboratory of Experimental Animal Biology, Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Rosa Isela Ortiz-Huidobro
- Department of Genomic Medicine and Environmental Toxicology, Instituto de Investigaciones Biomédicas, Ciudad de México, Mexico
| | - Marcia Hiriart
- Neuroscience Division, Cognitive Neuroscience Department, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
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9
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Yoshino S, Ishida E, Horiguchi K, Matsumoto S, Nakajima Y, Ozawa A, Yamada M, Yamada E. Mixed-Lineage Leukaemia Gene Regulates Glucose-Sensitive Gene Expression and Insulin Secretion in Pancreatic Beta Cells. Int J Mol Sci 2024; 25:4704. [PMID: 38731926 PMCID: PMC11082990 DOI: 10.3390/ijms25094704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
The escalating prevalence of diabetes mellitus underscores the need for a comprehensive understanding of pancreatic beta cell function. Interest in glucose effectiveness has prompted the exploration of novel regulatory factors. The myeloid/lymphoid or mixed-lineage leukaemia gene (MLL) is widely recognised for its role in leukemogenesis and nuclear regulatory mechanisms through its histone methyltransferase activity in active chromatin. However, its function within pancreatic endocrine tissues remains elusive. Herein, we unveil a novel role of MLL in glucose metabolism and insulin secretion. MLL knockdown in βHC-9 pancreatic beta cells diminished insulin secretion in response to glucose loading, paralleled by the downregulation of the glucose-sensitive genes SLC2a1 and SLC2a2. Similar observations were made in MLL heterozygous knockout mice (MLL+/-), which exhibited impaired glucose tolerance and reduced insulin secretion without morphological anomalies in pancreatic endocrine cells. The reduction in insulin secretion was independent of changes in beta cell mass or insulin granule morphology, suggesting the regulatory role of MLL in glucose-sensitive gene expression. The current results suggest that MLL interacts with circadian-related complexes to modulate the expression of glucose transporter genes, thereby regulating glucose sensing and insulin secretion. Our findings shed light on insulin secretion control, providing potential avenues for therapeutics against diabetes.
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Affiliation(s)
| | | | | | | | | | | | | | - Eijiro Yamada
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (S.Y.); (K.H.); (S.M.); (Y.N.); (A.O.); (M.Y.)
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Yamagata K, Tsuyama T, Sato Y. Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes. Int J Mol Sci 2024; 25:4186. [PMID: 38673770 PMCID: PMC11050445 DOI: 10.3390/ijms25084186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Type 2 diabetes is a chronic disease marked by hyperglycemia; impaired insulin secretion by pancreatic β-cells is a hallmark of this disease. Recent studies have shown that hypoxia occurs in the β-cells of patients with type 2 diabetes and hypoxia, in turn, contributes to the insulin secretion defect and β-cell loss through various mechanisms, including the activation of hypoxia-inducible factors, induction of transcriptional repressors, and activation of AMP-activated protein kinase. This review focuses on advances in our understanding of the contribution of β-cell hypoxia to the development of β-cell dysfunction in type 2 diabetes. A better understanding of β-cell hypoxia might be useful in the development of new strategies for treating type 2 diabetes.
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Affiliation(s)
- Kazuya Yamagata
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
- Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Tomonori Tsuyama
- Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Yoshifumi Sato
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
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Jafari-Rastegar N, Hosseininia HS, Mousavi-Niri N, Khakpai F, Naseroleslami M. Tyrosol-loaded Nano-niosomes Attenuate Diabetic Injury by TargetingGlucose Metabolism, Inflammation, and Glucose Transfer. Pharm Nanotechnol 2024; 12:351-364. [PMID: 37927074 DOI: 10.2174/0122117385251271231018104311] [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: 02/28/2023] [Revised: 08/01/2023] [Accepted: 08/17/2023] [Indexed: 11/07/2023]
Abstract
INTRODUCTION The increasing prevalence of type 2 diabetes, has become a global concern, making it imperative to control. Chemical drugs commonly recommended for diabetes treatment cause many complications and drug resistance over time. METHODS The polyphenol tyrosol has many health benefits, including anti-diabetes properties. Tyrosol's efficacy can be significantly increased when it is used as a niosome in the treatment of diabetes. In this study, Tyrosol and nano-Tyrosol are examined for their effects on genes implicated in type 2 diabetes in streptozotocin-treated rats. Niosome nanoparticles containing 300 mg surfactant (span60: tween60) and 10 mg cholesterol were hydrated in thin films with equal molar ratios. After 72 hours, nano-niosomal formulas were assessed for their physicochemical properties. MTT assays were conducted on HFF cells to assess the cellular toxicity of the nano niosome contacting optimal Tyrosol. Finally, the expression of PEPCK, GCK, TNF-ɑ, IL6, GLUT2 and GLUT9 was measured by real-time PCR. Physiochemical properties of the SEM images of niosomes loaded with Tyrosol revealed the nanoparticles had a vehicular structure. RESULTS In this study, there were two stages of release: initial release (8 hours) and sustainable release (72 hours). Meanwhile, free-form drugs were considerably more toxic than niosomal drugs in terms of their cellular toxicity. An in vivo comparison of oral Tyrosol gavage with nano-Tyrosol showed a significant increase in GCK (P < 0.001), GLUT2 (P < 0.001), and GLUT9 (P < 0.001). Furthermore, nano-Tyrosol decreased the expression of TNF-ɑ (P < 0.05), PEPCK (P < 0.001), and IL-6 (P < 0.05) which had been increased by diabetes mellitus. The results confirmed nano-Tyrosol's anti-diabetes and anti-inflammatory effects. CONCLUSION These findings suggest that nano-Tyrosol has potential applications in diabetes treatment and associated inflammation. Further research is needed to better understand the mechanism of action.
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Affiliation(s)
- Nima Jafari-Rastegar
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Herbal Pharmacology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Haniyeh Sadat Hosseininia
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Cytotech & Bioinformatics Research Group, Tehran, Iran
| | - Neda Mousavi-Niri
- Department of Biotechnology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Khakpai
- Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Naseroleslami
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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12
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Cheruiyot A, Hollister-Lock J, Sullivan B, Pan H, Dreyfuss JM, Bonner-Weir S, Schaffer JE. Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion. J Clin Invest 2023; 134:e173280. [PMID: 38032734 PMCID: PMC10849759 DOI: 10.1172/jci173280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 11/28/2023] [Indexed: 12/02/2023] Open
Abstract
Pancreatic β cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair β cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion is similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on β cell mRNA translation. Before induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during β cell glucose toxicity that impairs expression of proteins with critical roles in β cell function.
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13
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Morrice N, Vainio S, Mikkola K, van Aalten L, Gallagher JR, Ashford MLJ, McNeilly AD, McCrimmon RJ, Grosfeld A, Serradas P, Koffert J, Pearson ER, Nuutila P, Sutherland C. Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression. Mol Metab 2023; 77:101807. [PMID: 37717665 PMCID: PMC10550722 DOI: 10.1016/j.molmet.2023.101807] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/28/2023] [Accepted: 09/12/2023] [Indexed: 09/19/2023] Open
Abstract
OBJECTIVES Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice. METHODS We performed extensive metabolic phenotyping and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced Slc2a2 (Slc2a2+/-) and intestinal Slc2a2 KO, to assess the impact of metformin treatment. RESULTS Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2+/-) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2+/+) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2+/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2+/- animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells. CONCLUSIONS Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing.
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Affiliation(s)
- Nicola Morrice
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Susanne Vainio
- Turku PET Centre, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Kirsi Mikkola
- Turku PET Centre, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Lidy van Aalten
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Jennifer R Gallagher
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Michael L J Ashford
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Alison D McNeilly
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Rory J McCrimmon
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Alexandra Grosfeld
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012, Paris, France
| | - Patricia Serradas
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic approaches, NutriOmics, Research group, F-75013, Paris, France
| | - Jukka Koffert
- Turku PET Centre, University of Turku, Turku, Finland; Department of Gastroenterology, Turku University Hospital, Turku, Finland
| | - Ewan R Pearson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku, Turku, Finland; Department of Endocrinology, Turku University Hospital, Turku, Finland
| | - Calum Sutherland
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK.
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14
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Trepiccione F, Iervolino A, D'Acierno M, Siccardi S, Costanzo V, Sardella D, De La Motte LR, D'Apolito L, Miele A, Perna AF, Capolongo G, Zacchia M, Frische S, Nielsen R, Staiano L, Sambri I, De Cegli R, Unwin R, Eladari D, Capasso G. The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI. Sci Transl Med 2023; 15:eabn4214. [PMID: 37910600 DOI: 10.1126/scitranslmed.abn4214] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 10/10/2023] [Indexed: 11/03/2023]
Abstract
Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.
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Affiliation(s)
- Francesco Trepiccione
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Anna Iervolino
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | | | - Sabrina Siccardi
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Vincenzo Costanzo
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Donato Sardella
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Luigi R De La Motte
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Luciano D'Apolito
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Antonio Miele
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Alessandra F Perna
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
| | - Giovanna Capolongo
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
| | - Miriam Zacchia
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
| | | | - Rikke Nielsen
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
| | - Leopoldo Staiano
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
- Institute for Genetic and Biomedical Research, National Research Council (CNR), 20089 Milan, Italy
| | - Irene Sambri
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
- Department of Medical and Translational Science, Federico II University, 80131 Naples, Italy
| | - Rossella De Cegli
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
| | - Robert Unwin
- UCL Department of Renal Medicine, Royal Free Hospital, London NW3 2PF, UK
| | - Dominique Eladari
- Service de Médecine de Précision des maladies Métaboliques et Rénales, CHU Amiens-Picardie, Université de Picardie Jules Verne, 80054 Amiens, France
- FCRIN-INI-CRCT, 54500 Vandœuvre-lès-Nancy, France
- Paris Cardiovascular Research Center (PARCC), INSERM U970, F-75015, Paris, France
| | - Giovambattista Capasso
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
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15
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Cheruiyot A, Hollister-Lock J, Sullivan B, Pan H, Dreyfuss JM, Bonner-Weir S, Schaffer JE. Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.29.560203. [PMID: 37808767 PMCID: PMC10557781 DOI: 10.1101/2023.09.29.560203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Pancreatic β-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair β-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on β-cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our findings uncover a translational regulatory circuit during β-cell glucose toxicity that impairs expression of proteins with critical roles in β-cell function.
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16
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Sun B, Chen H, Xue J, Li P, Fu X. The role of GLUT2 in glucose metabolism in multiple organs and tissues. Mol Biol Rep 2023; 50:6963-6974. [PMID: 37358764 PMCID: PMC10374759 DOI: 10.1007/s11033-023-08535-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 05/17/2023] [Indexed: 06/27/2023]
Abstract
The glucose transporter family has an important role in the initial stage of glucose metabolism; Glucose transporters 2 (GLUTs, encoded by the solute carrier family 2, SLC2A genes) is the major glucose transporter in β-cells of pancreatic islets and hepatocytes but is also expressed in the small intestine, kidneys, and central nervous system; GLUT2 has a relatively low affinity to glucose. Under physiological conditions, GLUT2 transports glucose into cells and allows the glucose concentration to reach balance on the bilateral sides of the cellular membrane; Variation of GLUT2 is associated with various endocrine and metabolic disorders; In this study, we discussed the role of GLUT2 in participating in glucose metabolism and regulation in multiple organs and tissues and its effects on maintaining glucose homeostasis.
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Affiliation(s)
- Bo Sun
- Endorcrine and Metabolism Department, Lanzhou University Second Hospital, Lanzhou, 730000, China
- Department of Infantile Endocrine Genetic Metabolism, Gansu Maternal and child Health Care Hospital, Lanzhou, 730000, China
| | - Hui Chen
- Endorcrine and Metabolism Department, Lanzhou University Second Hospital, Lanzhou, 730000, China.
| | - Jisu Xue
- EndEnorcrine and Metabolism Department, Shenzhen Bao 'an People's Hospital (Group), Shenzhen, 518100, China
| | - Peiwu Li
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, 730000, China
| | - Xu Fu
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, 730000, China
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17
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Su Q, Yuan F, Li X, Wang X, Yang K, Shao L, Li W. Wfs1 loss-of-function disrupts the composition of mouse pancreatic endocrine cells from birth and impairs Glut2 localization to cytomembrane in pancreatic β cells. Biochem Biophys Res Commun 2023; 658:80-87. [PMID: 37027908 DOI: 10.1016/j.bbrc.2023.03.074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023]
Abstract
Wfs1 is an endoplasmic reticulum (ER) membrane located protein highly expressed in pancreatic β cells and brain. Wfs1 deficiency causes adult pancreatic β cells dysfunction following β cells apoptosis. Previous studies mainly focus on the Wfs1 function in adult mouse pancreatic β cells. However, whether Wfs1 loss-of-function impairs mouse pancreatic β cell from its early development is unknown. In our study, Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from early postnatal day 0 (P0) to 8 weeks old, with decreased percentage of β cells and increased percentage of α and δ cells. Meanwhile, Wfs1 loss-of-function leads to reduced intracellular insulin content. Notably, Wfs1 deficiency impairs Glut2 localization and causes the accumulation of Glut2 in mouse pancreatic β cell cytoplasm. In Wfs1-deficient mice, glucose homeostasis is disturbed from early 3 weeks old to 8 weeks old. This work reveals that Wfs1 is significantly required for the composition of pancreatic endocrine cells and is essential for Glut2 localization in mouse pancreatic β cells.
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Affiliation(s)
- Qiang Su
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Fei Yuan
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xiaobo Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xuan Wang
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Kaijiang Yang
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Li Shao
- Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, No. 1800 Yuntai Road, Pudong District, Shanghai, 200092, China.
| | - Weida Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China; Reg-Verse Therapeutics (Shanghai) Co. Ltd., Shanghai, 200120, China.
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18
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Tanaka A, Kosuda M, Yamana M, Furukawa A, Nagasawa A, Fujishiro M, Kohno G, Ishihara H. A large-scale functional analysis of genes expressed differentially in insulin secreting MIN6 sublines with high versus mildly reduced glucose-responsiveness. Sci Rep 2023; 13:5654. [PMID: 37024560 PMCID: PMC10079668 DOI: 10.1038/s41598-023-32589-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 03/29/2023] [Indexed: 04/08/2023] Open
Abstract
Molecular mechanisms of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells are not fully understood. GSIS deteriorations are believed to underlie the pathogenesis of type 2 diabetes mellitus. By comparing transcript levels of 3 insulin secreting MIN6 cell sublines with strong glucose-responsiveness and 3 with mildly reduced responsiveness, we identified 630 differentially expressed genes. Using our recently developed system based on recombinase-mediated cassette exchange, we conducted large-scale generation of stable clones overexpressing such genes in the doxycycline-regulated manner. We found that overexpressions of 18, out of 83, genes altered GSIS. Sox11 ((sex determining region Y)-box 11) was selected to confirm its roles in regulating insulin secretion, and the gene was subjected to shRNA-mediated suppression. While Sox11 overexpression decreased GSIS, its suppression increased GSIS, confirming the role of Sox11 as a negative regulator of insulin secretion. Furthermore, metabolic experiments using radiolabelled glucose showed Sox11 to participate in regulating glucose metabolism. Our data suggested that overexpression screening is a feasible option for systemic functional testing to identify important genes in GSIS.
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Affiliation(s)
- Aya Tanaka
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan
| | - Minami Kosuda
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan
| | - Midori Yamana
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan
| | - Asami Furukawa
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan
| | - Akiko Nagasawa
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan
| | - Midori Fujishiro
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan
| | - Genta Kohno
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan
| | - Hisamitsu Ishihara
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi, 173-8610, Japan.
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19
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Normal β-Cell Glut2 Expression Is not Required for Regulating Glucose-Stimulated Insulin Secretion and Systemic Glucose Homeostasis in Mice. Biomolecules 2023; 13:biom13030540. [PMID: 36979475 PMCID: PMC10046365 DOI: 10.3390/biom13030540] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/09/2023] [Accepted: 03/11/2023] [Indexed: 03/19/2023] Open
Abstract
Objective: Glucose transporter 2 (GLUT2) is expressed in the pancreatic β-cell, intestine, liver, and kidney in mice. Although GLUT2 is considered as a major regulator of insulin secretion, in vivo contribution of β-cell Glut2 to glucose-stimulated insulin secretion and systemic glucose homeostasis is undefined. Therefore, the main objective of this study is to determine the role of β-cell Glut2 in regulating insulin secretion and blood glucose levels in mice. Methods: We produced mice in which we can knock down Glut2 at a desired time specifically in β-cells (β-Glut2 KD) by crossing Glut2LoxP/LoxP mice with Ins1CreERT2 mouse strain and using the Cre-Lox recombination technique. We measured fasting blood glucose levels, glucose tolerance, and glucose-stimulated insulin secretion in the β-Glut2 KD mice. We used qRT-PCR and immunofluorescence to validate the deficiency of β-cell Glut2 in β-Glut2 KD mice. Results: We report that both male and female β-Glut2 KD mice have normal glucose-stimulated insulin secretion. Moreover, the β-Glut2 KD mice exhibit normal fasting blood glucose levels and glucose tolerance. The β-Glut2 KD mice have upregulated GLUT1 in islets. Conclusions: Our findings demonstrate that normal β-cell Glut2 expression is not essential for regulating glucose-stimulated insulin secretion and systemic glucose homeostasis in mice. Therefore, the currently assumed role of β-cell GLUT2 in regulating insulin secretion and blood glucose levels needs to be recalibrated. This will allow an opportunity to determine the contribution of other β-cell glucose transporters or factors whose normal expression may be necessary for mediating glucose stimulated insulin secretion.
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20
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Bacos K, Perfilyev A, Karagiannopoulos A, Cowan E, Ofori JK, Bertonnier-Brouty L, Rönn T, Lindqvist A, Luan C, Ruhrmann S, Ngara M, Nilsson Å, Gheibi S, Lyons CL, Lagerstedt JO, Barghouth M, Esguerra JL, Volkov P, Fex M, Mulder H, Wierup N, Krus U, Artner I, Eliasson L, Prasad RB, Cataldo LR, Ling C. Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets. J Clin Invest 2023; 133:163612. [PMID: 36656641 PMCID: PMC9927941 DOI: 10.1172/jci163612] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 01/05/2023] [Indexed: 01/20/2023] Open
Abstract
Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.
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Affiliation(s)
- Karl Bacos
- Epigenetics and Diabetes Unit, Department of Clinical Sciences and
| | | | - Alexandros Karagiannopoulos
- Unit of Islet Cell Exocytosis, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Scania, Sweden
| | - Elaine Cowan
- Unit of Islet Cell Exocytosis, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Scania, Sweden
| | - Jones K. Ofori
- Epigenetics and Diabetes Unit, Department of Clinical Sciences and
| | - Ludivine Bertonnier-Brouty
- Endocrine Cell Differentiation, Department of Laboratory Medicine, Lund Stem Cell Center, Malmö, Scania, Sweden
| | - Tina Rönn
- Epigenetics and Diabetes Unit, Department of Clinical Sciences and
| | - Andreas Lindqvist
- Neuroendocrine Cell Biology, Department of Experimental Medical Science
| | - Cheng Luan
- Unit of Islet Pathophysiology, Department of Clinical Sciences
| | - Sabrina Ruhrmann
- Epigenetics and Diabetes Unit, Department of Clinical Sciences and
| | - Mtakai Ngara
- Neuroendocrine Cell Biology, Department of Experimental Medical Science
| | - Åsa Nilsson
- Human Tissue Lab, Department of Clinical Sciences
| | - Sevda Gheibi
- Molecular Metabolism Unit, Department of Clinical Sciences, and
| | - Claire L. Lyons
- Molecular Metabolism Unit, Department of Clinical Sciences, and
| | - Jens O. Lagerstedt
- Unit of Islet Cell Exocytosis, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Scania, Sweden
| | | | - Jonathan L.S. Esguerra
- Unit of Islet Cell Exocytosis, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Scania, Sweden
| | - Petr Volkov
- Epigenetics and Diabetes Unit, Department of Clinical Sciences and
| | - Malin Fex
- Molecular Metabolism Unit, Department of Clinical Sciences, and
| | - Hindrik Mulder
- Molecular Metabolism Unit, Department of Clinical Sciences, and
| | - Nils Wierup
- Neuroendocrine Cell Biology, Department of Experimental Medical Science
| | - Ulrika Krus
- Human Tissue Lab, Department of Clinical Sciences
| | - Isabella Artner
- Endocrine Cell Differentiation, Department of Laboratory Medicine, Lund Stem Cell Center, Malmö, Scania, Sweden
| | - Lena Eliasson
- Unit of Islet Cell Exocytosis, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Scania, Sweden
| | - Rashmi B. Prasad
- Genomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Scania, Sweden.,Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland
| | - Luis Rodrigo Cataldo
- Molecular Metabolism Unit, Department of Clinical Sciences, and,The Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte Ling
- Epigenetics and Diabetes Unit, Department of Clinical Sciences and
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21
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Katz LS, Argmann C, Lambertini L, Scott DK. T3 and glucose increase expression of phosphoenolpyruvate carboxykinase (PCK1) leading to increased β-cell proliferation. Mol Metab 2022; 66:101646. [PMID: 36455788 PMCID: PMC9731891 DOI: 10.1016/j.molmet.2022.101646] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/18/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES Thyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for β-cell function and proliferation. METHODS RNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations and in the presence or absence of T3. Gene expression was also studies in sorted human β-cells, mouse islets and Ins-1 cells by RT-qPCR. Silencing of the thyroid hormone receptors (THR) was conducted using lentiviruses. Proliferation was assessed by ki67 immunostaining in primary human/mouse islets. Chromatin immunoprecipitation and proximity ligation assay were preformed to validate interactions of ChREBP and THR. RESULTS We found glucose-mediated expression of carbohydrate response element binding protein alpha and beta (ChREBPα and ChREBPβ) mRNAs and their target genes are highly dependent on T3 concentrations in rodent and human β-cells. In β-cells, T3 and glucose coordinately regulate the expression of ChREBPβ and PCK1 (phosphoenolpyruvate carboxykinase-1) among other important genes for β-cell maturation. Additionally, we show the thyroid hormone receptor (THR) and ChREBP interact, and their relative response elements are located near to each other on mutually responsive genes. In FACS-sorted adult human β-cells, we found that high concentrations of glucose and T3 induced the expression of PCK1. Next, we show that overexpression of Pck1 together with dimethyl malate (DMM), a substrate precursor, significantly increased β-cell proliferation in human islets. Finally, using a Cre-Lox approach, we demonstrated that ChREBPβ contributes to Pck1-dependent β-cell proliferation in mouse β-cells. CONCLUSIONS We conclude that T3 and glucose act together to regulate ChREBPβ, leading to increased expression and activity of Pck1, and ultimately increased β-cell proliferation.
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Affiliation(s)
- Liora S Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Carmen Argmann
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Luca Lambertini
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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22
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Golbasi H, Bayraktar B, Golbasi C, Omeroglu I, Adiyaman D, Sever B, Ekin A. Can sonographic imaging of the fetal pancreas predict perinatal outcomes in gestational diabetes mellitus? J Perinat Med 2022; 50:1189-1197. [PMID: 35607725 DOI: 10.1515/jpm-2022-0050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/27/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES To evaluate whether fetal pancreatic echogenicity and its measurements are associated with gestational diabetes mellitus (GDM) and perinatal outcomes. METHODS A prospective cohort study was conducted with 150 pregnant women with a singleton pregnancy. The study included pregnant women between 30 and 41 weeks with or without GDM. Fetal pancreatic circumference was measured using the free-hand tracking function. The echogenicity of the fetal pancreas was compared with the echogenicity of the liver and bone (ribs, spine) and classified as Grades 1, 2 and 3. The relationship between maternal characteristics and perinatal outcomes with fetal pancreas measurements and echogenicity was evaluated. RESULTS Pregnant women with 75 GDM and 75 without GDM were included in the study. Mean fetal pancreas circumference measurements were significantly higher in pregnant women with GDM than in those without GDM (p=0.001). Hyperechogenic (Grade 3) fetal pancreas was significantly higher in pregnant women with GDM than in pregnant women without GDM, and there was a positive correlation between pancreatic echogenicity and HbA1c levels in pregnant women with GDM (r=0.631, p<0.01). There was a significant relationship between pancreatic echogenicity, measurements and adverse neonatal outcomes in pregnant women with GDM, and pancreas measurements were significantly higher in pregnant women with cesarean delivery. CONCLUSIONS Fetal pancreatic echogenicity and measurements in pregnant women with GDM can give an idea about glucose regulation and adverse perinatal outcomes.
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Affiliation(s)
- Hakan Golbasi
- Department of Obstetrics and Gynecology Division of Perinatology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
| | - Burak Bayraktar
- Department of Obstetrics and Gynecology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
| | - Ceren Golbasi
- Department of Obstetrics and Gynecology, Izmir Tinaztepe University Faculty of Medicine, Izmir, Turkey
| | - Ibrahim Omeroglu
- Department of Obstetrics and Gynecology Division of Perinatology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
| | - Duygu Adiyaman
- Department of Obstetrics and Gynecology Division of Perinatology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
| | - Baris Sever
- Department of Obstetrics and Gynecology Division of Perinatology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
| | - Atalay Ekin
- Department of Obstetrics and Gynecology Division of Perinatology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
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23
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Chen K, Zhang J, Huang Y, Tian X, Yang Y, Dong A. Single-cell RNA-seq transcriptomic landscape of human and mouse islets and pathological alterations of diabetes. iScience 2022; 25:105366. [PMID: 36339258 PMCID: PMC9626680 DOI: 10.1016/j.isci.2022.105366] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 09/13/2022] [Accepted: 10/12/2022] [Indexed: 11/15/2022] Open
Abstract
Single-cell RNA sequencing has paved the way for delineating the pancreatic islet cell atlas and identifying hallmarks of diabetes. However, pathological alterations of type 2 diabetes (T2D) remain unclear. We isolated pancreatic islets from control and T2D mice for single-cell RNA sequencing (scRNA-seq) and retrieved multiple datasets from the open databases. The complete islet cell landscape and robust marker genes and transcription factors of each endocrine cell type were identified. GLRA1 was restricted to beta cells, and beta cells exhibited obvious heterogeneity. The beta subcluster in the T2D mice remarkably decreased the expression of Slc2a2, G6pc2, Mafa, Nkx6-1, Pdx1, and Ucn3 and had higher unfolded protein response (UPR) scores than in the control mice. Moreover, we developed a Web-based interactive tool, creating new opportunities for the data mining of pancreatic islet scRNA-seq datasets. In conclusion, our work provides a valuable resource for a deeper understanding of the pathological mechanism underlying diabetes.
Cross-species scRNA-seq reveals the complete cell landscape of the islets of Langerhans We identify the robust marker genes and TFs of each endocrine and exocrine cell type Pathological alterations of beta cells in type 2 diabetes are explored A Web-based interactive tool is established for pancreatic islet scRNA-seq datasets
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24
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Gottmann P, Speckmann T, Stadion M, Zuljan E, Aga H, Sterr M, Büttner M, Santos PM, Jähnert M, Bornstein SR, Theis FJ, Lickert H, Schürmann A. Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice. Diabetes 2022; 71:1962-1978. [PMID: 35771990 PMCID: PMC9862397 DOI: 10.2337/db21-1030] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 06/13/2022] [Indexed: 02/05/2023]
Abstract
Progressive dysfunction and failure of insulin-releasing β-cells are a hallmark of type 2 diabetes (T2D). To study mechanisms of β-cell loss in T2D, we performed islet single-cell RNA sequencing of two obese mouse strains differing in their diabetes susceptibility. With mice on a control diet, we identified six β-cell clusters with similar abundance in both strains. However, after feeding of a diabetogenic diet for 2 days, β-cell cluster composition markedly differed between strains. Islets of diabetes-resistant mice developed into a protective β-cell cluster (Beta4), whereas those of diabetes-prone mice progressed toward stress-related clusters with a strikingly different expression pattern. Interestingly, the protective cluster showed indications of reduced β-cell identity, such as downregulation of GLUT2, GLP1R, and MafA, and in vitro knockdown of GLUT2 in β-cells-mimicking its phenotype-decreased stress response and apoptosis. This might explain enhanced β-cell survival of diabetes-resistant islets. In contrast, β-cells of diabetes-prone mice responded with expression changes indicating metabolic pressure and endoplasmic reticulum stress, presumably leading to later β-cell loss. In conclusion, failure of diabetes-prone mice to adapt gene expression toward a more dedifferentiated state in response to rising blood glucose levels leads to β-cell failure and diabetes development.
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Affiliation(s)
- Pascal Gottmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Thilo Speckmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Mandy Stadion
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Erika Zuljan
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Heja Aga
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Michael Sterr
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany
| | - Maren Büttner
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
- Department of Mathematics, Technical University of Munich, Garching, Germany
| | - Patrícia Martínez Santos
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
| | - Markus Jähnert
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Stefan R. Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany
- Department of Diabetes, School of Life Course Science and Medicine, King’s College London, London, U.K
| | - Fabian J. Theis
- Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
- Department of Mathematics, Technical University of Munich, Garching, Germany
- TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Heiko Lickert
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Nutritional Sciences, University of Potsdam, Nuthetal, Germany
- Corresponding author: Annette Schürmann,
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25
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Liu G, Wang L, Wess J, Dean A. Enhancer looping protein LDB1 regulates hepatocyte gene expression by cooperating with liver transcription factors. Nucleic Acids Res 2022; 50:9195-9211. [PMID: 36018801 PMCID: PMC9458430 DOI: 10.1093/nar/gkac707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/22/2022] [Indexed: 12/24/2022] Open
Abstract
Enhancers establish proximity with distant target genes to regulate temporospatial gene expression and specify cell identity. Lim domain binding protein 1 (LDB1) is a conserved and widely expressed protein that functions as an enhancer looping factor. Previous studies in erythroid cells and neuronal cells showed that LDB1 forms protein complexes with different transcription factors to regulate cell-specific gene expression. Here, we show that LDB1 regulates expression of liver genes by occupying enhancer elements and cooperating with hepatic transcription factors HNF4A, FOXA1, TCF7 and GATA4. Using the glucose transporter SLC2A2 gene, encoding GLUT2, as an example, we find that LDB1 regulates gene expression by mediating enhancer-promoter interactions. In vivo, we find that LDB1 deficiency in primary mouse hepatocytes dysregulates metabolic gene expression and changes the enhancer landscape. Conditional deletion of LDB1 in adult mouse liver induces glucose intolerance. However, Ldb1 knockout hepatocytes show improved liver pathology under high-fat diet conditions associated with increased expression of genes related to liver fatty acid metabolic processes. Thus, LDB1 is linked to liver metabolic functions under normal and obesogenic conditions.
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Affiliation(s)
- Guoyou Liu
- Correspondence may also be addressed to Guoyou Liu. Tel: +1 301 435 9396;
| | - Lei Wang
- Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jürgen Wess
- Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ann Dean
- To whom correspondence should be addressed. Tel: +1 301 496 6068;
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26
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Chen CW, Guan BJ, Alzahrani MR, Gao Z, Gao L, Bracey S, Wu J, Mbow CA, Jobava R, Haataja L, Zalavadia AH, Schaffer AE, Lee H, LaFramboise T, Bederman I, Arvan P, Mathews CE, Gerling IC, Kaestner KH, Tirosh B, Engin F, Hatzoglou M. Adaptation to chronic ER stress enforces pancreatic β-cell plasticity. Nat Commun 2022; 13:4621. [PMID: 35941159 PMCID: PMC9360004 DOI: 10.1038/s41467-022-32425-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/01/2022] [Indexed: 11/30/2022] Open
Abstract
Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.
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Affiliation(s)
- Chien-Wen Chen
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
| | - Bo-Jhih Guan
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Mohammed R Alzahrani
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Zhaofeng Gao
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Long Gao
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Syrena Bracey
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Jing Wu
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Cheikh A Mbow
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Raul Jobava
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Leena Haataja
- The Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, MI, 48105, USA
| | - Ajay H Zalavadia
- Lerner Research Institute, Cleveland Clinic, 9620 Carnegie Ave N Bldg, Cleveland, OH, 44106, US
| | - Ashleigh E Schaffer
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Hugo Lee
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53706, USA
| | - Thomas LaFramboise
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Ilya Bederman
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Peter Arvan
- The Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, MI, 48105, USA
| | - Clayton E Mathews
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, US
| | - Ivan C Gerling
- Department of Medicine, University of Tennessee, Memphis, TN, US
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Boaz Tirosh
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA
- The Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Feyza Engin
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53706, USA.
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53705, USA.
| | - Maria Hatzoglou
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
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27
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Stancill JS, Hansen PA, Mathison AJ, Schmidt EE, Corbett JA. Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function. FUNCTION (OXFORD, ENGLAND) 2022; 3:zqac034. [PMID: 35873655 PMCID: PMC9301323 DOI: 10.1093/function/zqac034] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/17/2022] [Accepted: 06/27/2022] [Indexed: 01/07/2023]
Abstract
Reactive oxygen species (ROS) have been implicated as mediators of pancreatic β-cell damage. While β-cells are thought to be vulnerable to oxidative damage, we have shown, using inhibitors and acute depletion, that thioredoxin reductase, thioredoxin, and peroxiredoxins are the primary mediators of antioxidant defense in β-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and β-cell survival in vivo remains unclear. Here, we generated mice with a β-cell specific knockout of thioredoxin reductase 1 (Txnrd1fl/fl; Ins1Cre/+ , βKO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole-body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, βKO islets do not demonstrate increased sensitivity to ROS. RNA-sequencing analysis revealed that Txnrd1-deficient β-cells have increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated genes, and altered expression of genes involved in heme and glutathione metabolism, suggesting an adaptive response. Txnrd1-deficient β-cells also have decreased expression of factors controlling β-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout β-cells compensate for loss of this essential antioxidant pathway by increasing expression of Nrf2-regulated antioxidant genes, allowing for protection from excess ROS at the expense of normal β-cell function and identity.
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Affiliation(s)
| | - Polly A Hansen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA
| | - Angela J Mathison
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Edward E Schmidt
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MN 59717, USA,Redox Biology Laboratory, University of Veterinary Medicine, Budapest 1078, Hungary
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28
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de Souza Cordeiro LM, Bainbridge L, Devisetty N, McDougal DH, Peters DJM, Chhabra KH. Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity. Diabetologia 2022; 65:1032-1047. [PMID: 35290476 PMCID: PMC9081162 DOI: 10.1007/s00125-022-05676-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 01/05/2022] [Indexed: 01/14/2023]
Abstract
AIMS/HYPOTHESIS Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity. METHODS We used the tamoxifen-inducible CreERT2-Lox system in mice to knockout Glut2 specifically in the kidneys (Ks-Glut2 KO) to establish the contribution of renal GLUT2 to systemic glucose homeostasis in health and in insulin-dependent as well as non-insulin-dependent diabetes. We measured circulating glucose and insulin levels in response to OGTT or IVGTT under different experimental conditions in the Ks-Glut2 KO and their control mice. Moreover, we quantified urine glucose levels to explain the phenotype of the mice independently of insulin actions. We also used a transcription factor array to identify mechanisms underlying the crosstalk between renal GLUT2 and sodium-glucose cotransporter 2 (SGLT2). RESULTS The Ks-Glut2 KO mice exhibited improved glucose tolerance and massive glucosuria. Interestingly, this improvement in blood glucose control was eliminated when we knocked out Glut2 in the liver in addition to the kidneys, suggesting that the improvement is attributable to the lack of renal GLUT2. Remarkably, induction of renal Glut2 deficiency reversed hyperglycaemia and normalised body weight in mouse models of diabetes and obesity. Longitudinal monitoring of renal glucose transporters revealed that Sglt2 (also known as Slc5a2) expression was almost abolished 3 weeks after inducing renal Glut2 deficiency. To identify a molecular basis for this crosstalk, we screened for renal transcription factors that were downregulated in the Ks-Glut2 KO mice. Hnf1α (also known as Hnf1a) was among the genes most downregulated and its recovery restored Sglt2 expression in primary renal proximal tubular cells isolated from the Ks-Glut2 KO mice. CONCLUSIONS/INTERPRETATION Altogether, these results demonstrate a novel crosstalk between renal GLUT2 and SGLT2 in regulating systemic glucose homeostasis via glucose reabsorption. Our findings also indicate that inhibiting renal GLUT2 is a potential therapy for diabetes and obesity.
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Affiliation(s)
- Leticia Maria de Souza Cordeiro
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Lauren Bainbridge
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Nagavardhini Devisetty
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - David H McDougal
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Dorien J M Peters
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Kavaljit H Chhabra
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.
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29
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Sharma R, Sahoo B, Srivastava A, Tiwari S. Reduced insulin signaling and high glucagon in early insulin resistance impaired fast-fed regulation of renal gluconeogenesis via insulin receptor substrate. J Cell Biochem 2022; 123:1327-1339. [PMID: 35644013 DOI: 10.1002/jcb.30294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 11/08/2022]
Abstract
Gluconeogenesis is one of the key processes through which the kidney contributes to glucose homeostasis. Urinary exosomes (uE) have been used to study renal gene regulation noninvasively in humans and rodents. Recently, we demonstrated fast-fed regulation of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme for gluconeogenesis, in human uE. The regulation was impaired in subjects with early insulin resistance. Here, we studied primary human proximal tubule cells (hPT) and human uE to elucidate a potential link between insulin resistance and fast-fed regulation of renal PEPCK. We demonstrate that fasted hPTs had higher PEPCK and insulin receptor substrate-2 (IRS2) mRNA and protein levels, relative to fed cells. The fast-fed regulation was, however, attenuated in insulin receptor knockdown (IRKO) hPTs. The IRKO was confirmed by the blunted insulin-induced response on PEPCK, PGC1α, p-IR, and p-AKT expression in IRKO cells. Exosomes secreted by the wild-type or IRKO hPT showed similar regulation to the respective hPT. Similarly, in human uE, the relative abundance of IRS-2 mRNA (to IRS1) was higher in the fasted state relative to the fed condition. However, the fast-fed difference was absent in subjects with early insulin resistance. These subjects had higher circulating glucagon levels relative to subjects with optimal insulin sensitivity. Furthermore, in hPT cells, glucagon significantly induced PEPCK and IRS2 gene, and gluconeogenesis. IR knockdown in hPT cells further increased the gene expression levels. Together the data suggest that reduced insulin sensitivity and high glucagon in early insulin resistance may impair renal gluconeogenesis via IRS2 regulation.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Biswajit Sahoo
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Aneesh Srivastava
- Department of Urology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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30
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Liu P, Jiang L, Kong W, Xie Q, Li P, Liu X, Zhang J, Liu M, Wang Z, Zhu L, Yang H, Zhou Y, Zou J, Liu X, Liu L. PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4 α-GLUT2 pathway. Acta Pharm Sin B 2022; 12:2391-2405. [PMID: 35646519 PMCID: PMC9136535 DOI: 10.1016/j.apsb.2021.09.031] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/05/2021] [Accepted: 09/16/2021] [Indexed: 01/20/2023] Open
Abstract
Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.
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31
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Kappen C, Kruger C, Jones S, Salbaum JM. Nutrient Transporter Gene Expression in the Early Conceptus-Implications From Two Mouse Models of Diabetic Pregnancy. Front Cell Dev Biol 2022; 10:777844. [PMID: 35478964 PMCID: PMC9035823 DOI: 10.3389/fcell.2022.777844] [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] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/28/2022] [Indexed: 11/29/2022] Open
Abstract
Maternal diabetes in early pregnancy increases the risk for birth defects in the offspring, particularly heart, and neural tube defects. While elevated glucose levels are characteristic for diabetic pregnancies, these are also accompanied by hyperlipidemia, indicating altered nutrient availability. We therefore investigated whether changes in the expression of nutrient transporters at the conception site or in the early post-implantation embryo could account for increased birth defect incidence at later developmental stages. Focusing on glucose and fatty acid transporters, we measured their expression by RT-PCR in the spontaneously diabetic non-obese mouse strain NOD, and in pregnant FVB/N mouse strain dams with Streptozotocin-induced diabetes. Sites of expression in the deciduum, extra-embryonic, and embryonic tissues were determined by RNAscope in situ hybridization. While maternal diabetes had no apparent effects on levels or cellular profiles of expression, we detected striking cell-type specificity of particular nutrient transporters. For examples, Slc2a2/Glut2 expression was restricted to the endodermal cells of the visceral yolk sac, while Slc2a1/Glut1 expression was limited to the mesodermal compartment; Slc27a4/Fatp4 and Slc27a3/Fatp3 also exhibited reciprocally exclusive expression in the endodermal and mesodermal compartments of the yolk sac, respectively. These findings not only highlight the significance of nutrient transporters in the intrauterine environment, but also raise important implications for the etiology of birth defects in diabetic pregnancies, and for strategies aimed at reducing birth defects risk by nutrient supplementation.
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Affiliation(s)
- Claudia Kappen
- Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, United States
| | - Claudia Kruger
- Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, United States
| | - Sydney Jones
- Regulation of Gene Expression, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, United States
| | - J. Michael Salbaum
- Regulation of Gene Expression, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, United States
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Kim SQ, Mohallem R, Franco J, Buhman KK, Kim KH, Aryal UK. Multi-Omics Approach Reveals Dysregulation of Protein Phosphorylation Correlated with Lipid Metabolism in Mouse Non-Alcoholic Fatty Liver. Cells 2022; 11:cells11071172. [PMID: 35406736 PMCID: PMC8997945 DOI: 10.3390/cells11071172] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/24/2022] [Accepted: 03/26/2022] [Indexed: 02/04/2023] Open
Abstract
Obesity caused by overnutrition is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Several lipid intermediates such as fatty acids, glycerophospholipids and sphingolipids are implicated in NAFLD, but detailed characterization of lipids and their functional links to proteome and phosphoproteome remain to be elucidated. To characterize this complex molecular relationship, we used a multi-omics approach by conducting comparative proteomic, phoshoproteomic and lipidomic analyses of high fat (HFD) and low fat (LFD) diet fed mice livers. We quantified 2447 proteins and 1339 phosphoproteins containing 1650 class I phosphosites, of which 669 phosphosites were significantly different between HFD and LFD mice livers. We detected alterations of proteins associated with cellular metabolic processes such as small molecule catabolic process, monocarboxylic acid, long- and medium-chain fatty acid, and ketone body metabolic processes, and peroxisome organization. We observed a significant downregulation of protein phosphorylation in HFD fed mice liver in general. Untargeted lipidomics identified upregulation of triacylglycerols, glycerolipids and ether glycerophosphocholines and downregulation of glycerophospholipids, such as lysoglycerophospholipids, as well as ceramides and acylcarnitines. Analysis of differentially regulated phosphosites revealed phosphorylation dependent deregulation of insulin signaling as well as lipogenic and lipolytic pathways during HFD induced obesity. Thus, this study reveals a molecular connection between decreased protein phosphorylation and lipolysis, as well as lipid-mediated signaling in diet-induced obesity.
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Affiliation(s)
- Sora Q. Kim
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA; (S.Q.K.); (K.K.B.)
| | - Rodrigo Mohallem
- Bindley Bioscience Center, Purdue Proteomics Facility, Purdue University, West Lafayette, IN 47907, USA; (R.M.); (J.F.)
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
| | - Jackeline Franco
- Bindley Bioscience Center, Purdue Proteomics Facility, Purdue University, West Lafayette, IN 47907, USA; (R.M.); (J.F.)
| | - Kimberly K. Buhman
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA; (S.Q.K.); (K.K.B.)
| | - Kee-Hong Kim
- Department of Food Science, Purdue University, West Lafayette, IN 47907, USA;
| | - Uma K. Aryal
- Bindley Bioscience Center, Purdue Proteomics Facility, Purdue University, West Lafayette, IN 47907, USA; (R.M.); (J.F.)
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
- Correspondence: ; Tel.: +1-765-494-4960
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Xu B, Li Z, Zeng T, Zhan J, Wang S, Ho CT, Li S. Bioactives of Momordica charantia as Potential Anti-Diabetic/Hypoglycemic Agents. Molecules 2022; 27:2175. [PMID: 35408574 PMCID: PMC9000558 DOI: 10.3390/molecules27072175] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/23/2022] [Accepted: 03/23/2022] [Indexed: 11/17/2022] Open
Abstract
Momordica charantia L., a member of the Curcubitaceae family, has traditionally been used as herbal medicine and as a vegetable. Functional ingredients of M. charantia play important roles in body health and human nutrition, which can be used directly or indirectly in treating or preventing hyperglycemia-related chronic diseases in humans. The hypoglycemic effects of M. charantia have been known for years. In this paper, the research progress of M. charantia phytobioactives and their hypoglycemic effects and related mechanisms, especially relating to diabetes mellitus, has been reviewed. Moreover, the clinical application of M. charantia in treating diabetes mellitus is also discussed, hoping to broaden the application of M. charantia as functional food.
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Affiliation(s)
- Bilin Xu
- College of Biology and Agricultural Resources, Huanggang Normal University, Huanggang 438000, China; (B.X.); (Z.L.); (J.Z.); (S.W.)
| | - Zhiliang Li
- College of Biology and Agricultural Resources, Huanggang Normal University, Huanggang 438000, China; (B.X.); (Z.L.); (J.Z.); (S.W.)
| | - Ting Zeng
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
| | - Jianfeng Zhan
- College of Biology and Agricultural Resources, Huanggang Normal University, Huanggang 438000, China; (B.X.); (Z.L.); (J.Z.); (S.W.)
| | - Shuzhen Wang
- College of Biology and Agricultural Resources, Huanggang Normal University, Huanggang 438000, China; (B.X.); (Z.L.); (J.Z.); (S.W.)
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA;
| | - Shiming Li
- College of Biology and Agricultural Resources, Huanggang Normal University, Huanggang 438000, China; (B.X.); (Z.L.); (J.Z.); (S.W.)
- Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA;
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Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets. Biomolecules 2022; 12:biom12030407. [PMID: 35327599 PMCID: PMC8945998 DOI: 10.3390/biom12030407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/19/2022] [Accepted: 02/27/2022] [Indexed: 02/07/2023] Open
Abstract
Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio in Ghsr−/− islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in Ghsr−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr−/− mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.
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35
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Dubey R, Prabhakar PK, Gupta J. Epigenetics: key to improve delayed wound healing in type 2 diabetes. Mol Cell Biochem 2022; 477:371-383. [PMID: 34739665 DOI: 10.1007/s11010-021-04285-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 10/23/2021] [Indexed: 12/13/2022]
Abstract
Diabetes-related delayed wound healing is a multifactorial, nuanced, and intertwined complication that causes substantial clinical morbidity. The etiology of diabetes and its related microvascular complications is affected by genes, diet, and lifestyle factors. Epigenetic modifications such as DNA methylation, histone modifications, and post-transcriptional RNA regulation (microRNAs) are subsequently recognized as key facilitators of the complicated interaction between genes and the environment. Current research suggests that diabetes-persuaded dysfunction of epigenetic pathways, which results in changed expression of genes in target cells and cause diabetes-related complications including cardiomyopathy, nephropathy, retinopathy, delayed wound healing, etc., which are foremost drivers to diabetes-related adverse outcomes. In this paper, we discuss the role of epigenetic mechanisms in controlling tissue repair, angiogenesis, and expression of growth factors, as well as recent findings that show the alteration of epigenetic events during diabetic wound healing.
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Affiliation(s)
- Rupal Dubey
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University (LPU), Jalandhar-Delhi G.T. Road, 144411, Phagwara, Punjab, India
| | - Pranav Kumar Prabhakar
- Department of Medical Laboratory Sciences, School of Physiotherapy and Paramedical Sciences, Lovely Professional University, 144411, Phagwara, Punjab, India
| | - Jeena Gupta
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University (LPU), Jalandhar-Delhi G.T. Road, 144411, Phagwara, Punjab, India.
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36
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Wu Y, Wang MH, Yang T, Qin TY, Qin LL, Hu YM, Zhang CF, Sun BJ, Ding L, Wu LL, Liu TH. Mechanisms for Improving Hepatic Glucolipid Metabolism by Cinnamic Acid and Cinnamic Aldehyde: An Insight Provided by Multi-Omics. Front Nutr 2022; 8:794841. [PMID: 35087857 PMCID: PMC8786797 DOI: 10.3389/fnut.2021.794841] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/13/2021] [Indexed: 12/15/2022] Open
Abstract
Cinnamic acid (AC) and cinnamic aldehyde (AL) are two chemicals enriched in cinnamon and have been previously proved to improve glucolipid metabolism, thus ameliorating metabolic disorders. In this study, we employed transcriptomes and proteomes on AC and AL treated db/db mice in order to explore the underlying mechanisms for their effects. Db/db mice were divided into three groups: the control group, AC group and AL group. Gender- and age-matched wt/wt mice were used as a normal group. After 4 weeks of treatments, mice were sacrificed, and liver tissues were used for further analyses. Functional enrichment of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. DEPs were further verified by parallel reaction monitoring (PRM). The results suggested that AC and AL share similar mechanisms, and they may improve glucolipid metabolism by improving mitochondrial functions, decreasing serotonin contents and upregulating autophagy mediated lipid clearance. This study provides an insight into the molecular mechanisms of AC and AL on hepatic transcriptomes and proteomes in disrupted metabolic situations and lays a foundation for future experiments.
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Affiliation(s)
- You Wu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China.,Key Laboratory of Health Cultivation of Beijing, Beijing University of Chinese Medicine, Beijing, China
| | - Ming-Hui Wang
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Tao Yang
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China.,Key Laboratory of Health Cultivation of Beijing, Beijing University of Chinese Medicine, Beijing, China
| | - Tian-Yu Qin
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Ling-Ling Qin
- Department of Science and Technology, Beijing University of Chinese Medicine, Beijing, China
| | - Yao-Mu Hu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China.,Key Laboratory of Health Cultivation of Beijing, Beijing University of Chinese Medicine, Beijing, China
| | - Cheng-Fei Zhang
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China.,Key Laboratory of Health Cultivation of Beijing, Beijing University of Chinese Medicine, Beijing, China
| | - Bo-Ju Sun
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Lei Ding
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China.,Key Laboratory of Health Cultivation of Beijing, Beijing University of Chinese Medicine, Beijing, China
| | - Li-Li Wu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China.,Key Laboratory of Health Cultivation of Beijing, Beijing University of Chinese Medicine, Beijing, China
| | - Tong-Hua Liu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China.,Key Laboratory of Health Cultivation of Beijing, Beijing University of Chinese Medicine, Beijing, China
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37
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Xi Y, Zhang D, Liang Y, Shan Z, Teng X, Teng W. Proteomic Analysis of the Intestinal Resistance to Thyroid Hormone Mouse Model With Thyroid Hormone Receptor Alpha Mutations. Front Endocrinol (Lausanne) 2022; 13:773516. [PMID: 35574030 PMCID: PMC9095823 DOI: 10.3389/fendo.2022.773516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 03/24/2022] [Indexed: 11/23/2022] Open
Abstract
Thyroid hormone is critical during the development of vertebrates and affects the function of many organs and tissues, especially the intestine. Triiodothyronine (T3) is the active form and can bind to thyroid hormone nuclear receptors (TRs) to play a vital role in the development of vertebrates. The resistance to thyroid hormone α, as seen in patients, has been mimicked by the ThraE403X mutation. To investigate the mechanisms underlying the effect of TRα1 on intestinal development, the present study employed proteomic analysis to identify differentially expressed proteins (DEPs) in the distal ileum between homozygous ThraE403X/E403X and wild-type Thra+/+ mice. A total of 1,189 DEPs were identified, including 603 upregulated and 586 downregulated proteins. Proteomic analysis revealed that the DEPs were highly enriched in the metabolic process, the developmental process, the transporter of the nutrients, and the intestinal immune system-related pathway. Of these DEPs, 20 proteins were validated by parallel reaction monitoring analysis. Our intestinal proteomic results provide promising candidates for future studies, as they suggest novel mechanisms by which TRα1 may influence intestinal development, such as the transport of intestinal nutrients and the establishment of innate and adaptive immune barriers of the intestine.
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Affiliation(s)
- Yue Xi
- Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Dan Zhang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Yue Liang
- Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China
| | - Zhongyan Shan
- Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China
| | - Xiaochun Teng
- Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Xiaochun Teng, ; Weiping Teng,
| | - Weiping Teng
- Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Xiaochun Teng, ; Weiping Teng,
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38
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Roberts A, Phuah P, Cheng S, Murphy KG. Targeting Enteroendocrine Cells to Treat Metabolic Disease. COMPREHENSIVE PHARMACOLOGY 2022:344-372. [DOI: 10.1016/b978-0-12-820472-6.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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39
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López-Pérez A, Norlin S, Steneberg P, Remeseiro S, Edlund H, Hörnblad A. Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice. Sci Rep 2021; 11:24410. [PMID: 34949756 PMCID: PMC8702551 DOI: 10.1038/s41598-021-03567-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/06/2021] [Indexed: 12/25/2022] Open
Abstract
AMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.
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Affiliation(s)
- Ana López-Pérez
- Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures väg 12, 90187, Umeå, Sweden
| | - Stefan Norlin
- Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures väg 12, 90187, Umeå, Sweden
| | - Pär Steneberg
- Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures väg 12, 90187, Umeå, Sweden
| | - Silvia Remeseiro
- Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures väg 12, 90187, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, 90187, Umeå, Sweden
| | - Helena Edlund
- Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures väg 12, 90187, Umeå, Sweden.
| | - Andreas Hörnblad
- Umeå Centre for Molecular Medicine (UCMM), Umeå University, Johan Bures väg 12, 90187, Umeå, Sweden.
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Matsubara Y, Kiyohara H, Teratani T, Mikami Y, Kanai T. Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases. Neuropharmacology 2021; 205:108915. [PMID: 34919906 DOI: 10.1016/j.neuropharm.2021.108915] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
The liver is the largest organ in the human body and is responsible for the metabolism and storage of the three principal nutrients: carbohydrates, fats, and proteins. In addition, the liver contributes to the breakdown and excretion of alcohol, medicinal agents, and toxic substances and the production and secretion of bile. In addition to its role as a metabolic centre, the liver has recently attracted attention for its function in the liver-brain axis, which interacts closely with the central nervous system via the autonomic nervous system, including the vagus nerve. The liver-brain axis influences the control of eating behaviour in the central nervous system through stimuli from the liver. Conversely, neural signals from the central nervous system influence glucose, lipid, and protein metabolism in the liver. The liver also receives a constant influx of nutrients and hormones from the intestinal tract and compounds of bacterial origin via the portal system. As a result, the intestinal tract and liver are involved in various immunological interactions. A good example is the co-occurrence of primary sclerosing cholangitis and ulcerative colitis. These heterogeneous roles of the liver-brain axis are mediated via the vagus nerve in an asymmetrical manner. In this review, we provide an overview of these interactions, mainly with the liver but also with the brain and gut.
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Affiliation(s)
- Yuta Matsubara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan.
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Stancill JS, Kasmani MY, Khatun A, Cui W, Corbett JA. Cytokine and Nitric Oxide-Dependent Gene Regulation in Islet Endocrine and Nonendocrine Cells. FUNCTION (OXFORD, ENGLAND) 2021; 3:zqab063. [PMID: 34927076 PMCID: PMC8674205 DOI: 10.1093/function/zqab063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/05/2021] [Accepted: 11/29/2021] [Indexed: 02/02/2023]
Abstract
While exposure to inflammatory cytokines is thought to contribute to pancreatic β-cell damage during diabetes, primarily because cytokine-induced nitric oxide impairs β-cell function and causes cell death with prolonged exposure, we hypothesize that there is a physiological role for cytokine signaling that protects β-cells from a number of environmental stresses. This hypothesis is derived from the knowledge that β-cells are essential for survival even though they have a limited capacity to replicate, yet they are exposed to high cytokine levels during infection as most of the pancreatic blood flow is directed to islets. Here, mouse islets were subjected to single-cell RNA sequencing following 18-h cytokine exposure. Treatment with IL-1β and IFN-γ stimulates expression of inducible nitric oxide synthase (iNOS) mRNA and antiviral and immune-associated genes as well as repression of islet identity factors in a subset of β- and non-β-endocrine cells in a nitric oxide-independent manner. Nitric oxide-dependent expression of genes encoding heat shock proteins was observed in both β- and non-β-endocrine cells. Interestingly, cells with high expression of heat shock proteins failed to increase antiviral and immune-associated gene expression, suggesting that nitric oxide may be an internal "off switch" to prevent the negative effects of prolonged cytokine signaling in islet endocrine cells. We found no evidence for pro-apoptotic gene expression following 18-h cytokine exposure. Our findings suggest that the primary functions of cytokines and nitric oxide are to protect islet endocrine cells from damage, and only when regulation of cytokine signaling is lost does irreversible damage occur.
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Affiliation(s)
| | - Moujtaba Y Kasmani
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Blood Research Institute, Versiti, Milwaukee, WI 53226, USA
| | - Achia Khatun
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Blood Research Institute, Versiti, Milwaukee, WI 53226, USA
| | - Weiguo Cui
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Blood Research Institute, Versiti, Milwaukee, WI 53226, USA
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Scully KJ, Wolfsdorf J, Dedekian M. Acquired growth hormone deficiency in Fanconi-Bickel syndrome. BMJ Case Rep 2021; 14:e246212. [PMID: 34728514 PMCID: PMC8565550 DOI: 10.1136/bcr-2021-246212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2021] [Indexed: 11/04/2022] Open
Abstract
Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disease, resulting from mutations in the SLC2A2 gene, causing impaired glucose transporter 2 protein transporter protein function, impaired glucose and galactose utilisation, hepatorenal glycogen accumulation and organ dysfunction. Clinical features include failure to thrive, hepatomegaly, rickets, short stature and delayed puberty. Therapy includes electrolyte supplementation and uncooked cornstarch. We present a 15-year-old boy diagnosed with FBS in infancy. Growth velocity was normal on standard treatment until age 8.5 years, at which time growth failure led to a diagnosis of acquired growth hormone (GH) deficiency. Initiation of recombinant human GH (rhGH) replacement of 0.25 μg/kg/week resulted in marked improvement in growth velocity and height. While short stature is expected in FBS, growth velocity that falls below the normal range despite adequate therapy should prompt further evaluation. Our case suggests that acquired GH deficiency can arise in FBS and benefits from rhGH therapy.
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Affiliation(s)
- Kevin J Scully
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Joseph Wolfsdorf
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Michael Dedekian
- Division of Pediatric Endocrinology, Maine Medical Center, Portland, Maine, USA
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43
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Hyun J, Park MH, Lee YH, Lee Y, Jeong SJ, Choi SS, Khim KW, Eom HJ, Hur JH, Park CY, Kim JI, Park J, Ryu HW, Jang HJ, Oh SR, Choi JH. Vernicia fordii (Hemsl.) Airy Shaw extract stimulates insulin secretion in pancreatic β-cells and improves insulin sensitivity in diabetic mice. JOURNAL OF ETHNOPHARMACOLOGY 2021; 278:114238. [PMID: 34048878 DOI: 10.1016/j.jep.2021.114238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/15/2021] [Accepted: 05/21/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Vernicia fordii (Hemsl.) Airy Shaw (V. fordii) is also known as the tung tree and its leaves and fruit are used as an oriental treatment for dyspepsia, edema, and skin diseases, which are known as diabetic complications. AIM OF THE STUDY In this study, we aimed to investigate the methanolic extract (VF5) of the leaves of V. fordii as an insulin secretagogue and its probable mechanism and verify the effect in HFD-fed mice. MATERIALS AND METHODS The insulin secretagogue activity of different doses of VF5 (0.1, 0.3 and 1.0 μg/ml) was assessed using in vitro insulin secretion assay and confirmed the anti-diabetic effect in mice fed HFD for 4 weeks with different doses of VF5 (10, 20 and 50 mg/kg oral) for another 6 weeks. Glbenclamide (30 mg/kg, oral) was used as positive control drug. The possible mechanisms were evaluated by using Gö6983 (10 μM), U73122 (10 μM) and nifedipine (10 μM). The major constituents of VF5 were analyzed by UPLC-QToF-MS and 1H and 13C NMR spectroscopy. RESULTS UPLC-QToF-MS and NMR spectroscopy analysis indicated that one of the main active components of VF5 was tigliane-diterpene esters. VF5 functioned as an insulin secretagogue and enhanced mitochondria respiration and insulin homeostasis. We confirmed that VF5 preserved the β-cell and reduced the β-cell expansion which caused by metabolic stress under HFD. The antidiabetic role of VF5 in HFD fed mice was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT), fasting plasma insulin level, fasting blood glucose level, AKT signal in peripheral tissue in the absence of toxic effects. Mechanistically, insulinotropic effect of VF5 was mediated by activation of PKCα via intracellular Ca2+ influx and enhanced mitochondria function. CONCLUSION VF5 exhibits potent insulin secretagogue function and improves insulin sensitivity and protection of pancreatic β-cells from metabolic stress without toxicity. Taken together, our study suggests that VF5 could be potentially used for treating diabetes and metabolic diseases through improving β-cell function.
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Affiliation(s)
- Jimin Hyun
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Mi Hyeon Park
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheong-ju Si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Yo Han Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Youngeun Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Su Ji Jeong
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Sun Sil Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Keon Woo Khim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Hye Jin Eom
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Jin-Hoe Hur
- UNIST-Optical Biomed Imaging Center (UOBC), UNIST, Ulsan, 44919, Republic of Korea
| | - Chan Young Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Jae-Ick Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Jiyoung Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Hyung Won Ryu
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheong-ju Si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Hyun-Jun Jang
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
| | - Sei-Ryang Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheong-ju Si, Chungcheongbuk-do, 28116, Republic of Korea.
| | - Jang Hyun Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
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Sato M, Minabe S, Sakono T, Magata F, Nakamura S, Watanabe Y, Inoue N, Uenoyama Y, Tsukamura H, Matsuda F. Morphological Analysis of the Hindbrain Glucose Sensor-Hypothalamic Neural Pathway Activated by Hindbrain Glucoprivation. Endocrinology 2021; 162:6308440. [PMID: 34161572 DOI: 10.1210/endocr/bqab125] [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: 06/06/2020] [Indexed: 01/06/2023]
Abstract
Lowered glucose availability, sensed by the hindbrain, has been suggested to enhance gluconeogenesis and food intake as well as suppress reproductive function. In fact, our previous histological and in vitro studies suggest that hindbrain ependymal cells function as a glucose sensor. The present study aimed to clarify the hindbrain glucose sensor-hypothalamic neural pathway activated in response to hindbrain glucoprivation to mediate counterregulatory physiological responses. Administration of 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, into the fourth ventricle (4V) of male rats for 0.5 hour induced messenger RNA (mRNA) expression of c-fos, a marker for cellular activation, in ependymal cells in the 4V, but not in the lateral ventricle, the third ventricle or the central canal without a significant change in blood glucose and testosterone levels. Administration of 2DG into the 4V for 1 hour significantly increased blood glucose levels, food intake, and decreased blood testosterone levels. Simultaneously, the expression of c-Fos protein was detected in the 4V ependymal cells; dopamine β-hydroxylase-immunoreactive cells in the C1, C2, and A6 regions; neuropeptide Y (NPY) mRNA-positive cells in the C2; corticotropin-releasing hormone (CRH) mRNA-positive cells in the hypothalamic paraventricular nucleus (PVN); and NPY mRNA-positive cells in the arcuate nucleus (ARC). Taken together, these results suggest that lowered glucose availability, sensed by 4V ependymal cells, activates hindbrain catecholaminergic and/or NPY neurons followed by CRH neurons in the PVN and NPY neurons in the ARC, thereby leading to counterregulatory responses, such as an enhancement of gluconeogenesis, increased food intake, and suppression of sex steroid secretion.
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Affiliation(s)
- Marimo Sato
- Department of Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
| | - Shiori Minabe
- Department of Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
| | - Takahiro Sakono
- Department of Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
| | - Fumie Magata
- Department of Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
| | - Sho Nakamura
- Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Ehime 794-8555, Japan
| | - Youki Watanabe
- Department of Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
| | - Naoko Inoue
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan
| | - Yoshihisa Uenoyama
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan
| | - Hiroko Tsukamura
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan
| | - Fuko Matsuda
- Department of Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
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45
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Liu Y, He S, Zhou R, Zhang X, Yang S, Deng D, Zhang C, Yu X, Chen Y, Su Z. Nuclear Factor-Y in Mouse Pancreatic β-Cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion. Diabetes 2021; 70:1703-1716. [PMID: 33980692 DOI: 10.2337/db20-1238] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 05/06/2021] [Indexed: 02/05/2023]
Abstract
Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The current study was undertaken in a conditional knockout of Nf-ya specifically in pancreatic β-cells (Nf-ya βKO) to define the essential physiological role of NF-Y in β-cells. Nf-ya βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca2+ influx in response to glucose, which was associated with an inefficient glucose uptake into β-cells due to a decreased expression of GLUT2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islet homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.
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Affiliation(s)
- Yin Liu
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Siyuan He
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Ruixue Zhou
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Xueping Zhang
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Shanshan Yang
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Dan Deng
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Caixia Zhang
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Xiaoqian Yu
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Yulong Chen
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Zhiguang Su
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
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46
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Stancill JS, Kasmani MY, Khatun A, Cui W, Corbett JA. Single-cell RNA sequencing of mouse islets exposed to proinflammatory cytokines. Life Sci Alliance 2021; 4:e202000949. [PMID: 33883217 PMCID: PMC8091599 DOI: 10.26508/lsa.202000949] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 04/01/2021] [Accepted: 04/07/2021] [Indexed: 02/02/2023] Open
Abstract
Exposure to proinflammatory cytokines is believed to contribute to pancreatic β-cell damage during diabetes development. Although some cytokine-mediated changes in islet gene expression are known, the heterogeneity of the response is not well-understood. After 6-h treatment with IL-1β and IFN-γ alone or together, mouse islets were subjected to single-cell RNA sequencing. Treatment with both cytokines together led to expression of inducible nitric oxide synthase mRNA (Nos2) and antiviral and immune-associated genes in a subset of β-cells. Interestingly, IL-1β alone activated antiviral genes. Subsets of δ- and α-cells expressed Nos2 and exhibited similar gene expression changes as β-cells, including increased expression of antiviral genes and repression of identity genes. Finally, cytokine responsiveness was inversely correlated with expression of genes encoding heat shock proteins. Our findings show that all islet endocrine cell types respond to cytokines, IL-1β induces the expression of protective genes, and cellular stress gene expression is associated with inhibition of cytokine signaling.
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Affiliation(s)
- Jennifer S Stancill
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Moujtaba Y Kasmani
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Achia Khatun
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Weiguo Cui
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
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47
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Mikawa T, Shibata E, Shimada M, Ito K, Ito T, Kanda H, Takubo K, Shimada A, Lleonart ME, Inagaki N, Yokode M, Kondoh H. Characterization of genetically modified mice for phosphoglycerate mutase, a vitally-essential enzyme in glycolysis. PLoS One 2021; 16:e0250856. [PMID: 33914812 PMCID: PMC8084212 DOI: 10.1371/journal.pone.0250856] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/15/2021] [Indexed: 01/14/2023] Open
Abstract
Glycolytic metabolism is closely involved in physiological homeostasis and pathophysiological states. Among glycolytic enzymes, phosphoglycerate mutase (PGAM) has been reported to exert certain physiological role in vitro, whereas its impact on glucose metabolism in vivo remains unclear. Here, we report the characterization of Pgam1 knockout mice. We observed that homozygous knockout mice of Pgam1 were embryonic lethal. Although we previously reported that both PGAM-1 and -2 affect global glycolytic profile of cancers in vitro, in vivo glucose parameters were less affected both in the heterozygous knockout of Pgam1 and in Pgam2 transgenic mice. Thus, the impact of PGAM on in vivo glucose metabolism is rather complex than expected before.
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Affiliation(s)
- Takumi Mikawa
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eri Shibata
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Midori Shimada
- Joint Faculty of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - Ken Ito
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomiko Ito
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, Saitama, Japan
| | - Keiyo Takubo
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | | | | | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masayuki Yokode
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Kondoh
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- * E-mail:
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48
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Zardooz H, Sadeghimahalli F, Khodagholi F. Early postnatal stress impairs insulin secretion in response to psychological stress in adult rats. J Endocrinol Invest 2021; 44:277-286. [PMID: 32458408 DOI: 10.1007/s40618-020-01291-9] [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: 02/13/2020] [Accepted: 05/03/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Adversity in early life can induce metabolic defects in exposure to stress in adulthood. Therefore, the exploration of involving mechanisms can be helpful in the treatment of metabolic disorders. So, the present study was conducted in terms of exploring the effects of interaction between early postnatal stress and young adulthood psychological stress on insulin secretion and pancreatic GLUT-2 levels in male rats. METHODS Footshock as a model of early life stress (at 2 weeks of age) and psychological stress induced by communication box as a model of young adulthood stress (at 8-10 weeks of age) were induced in male Wistar rats for five consecutive days (2 times/day). Blood samples were drawn to measure glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell dysfunction (HOMA-B), before and after stress protocol in young adult rats. Corticosterone was measured on days 1 and 5 of stress induction. The day after the stress period, factors including glucose tolerance, TNF-alpha, isolated islets' insulin output and levels of pancreatic GLUT-2 protein via western blotting were determined. RESULTS The combination of early footshock exposure and psychological stress during adulthood did not affect plasma corticosterone, but increased plasma insulin, HOMA-IR, HOMA-B and TNF-alpha levels. Plasma TNF was not only increased by the combination of both stressors, but also after only E STR exposure. HOMA-IR was increased in both Psy STR and E + Psy-STR groups. Plasma glucose just increased in Psy STR group. The combination of these two life stressors further increased the in vitro insulin secretion from isolated islets in response to 16.7-mM glucose. The level of Glut2 was increased in Psy STR and decreased in both E STR and E + Psy STR groups. Finally, glucose tolerance was impaired and glucose-stimulated insulin secretion was increased in E + Psy STR group. CONCLUSIONS In conclusion, inducing stress in early life makes the organism more susceptible to metabolic defects in exposure to psychological stress later in life.
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Affiliation(s)
- H Zardooz
- Department of Physiology and Neurophysiology Research Center, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - F Sadeghimahalli
- Department of Physiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - F Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme. Biomedicines 2021; 9:biomedicines9010086. [PMID: 33477364 PMCID: PMC7830943 DOI: 10.3390/biomedicines9010086] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/15/2022] Open
Abstract
Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE’s function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.
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50
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Eghbali M, Fatemi KS, Salehpour S, Abiri M, Saei H, Talebi S, Olyaei NA, Yassaee VR, Modarressi MH. Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi-Bickel Syndrome. Front Genet 2021; 11:601566. [PMID: 33505429 PMCID: PMC7831547 DOI: 10.3389/fgene.2020.601566] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/07/2020] [Indexed: 01/08/2023] Open
Abstract
Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG's list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG's list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.
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Affiliation(s)
- Maryam Eghbali
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kiyana Sadat Fatemi
- Dr. Zenali’s Medical Genetics Laboratory, Kawsar Human Genetics Research Center, Tehran, Iran
| | - Shadab Salehpour
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Pediatric Endocrinology and Metabolism, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Abiri
- Shahid Akbarabadi Clinical Research Development Unit, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hassan Saei
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Talebi
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nasrin Alipour Olyaei
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Reza Yassaee
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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