[6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pancreatic β-cells and increases RAB8/RAB10-regulated membrane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Leprdb/db type 2 diabetic mice

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.

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γ-Oryzanol Protects Pancreatic β-Cells Against Endoplasmic Reticulum Stress in Male Mice

Endocrinology ◽

10.1210/en.2014-1748 ◽

2015 ◽

Vol 156 (4) ◽

pp. 1242-1250 ◽

Cited By ~ 21

Author(s):

Chisayo Kozuka ◽

Sumito Sunagawa ◽

Rei Ueda ◽

Moritake Higa ◽

Hideaki Tanaka ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Insulin Secretion ◽

Er Stress ◽

High Fat Diet ◽

Diabetic Mice ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Glucose Stimulated Insulin Secretion

Abstract Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

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A Novel TGR5 Activator WB403 Promotes GLP-1 Secretion and Preserves Pancreatic β-Cells in Type 2 Diabetic Mice

PLoS ONE ◽

10.1371/journal.pone.0134051 ◽

2015 ◽

Vol 10 (7) ◽

pp. e0134051 ◽

Cited By ~ 6

Author(s):

Chunbing Zheng ◽

Wenbo Zhou ◽

Tongtong Wang ◽

Panpan You ◽

Yongliang Zhao ◽

...

Keyword(s):

Diabetic Mice ◽

Β Cells ◽

Pancreatic Β Cells ◽

Type 2 Diabetic

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

Endocrine Connections ◽

10.1530/ec-21-0357 ◽

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.

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

Journal of Endocrinology ◽

10.1530/joe-16-0317 ◽

2016 ◽

Vol 231 (2) ◽

pp. 159-165 ◽

Cited By ~ 25

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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Carbon monoxide enhances calcium transients and glucose-stimulated insulin secretion from pancreatic β-cells by activating Phospholipase C signal pathway in diabetic mice

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.10.030 ◽

2021 ◽

Author(s):

Shenghui Liang ◽

Jia Zhao ◽

Quanyi Wang ◽

Min Yang ◽

Xiaozhi Wang ◽

...

Keyword(s):

Carbon Monoxide ◽

Insulin Secretion ◽

Phospholipase C ◽

Signal Pathway ◽

Calcium Transients ◽

Diabetic Mice ◽

Β Cells ◽

Pancreatic Β Cells ◽

Glucose Stimulated Insulin Secretion

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The Nucleosome Binding Protein HMGN3 Modulates the Transcription Profile of Pancreatic β Cells and Affects Insulin Secretion

Molecular and Cellular Biology ◽

10.1128/mcb.00526-09 ◽

2009 ◽

Vol 29 (19) ◽

pp. 5264-5276 ◽

Cited By ~ 20

Author(s):

Tetsuya Ueda ◽

Takashi Furusawa ◽

Toshihiro Kurahashi ◽

Lino Tessarollo ◽

Michael Bustin

Keyword(s):

Insulin Secretion ◽

Glucose Transporter ◽

Specific Binding ◽

Structural Protein ◽

Β Cells ◽

Pancreatic Β Cells ◽

Protein Levels ◽

Glucose Stimulated Insulin Secretion ◽

Nucleosome Binding

ABSTRACT Improper glucose-stimulated insulin secretion from pancreatic β cells is a major factor in the onset of type 2 diabetes. We now report that HMGN3, a nuclear protein that binds to nucleosomes and affects chromatin function, is highly expressed in β cells and that in mice, loss of HMGN3 impairs glucose-stimulated insulin secretion and leads to a diabetic phenotype. In pancreatic β cells, loss of HMGN3 affects the transcription of several genes involved in glucose-stimulated insulin secretion, including that of the Glut2 glucose transporter. Chromatin immunoprecipitation reveals that HMGN3 and the transcription factor PDX1 mutually reinforce their specific binding to the chromatin in the promoter of the Glut2 gene, thereby regulating GLUT2 protein levels in pancreatic islets and in β cells. Our results identify a new regulator of glucose homeostasis and demonstrate a link between the activity of a nucleosome binding structural protein and the regulation of insulin secretion.

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