scholarly journals Regulation and functional effects of ZNT8 in human pancreatic islets

2012 ◽  
Vol 214 (2) ◽  
pp. 225-232 ◽  
Author(s):  
Bruno Lefebvre ◽  
Brigitte Vandewalle ◽  
Anne-Sophie Balavoine ◽  
Gurvan Queniat ◽  
Ericka Moerman ◽  
...  
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Metabolic Stress ◽  
Human Islets ◽  
Β Cells ◽  
Prediabetic State ◽  
Zinc Depletion ◽  
Packaging Efficiency ◽  
Glucose Stimulated Insulin Secretion

Zinc ions are essential for the formation of insulin crystals in pancreatic β cells, thereby contributing to packaging efficiency of stored insulin. Zinc fluxes are regulated through the SLC30A (zinc transporter, ZNT) family. Here, we investigated the effect of metabolic stress associated with the prediabetic state (zinc depletion, glucotoxicity, and lipotoxicity) on ZNT expression and human pancreatic islet function. Both zinc depletion and lipotoxicity (but not glucotoxicity) downregulatedZNT8(SLC30A8) expression and altered the glucose-stimulated insulin secretion index (GSIS).ZNT8overexpression in human islets protected them from the decrease in GSIS induced by tetrakis-(2-pyridylmethyl) ethylenediamine and palmitate but not from cell death. In addition, zinc supplementation decreased palmitate-induced human islet cell death without restoring GSIS. Altogether, we showed thatZNT8expression responds to variation in zinc and lipid levels in human β cells, with repercussions on insulin secretion. Prospects for increasingZNT8expression and/or activity may prove beneficial in type 2 diabetes in humans.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

scholarly journals L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jaeyong Cho ◽  
Yukio Horikawa ◽  
Mayumi Enya ◽  
Jun Takeda ◽  
Yoichi Imai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Direct Stimulation ◽  
Glucose Ratio ◽  
Glucose Stimulated Insulin Secretion

Abstract We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in β-cells by finding a protein with affinity to L-arginine using arginine-immobilized magnetic nanobeads technology. Glucokinase (GCK), the key regulator of GSIS and a disease-causing gene of maturity-onset diabetes of the young type 2 (MODY2), was found to bind L-arginine. L-Arginine stimulated production of glucose-6-phosphate (G6P) and induced insulin secretion. We analyzed glucokinase mutants and identified three glutamate residues that mediate binding to L-arginine. One MODY2 patient with GCKE442* demonstrated lower C-peptide-to-glucose ratio after arginine administration. In β-cell line, GCKE442* reduced L-arginine-induced insulin secretion compared with GCKWT. In addition, we elucidated that the binding of arginine protects glucokinase from degradation by E3 ubiquitin ligase cereblon mediated ubiquitination. We conclude that L-arginine induces insulin secretion by increasing G6P production by glucokinase through direct stimulation and by prevention of degradation.

scholarly journals Metabolic cycling in control of glucose-stimulated insulin secretion

2008 ◽  
Vol 295 (6) ◽  
pp. E1287-E1297 ◽  
Author(s):  
Mette V. Jensen ◽  
Jamie W. Joseph ◽  
Sarah M. Ronnebaum ◽  
Shawn C. Burgess ◽  
A. Dean Sherry ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pyruvate Metabolism ◽  
Coupling Factors ◽  
Stimulus Secretion Coupling ◽  
Channel Dependent ◽  
Glucose Stimulated Insulin Secretion ◽  
Dependent Mechanism

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of β-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in β-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K+ (KATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. Whereas this KATP channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet β-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and α-ketoglutarate, in control of GSIS.

Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion

2004 ◽  
Vol 286 (6) ◽  
pp. E1023-E1031 ◽  
Author(s):  
Isabelle Leclerc ◽  
Wolfram W. Woltersdorf ◽  
Gabriela da Silva Xavier ◽  
Rebecca L. Rowe ◽  
Sarah E. Cross ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Pancreatic Islets ◽  
Human Islets ◽  
Β Cells ◽  
Min6 Cells ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761–774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2–1 mM) activated AMPK in both human islets and MIN6 β-cells in parallel with an inhibition of insulin secretion, whereas leptin (10–100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal β-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.

scholarly journals Minireview: Intraislet Regulation of Insulin Secretion in Humans

2013 ◽  
Vol 27 (12) ◽  
pp. 1984-1995 ◽  
Author(s):  
Guy A. Rutter ◽  
David J. Hodson
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Cell Activity ◽  
Cell Communication ◽  
Human Islets ◽  
Β Cells ◽  
Cell Cell

The higher organization of β-cells into spheroid structures termed islets of Langerhans is critical for the proper regulation of insulin secretion. Thus, rodent β-cells form a functional syncytium that integrates and propagates information encoded by secretagogues, producing a “gain-of-function” in hormone release through the generation of coordinated cell-cell activity. By contrast, human islets possess divergent topology, and this may have repercussions for the cell-cell communication pathways that mediate the population dynamics underlying the intraislet regulation of insulin secretion. This is pertinent for type 2 diabetes mellitus pathogenesis, and its study in rodent models, because environmental and genetic factors may converge on these processes in a species-specific manner to precipitate the defective insulin secretion associated with glucose intolerance. The aim of the present minireview is therefore to discuss the structural and functional underpinnings that influence insulin secretion from human islets, and the possibility that dyscoordination between individual β-cells may play an important role in some forms of type 2 diabetes mellitus.

scholarly journals Resveratrol Potentiates Glucose-stimulated Insulin Secretion in INS-1E β-Cells and Human Islets through a SIRT1-dependent Mechanism

2010 ◽  
Vol 286 (8) ◽  
pp. 6049-6060 ◽  
Author(s):  
Laurène Vetterli ◽  
Thierry Brun ◽  
Laurianne Giovannoni ◽  
Domenico Bosco ◽  
Pierre Maechler
Keyword(s):  
Insulin Secretion ◽  
Human Islets ◽  
Β Cells ◽  
Glucose Stimulated Insulin Secretion ◽  
Dependent Mechanism

scholarly journals Angiotensin(1–7) activates MAS-1 and upregulates CFTR to promote insulin secretion in pancreatic β-cells: the association with type 2 diabetes

2021 ◽  
Author(s):  
Xue-Lian Zhang ◽  
Xinyi Zhao ◽  
Yong Wu ◽  
Wen-qing Huang ◽  
Jun-jiang Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Human Blood ◽  
Human Subjects ◽  
Blood Levels ◽  
Intracellular Camp ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Objective: The beneficial effect of angiotensin(1–7), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how angiotensin(1–7) or MAS-1 affects insulin secretion remains elusive and whether endogenous level of angiotensin(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of CFTR, a cAMP-activated Cl- channel, in regulation of insulin secretion. Here, we tested possible involvement of CFTR in mediating angiotensin(1–7)’s effect on insulin secretion and measured the level of angiotensin(1–7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes. Methods: Angiotensin(1–7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, western blotting as well as insulin ELISA in a pancreatic β cell line, RINm5F. Human blood samples were collected from 333 individuals with (n=197) and without (n=136) type 2 diabetes. Angiotensin(1–7), MAS-1 and CFTR level in the human blood were determined by ELISA. Results: In RINm5F cells, angiotensin(1–7) induced intracellular cAMP increase, CREB activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not angiotensin(1–7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2-diabetic but not non-diabetic subjects. Conclusion: These results suggested MAS-1 and CFTR as key players in mediating angiotensin(1–7)-promoted insulin secretion in pancreatic β cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

scholarly journals Perilipin Is Present in Islets of Langerhans and Protects against Lipotoxicity When Overexpressed in the β-Cell Line INS-1

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3049-3057 ◽  
Author(s):  
Jörgen Borg ◽  
Cecilia Klint ◽  
Nils Wierup ◽  
Kristoffer Ström ◽  
Sara Larsson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Line ◽  
Islets Of Langerhans ◽  
Prolonged Exposure ◽  
Human Islets ◽  
Lipid Storage ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
In Cells

Lipids have been shown to play a dual role in pancreatic β-cells: a lipid-derived signal appears to be necessary for glucose-stimulated insulin secretion, whereas lipid accumulation causes impaired insulin secretion and apoptosis. The ability of the protein perilipin to regulate lipolysis prompted an investigation of the presence of perilipin in the islets of Langerhans. In this study evidence is presented for perilipin expression in rat, mouse, and human islets of Langerhans as well as the rat clonal β-cell line INS-1. In rat and mouse islets, perilipin was verified to be present in β-cells. To examine whether the development of lipotoxicity could be prevented by manipulating the conditions for lipid storage in the β-cell, INS-1 cells with adenoviral-mediated overexpression of perilipin were exposed to lipotoxic conditions for 72 h. In cells exposed to palmitate, perilipin overexpression caused increased accumulation of triacylglycerols and decreased lipolysis compared with control cells. Whereas glucose-stimulated insulin secretion was retained after palmitate exposure in cells overexpressing perilipin, it was completely abolished in control β-cells. Thus, overexpression of perilipin appears to confer protection against the development of β-cell dysfunction after prolonged exposure to palmitate by promoting lipid storage and limiting lipolysis.

scholarly journals Dopamine-Mediated Autocrine Inhibitory Circuit Regulating Human Insulin Secretion in Vitro

2012 ◽  
Vol 26 (10) ◽  
pp. 1757-1772 ◽  
Author(s):  
Norman Simpson ◽  
Antonella Maffei ◽  
Matthew Freeby ◽  
Steven Burroughs ◽  
Zachary Freyberg ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Secretory Granules ◽  
Human Islets ◽  
Negative Regulator ◽  
Β Cells ◽  
Regulatory Circuit ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Secretion In Vitro

Abstract We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity.

scholarly journals SIRT6 protects against palmitate-induced pancreatic β-cell dysfunction and apoptosis

2016 ◽  
Vol 231 (2) ◽  
pp. 159-165 ◽  
Author(s):  
Xiwen Xiong ◽  
Xupeng Sun ◽  
Qingzhi Wang ◽  
Xinlai Qian ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mrna Levels ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulation ◽  
Cell Dysfunction ◽  
High Concentrations ◽  
Glucose Stimulated Insulin Secretion

Chronic exposure of pancreatic β-cells to abnormally elevated levels of free fatty acids can lead to β-cell dysfunction and even apoptosis, contributing to type 2 diabetes pathogenesis. In pancreatic β-cells, sirtuin 6 (SIRT6) has been shown to regulate insulin secretion in response to glucose stimulation. However, the roles played by SIRT6 in β-cells in response to lipotoxicity remain poorly understood. Our data indicated that SIRT6 protein and mRNA levels were reduced in islets from diabetic and aged mice. High concentrations of palmitate (PA) also led to a decrease in SIRT6 expression in MIN6 β-cells and resulted in cell dysfunction and apoptosis. Knockdown of Sirt6 caused an increase in cell apoptosis and impairment in insulin secretion in response to glucose in MIN6 cells even in the absence of PA exposure. Furthermore, overexpression of SIRT6 alleviated the palmitate-induced lipotoxicity with improved cell viability and increased glucose-stimulated insulin secretion. In summary, our data suggest that SIRT6 can protect against palmitate-induced β-cell dysfunction and apoptosis.

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