scholarly journals Menaquinone-4 Amplified Glucose-Stimulated Insulin Secretion in Isolated Mouse Pancreatic Islets and INS-1 Rat Insulinoma Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 1995 ◽  
Author(s):  
Hsin-Jung Ho ◽  
Hitoshi Shirakawa ◽  
Keisukei Hirahara ◽  
Hideyuki Sone ◽  
Shin Kamiyama ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Vitamin K2 ◽  
Cell Dysfunction ◽  
Mouse Pancreatic Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulinoma Cells ◽  
Camp Levels ◽  
Dependent Pathway

Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic β-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects.

scholarly journals G6PD Up-Regulation Promotes Pancreatic β-Cell Dysfunction

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 793-803 ◽  
Author(s):  
Joo-Won Lee ◽  
A Hyun Choi ◽  
Mira Ham ◽  
Ji-Won Kim ◽  
Sung Sik Choe ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Cell Apoptosis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Ros Accumulation ◽  
Glucose Stimulated Insulin Secretion ◽  
Reduced Nicotinamide Adenine Dinucleotide

Increased reactive oxygen species (ROS) induce pancreatic β-cell dysfunction during progressive type 2 diabetes. Glucose-6-phosphate dehydrogenase (G6PD) is a reduced nicotinamide adenine dinucleotide phosphate-producing enzyme that plays a key role in cellular reduction/oxidation regulation. We have investigated whether variations in G6PD contribute to β-cell dysfunction through regulation of ROS accumulation and β-cell gene expression. When the level of G6PD expression in pancreatic islets was examined in several diabetic animal models, such as db/db mice and OLEFT rats, G6PD expression was evidently up-regulated in pancreatic islets in diabetic animals. To investigate the effect of G6PD on β-cell dysfunction, we assessed the levels of cellular ROS, glucose-stimulated insulin secretion and β-cell apoptosis in G6PD-overexpressing pancreatic β-cells. In INS-1 cells, G6PD overexpression augmented ROS accumulation associated with increased expression of prooxidative enzymes, such as inducible nitric oxide synthase and reduced nicotinamide adenine dinucleotide phosphate oxidase. G6PD up-regulation also caused decrease in glucose-stimulated insulin secretion in INS-1 cells and primary pancreatic islets. Moreover, elevated G6PD expression led to β-cell apoptosis, concomitant with the increase in proapoptotic gene expression. On the contrary, suppression of G6PD with small interference RNA attenuated palmitate-induced β-cell apoptosis. Together, these data suggest that up-regulation of G6PD in pancreatic β-cells would induce β-cell dysregulation through ROS accumulation in the development of type 2 diabetes.

scholarly journals Preventing p38 MAPK-Mediated MafA Degradation Ameliorates β-Cell Dysfunction under Oxidative Stress

2013 ◽  
Vol 27 (7) ◽  
pp. 1078-1090 ◽  
Author(s):  
Ilham El Khattabi ◽  
Arun Sharma
Keyword(s):  
Oxidative Stress ◽  
Insulin Secretion ◽  
P38 Mapk ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase 3 ◽  
Protein Kinase D ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Glucose Stimulated Insulin Secretion

Abstract The reduction in the expression of glucose-responsive insulin gene transcription factor MafA accompanies the development of β-cell dysfunction under oxidative stress/diabetic milieu. Humans with type 2 diabetes have reduced MafA expression, and thus preventing this reduction could overcome β-cell dysfunction and diabetes. We previously showed that p38 MAPK, but not glycogen synthase kinase 3 (GSK3), is a major regulator of MafA degradation under oxidative stress. Here, we examined the mechanisms of this degradation and whether preventing MafA degradation under oxidative stress will overcome β-cell dysfunction. We show that under oxidative and nonoxidative conditions p38 MAPK directly binds to MafA and triggers MafA degradation via ubiquitin proteasomal pathway. However, unlike nonoxidative conditions, MafA degradation under oxidative stress depended on p38 MAPK-mediated phosphorylation at threonine (T) 134, and not T57. Furthermore the expression of alanine (A) 134-MafA, but not A57-MafA, reduced the oxidative stress-mediated loss of glucose-stimulated insulin secretion, which was independent of p38 MAPK action on protein kinase D, a regulator of insulin secretion. Interestingly, the expression of proteasomal activator PA28γ that degrades GSK3-phosphorylated (including T57) MafA was reduced under oxidative stress, explaining the dominance of p38 MAPK over the GSK3 pathway in regulating MafA stability under oxidative stress. These results identify two distinct pathways mediating p38 MAPK-dependent MafA degradation under oxidative and nonoxidative conditions and show that inhibiting MafA degradation under oxidative stress ameliorates β-cell dysfunction and could lead to novel therapies for diabetes.

scholarly journals Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes

2011 ◽  
Vol 165 (4) ◽  
pp. 589-595 ◽  
Author(s):  
Anders H Olsson ◽  
Beatrice T Yang ◽  
Elin Hall ◽  
Jalal Taneera ◽  
Albert Salehi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Insulin Secretion ◽  
Oxidative Phosphorylation ◽  
Pancreatic Islets ◽  
Human Pancreatic Islets ◽  
Qrt Pcr ◽  
Glucose Stimulated Insulin Secretion

ObjectiveGene expression alterations, especially in target tissues of insulin, have been associated with type 2 diabetes (T2D). In this study, we examined if genes involved in oxidative phosphorylation (OXPHOS) show differential gene expression and DNA methylation in pancreatic islets from patients with T2D compared with non-diabetic donors.Design and methodsGene expression was analyzed in human pancreatic islets from 55 non-diabetic donors and nine T2D donors using microarray.ResultsWhile the expected number of OXPHOS genes with reduced gene expression is 7.21, we identified 21 downregulated OXPHOS genes in pancreatic islets from patients with T2D using microarray analysis. This gives a ratio of observed over expected OXPHOS genes of 26.37 by aχ2-test withP=2.81×10−7. The microarray data was validated by qRT-PCR for four selected OXPHOS genes:NDUFA5, NDUFA10, COX11, andATP6V1H. All four OXPHOS genes were significantly downregulated in islets from patients with T2D compared with non-diabetic donors using qRT-PCR (P≤0.01). Furthermore, HbAlc levels correlated negatively with gene expression ofNDUFA5, COX11, andATP6V1H(P<0.05). Gene expression ofNDUFA5, NDUFA10, COX11, andATP6V1Hcorrelated positively with glucose-stimulated insulin secretion (P<0.03). Finally, DNA methylation was analyzed upstream of the transcription start forNDUFA5, COX11, andATP6V1H. However, none of the analyzed CpG sites in the three genes showed differences in DNA methylation in islets from donors with T2D compared with non-diabetic donors.ConclusionPancreatic islets from patients with T2D show decreased expression of a set of OXPHOS genes, which may lead to impaired insulin secretion.

scholarly journals Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway

2005 ◽  
Vol 152 (4) ◽  
pp. 671-677 ◽  
Author(s):  
Peter Thams ◽  
Mohammad R Anwar ◽  
Kirsten Capito
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Adenylyl Cyclase ◽  
Pancreatic Islets ◽  
Mouse Pancreatic Islets ◽  
Channel Dependent ◽  
Dependent Pathway ◽  
Cyclase Activator ◽  
Kinase A

Objective: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K+ (K+ATP) channel-dependent insulin secretion and in glucose amplification of K+ATP channel-independent insulin secretion. Methods: Insulin release from cultured perifused mouse pancreatic islets was determined by radioimmunoassay. Results: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs–Ringer medium, the PKA inhibitors, H89 (10 μmol/l) and PKI 6–22 amide (30 μmol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion, but inhibited stimulation by the adenylyl cyclase activator, forskolin (10 μmol/l). In the presence of 60 mmol/l K+ and 250 μmol/l diazoxide, which stimulates maximum Ca2+ influx independently of K+ATP channels, H89 (10 μmol/l) inhibited Ca2+-evoked insulin secretion, but failed to prevent glucose amplification of K+ATP channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 μmol/l diazoxide, which cause modest Ca2+ influx, glucose amplification of K+ATP channel-independent insulin secretion was observed without concomitant Ca2+ stimulation of PKA activity. In islets cultured at 16.7 mmol/l glucose, glucose (16.7 mmol/l)-induced insulin secretion in physiological Krebs–Ringer medium was augmented and now inhibited by H89 (10 μmol/l), implicating that culture at 16.7 mmol/l glucose may increase Ca2+-sensitive adenylyl cyclase activity and hence PKA activity. In accordance, Ca2+-evoked insulin secretion at 60 mmol/l K+ and 250 μmol/l diazoxide was improved, whereas glucose amplification of K+ATP channel-independent insulin secretion was unaffected. Conclusions: Glucose may activate PKA through triggering of the K+ATP channel-dependent pathway. Glucose amplification of K+ATP channel-independent insulin secretion, on the other hand, occurs by PKA-independent mechanisms.

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.

scholarly journals Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice

2008 ◽  
Vol 294 (4) ◽  
pp. G1017-G1024 ◽  
Author(s):  
Anthony R. Sheets ◽  
Péter Fülöp ◽  
Zoltán Derdák ◽  
Andrea Kassai ◽  
Edmond Sabo ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Metabolic Response ◽  
Uncoupling Protein ◽  
Serum Insulin ◽  
Uncoupling Protein 2 ◽  
Cell Dysfunction ◽  
Hepatic Fat ◽  
Glucose Stimulated Insulin Secretion

Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in β-cells. Although UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to β-cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2−/− mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates but culminates in protracted steatosis, indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting.

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