scholarly journals Pancreatic β-cells respond to fuel pressure with an early metabolic switch

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ronja M. Malinowski ◽  
Seyed M. Ghiasi ◽  
Thomas Mandrup-Poulsen ◽  
Sebastian Meier ◽  
Mathilde H. Lerche ◽  
...  
Keyword(s):  
Cell Metabolism ◽  
Polyol Pathway ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Metabolic Switch ◽  
Cell Dysfunction ◽  
Similar Quantity ◽  
Glucose Stimulated Insulin Secretion

Abstract Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. The β-cells are not able to control glucose uptake and they are therefore left vulnerable for endogenous toxicity from metabolites produced in excess amounts upon increased glucose availability. In order to handle excess fuel, the β-cells possess specific metabolic pathways, but little is known about these pathways. We present a study of β-cell metabolism under increased fuel pressure using a stable isotope resolved NMR approach to investigate early metabolic events leading up to β-cell dysfunction. The approach is based on a recently described combination of 13C metabolomics combined with signal enhanced NMR via dissolution dynamic nuclear polarization (dDNP). Glucose-responsive INS-1 β-cells were incubated with increasing concentrations of [U-13C] glucose under conditions where GSIS was not affected (2–8 h). We find that pyruvate and DHAP were the metabolites that responded most strongly to increasing fuel pressure. The two major divergence pathways for fuel excess, the glycerolipid/fatty acid metabolism and the polyol pathway, were found not only to operate at unchanged rate but also with similar quantity.

scholarly journals Activation of ATP-sensitive potassium channels in rat pancreatic β-cells by linoleic acid through both intracellular metabolites and membrane receptor signalling pathway

2008 ◽  
Vol 198 (3) ◽  
pp. 533-540 ◽  
Author(s):  
Yu-Feng Zhao ◽  
Jianming Pei ◽  
Chen Chen
Keyword(s):  
Linoleic Acid ◽  
Potassium Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Intracellular Metabolites ◽  
Cell Dysfunction ◽  
Triacsin C ◽  
Glucose Stimulated Insulin Secretion ◽  
G Protein Coupled

ATP-sensitive potassium channels (KATP channels) determine the excitability of pancreatic β-cells and importantly regulate glucose-stimulated insulin secretion (GSIS). Long-chain free fatty acids (FFAs) decrease GSIS after long-term exposure to β-cells, but the effects of exogenous FFAs on KATP channels are not yet well clarified. In this study, the effects of linoleic acid (LA) on membrane potential (MP) and KATP channels were observed in primary cultured rat pancreatic β-cells. LA (20 μM) induced hyperpolarization of MP and opening of KATP channels, which was totally reversed and inhibited by tolbutamide, a KATP channel blocker. Inhibition of LA metabolism by acyl-CoA synthetase inhibitor, triacsin C (10 μM), partially inhibited LA-induced opening of KATP channels by 64%. The non-FFA G protein-coupled receptor (GPR) 40 agonist, GW9508 (40 μM), induced an opening of KATP channels, which was similar to that induced by LA under triacsin C treatment. Blockade of protein kinases A and C did not influence the opening of KATP channels induced by LA and GW9508, indicating that these two protein kinase pathways are not involved in the action of LA on KATP channels. The present study demonstrates that LA induces hyperpolarization of MP by activating KATP channels via both intracellular metabolites and activation of GPR40. It indicates that not only intracellular metabolites of FFAs but also GPR40-mediated pathways take part in the inhibition of GSIS and β-cell dysfunction induced by FFAs.

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 Hypoxylonol F Isolated from Annulohypoxylon annulatum Improves Insulin Secretion by Regulating Pancreatic β-cell Metabolism

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 335 ◽  
Author(s):  
Dahae Lee ◽  
Buyng Su Hwang ◽  
Pilju Choi ◽  
Taejung Kim ◽  
Youngseok Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Molecular Mechanisms ◽  
Cell Metabolism ◽  
Peroxisome Proliferator ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Stimulated Insulin Secretion

Insulin plays a key role in glucose homeostasis and is hence used to treat hyperglycemia, the main characteristic of diabetes mellitus. Annulohypoxylon annulatum is an inedible ball-shaped wood-rotting fungus, and hypoxylon F is one of the major compounds of A. annulatum. The aim of this study is to evaluate the effects of hypoxylonol F isolated from A. annulatum on insulin secretion in INS-1 pancreatic β-cells and demonstrate the molecular mechanisms involved. Glucose-stimulated insulin secretion (GSIS) values were evaluated using a rat insulin ELISA kit. Moreover, the expression of proteins related to pancreatic β-cell metabolism and insulin secretion was evaluated using Western blotting. Hypoxylonol F isolated from A. annulatum was found to significantly enhance glucose-stimulated insulin secretion without inducing cytotoxicity. Additionally, hypoxylonol F enhanced insulin receptor substrate-2 (IRS-2) levels and activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Interestingly, it also modulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic and duodenal homeobox 1 (PDX-1). Our findings showed that A. annulatum and its bioactive compounds are capable of improving insulin secretion by pancreatic β-cells. This suggests that A. annulatum can be used as a therapeutic agent to treat diabetes.

scholarly journals 5-Bromoprotocatechualdehyde Combats against Palmitate Toxicity by Inhibiting Parkin Degradation and Reducing ROS-Induced Mitochondrial Damage in Pancreatic β-Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 264
Author(s):  
Seon-Heui Cha ◽  
Chunying Zhang ◽  
Soo-Jin Heo ◽  
Hee-Sook Jun
Keyword(s):  
Cell Loss ◽  
Cellular Damage ◽  
Mitochondrial Morphology ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Zebrafish Model ◽  
Cell Dysfunction ◽  
Glucose Stimulated Insulin Secretion

Pancreatic β-cell loss is critical in diabetes pathogenesis. Up to now, no effective treatment has become available for β-cell loss. A polyphenol recently isolated from Polysiphonia japonica, 5-Bromoprotocatechualdehyde (BPCA), is considered as a potential compound for the protection of β-cells. In this study, we examined palmitate (PA)-induced lipotoxicity in Ins-1 cells to test the protective effects of BPCA on insulin-secreting β-cells. Our results demonstrated that BPCA can protect β-cells from PA-induced lipotoxicity by reducing cellular damage, preventing reactive oxygen species (ROS) overproduction, and enhancing glucose-stimulated insulin secretion (GSIS). BPCA also improved mitochondrial morphology by preserving parkin protein expression. Moreover, BPCA exhibited a protective effect against PA-induced β-cell dysfunction in vivo in a zebrafish model. Our results provide strong evidence that BPCA could be a potential therapeutic agent for the management of diabetes.

Chlorogenic acid and β-glucan from highland barley grain ameliorate β cell dysfunction via inhibiting apoptosis and improving cell proliferation

2021 ◽  
Author(s):  
Zehua Liu ◽  
Bo Li
Keyword(s):  
Cell Proliferation ◽  
Chlorogenic Acid ◽  
Barley Grain ◽  
Whole Grain ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Active Compounds ◽  
Cell Dysfunction ◽  
Highland Barley

Recent studies support the view that highland barley as whole grain diet showed anti-hyperglycemic effects, while little information is available about the active compounds that could ameliorate pancreatic β cells...

scholarly journals Peroxisome Proliferator-Activated Receptor α (PPARα) Potentiates, whereas PPARγ Attenuates, Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3266-3276 ◽  
Author(s):  
Kim Ravnskjaer ◽  
Michael Boergesen ◽  
Blanca Rubi ◽  
Jan K. Larsen ◽  
Tina Nielsen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mitochondrial Membrane ◽  
Uncoupling Protein ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Stimulated Insulin Secretion

Abstract Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic β-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of β-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARα and retinoid X receptor α (RXRα) in INS-1E β-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARα target genes and enhances FA uptake and β-oxidation. In contrast, ectopic expression of PPARγ/RXRα increases FA uptake and deposition as triacylglycerides. Although the expression of PPARα/RXRα leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARγ/RXRα attenuates GSIS, the expression of PPARα/RXRα potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes α and γ on lipid partitioning and insulin secretion when systematically compared in a β-cell context.

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 The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells

2020 ◽  
Vol 117 (45) ◽  
pp. 28307-28315
Author(s):  
Baile Wang ◽  
Huige Lin ◽  
Xiaomu Li ◽  
Wenqi Lu ◽  
Jae Bum Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Adaptor Protein ◽  
Hek293 Cells ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Actin Remodeling ◽  
Actin Depolymerization ◽  
Glucose Stimulated Insulin Secretion

Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells.

scholarly journals Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

MedChemComm ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 280-293
Author(s):  
Anna Munder ◽  
Yoni Moskovitz ◽  
Aviv Meir ◽  
Shirin Kahremany ◽  
Laura Levy ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cellular Stress ◽  
Pamam Dendrimers ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Functions ◽  
Functional Maturation ◽  
Glucose Stimulated Insulin Secretion

The nanoscale composite improved β-cell functions in terms of rate of proliferation, glucose-stimulated insulin secretion, resistance to cellular stress and functional maturation.

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.

Sign in / Sign up

Export Citation Format

Share Document