Activation of autophagy through modulation of 5′-AMP-activated protein kinase protects pancreatic β-cells from high glucose

2010 ◽  
Vol 425 (3) ◽  
pp. 541-551 ◽  
Author(s):  
Diana Han ◽  
Byungho Yang ◽  
L. Karl Olson ◽  
Alexander Greenstein ◽  
Seung-Hoon Baek ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Survival ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

Chronic hyperglycaemia is detrimental to pancreatic β-cells by causing impaired insulin secretion and diminished β-cell function through glucotoxicity. Understanding the mechanisms underlying β-cell survival is crucial for the prevention of β-cell failure associated with glucotoxicity. Autophagy is a dynamic lysosomal degradation process that protects organisms against metabolic stress. To date, little is known about the physiological function of autophagy in the pathogenesis of diabetes. In the present study, we explored the roles of autophagy in the survival of pancreatic β-cells exposed to high glucose using pharmacological and genetic manipulation of autophagy. We demonstrated that chronic high glucose increases autophagy in rat INS-1 (832/13) cells and pancreatic islets, and that this increase is enhanced by inhibition of 5′-AMP-activated protein kinase. Our results also indicate that stimulation of autophagy rescues pancreatic β-cells from high-glucose-induced cell death and inhibition of autophagy augments caspase-3 activation, suggesting that autophagy plays a protective role in the survival of pancreatic β-cells. Greater knowledge of the molecular mechanisms linking autophagy and β-cell survival may unveil novel therapeutic targets needed to preserve β-cell function.

scholarly journals AMP-activated protein kinase agonist dose dependently improves function and reduces apoptosis in glucotoxic β-cells without changing triglyceride levels

2008 ◽  
Vol 41 (3) ◽  
pp. 187-194 ◽  
Author(s):  
Hanna K Nyblom ◽  
Ernest Sargsyan ◽  
Peter Bergsten
Keyword(s):  
Protein Kinase ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Downstream Target ◽  
Homologous Protein ◽  
Prolonged Culture ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Amp Activated Protein Kinase

Prolonged hyperglycaemia leads to impaired glucose-stimulated insulin secretion (GSIS) and apoptosis in insulin-producing β-cells. The detrimental effects have been connected with glucose-induced lipid accumulation in the β-cell. AMP-activated protein kinase (AMPK) agonist, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), promotes utilization of nutrient stores for energy production. It was tested how impaired GSIS and elevated apoptosis observed in insulinoma (INS)-1E cells after prolonged culture at 27 mM glucose were affected by the inclusion of 0.3 or 1 mM AICAR during culture. Glucose-induced impairment of insulin release was reverted by the inclusion of 0.3 but not 1 mM AICAR, which did not affect insulin content. The glucose-induced rise in triglyceride (TG) content observed in the cells cultured at 27 mM glucose was not altered by the inclusion of either 0.3 or 1 mM AICAR. Inclusion of 1 but not 0.3 mM AICAR during culture induced phosphorylation of AMPK and its downstream target acyl-CoA carboxylase. Phosphorylation was paralleled by reduced number of apoptotic cells and lowered expression of pro-apoptotic C/EBP homologous protein (CHOP). In conclusion, AICAR dose dependently improves β-cell function and reduces apoptosis in β-cells exposed to prolonged hyperglycaemia without changing TG levels.

BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner

2009 ◽  
Vol 296 (2) ◽  
pp. C346-C354 ◽  
Author(s):  
Fan Zhang ◽  
Deben Dey ◽  
Robert Bränström ◽  
Lars Forsberg ◽  
Ming Lu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
High Glucose ◽  
Cell Function ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

BLX-1002 is a novel small thiazolidinedione with no apparent affinity to peroxisome proliferator-activated receptors (PPAR) that has been shown to reduce glycemia in type 2 diabetes without adipogenic effects. Its precise mechanisms of action, however, remain elusive, and no studies have been done with respect to possible effects of BLX-1002 on pancreatic β-cells. We have investigated the influence of the drug on β-cell function in mouse islets in vitro. BLX-1002 enhanced insulin secretion stimulated by high, but not low or intermediate, glucose concentrations. BLX-1002 also augmented cytoplasmic free Ca2+ concentration ([Ca2+]i) at high glucose, an effect that was abolished by pretreatment with the Ca2+-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca2+ channel or ATP-sensitive K+ channel activities. In addition, cellular NAD(P)H stimulated by glucose was not affected by the drug. The stimulatory effect of BLX-1002 on insulin secretion at high glucose was completely abolished by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY-294002. Stimulation of the β-cells with BLX-1002 also induced activation of AMP-activated protein kinase (AMPK) at high glucose. Our study suggests that BLX-1002 potentiates insulin secretion only at high glucose in β-cells in a PI3K-dependent manner. This effect of BLX-1002 is associated with an increased [Ca2+]i mediated through Ca2+ mobilization, and an enhanced activation of AMPK. The glucose-sensitive stimulatory impact of BLX-1002 on β-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.

scholarly journals FMK, an Inhibitor of p90RSK, Inhibits High Glucose-Induced TXNIP Expression via Regulation of ChREBP in Pancreatic β Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4424
Author(s):  
Jung-Hwa Han ◽  
Suji Kim ◽  
Suji Kim ◽  
Heejung Lee ◽  
So-Young Park ◽  
...  
Keyword(s):  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Ros Generation ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Interacting Protein ◽  
Cell Dysfunction

Hyperglycemia is the major characteristic of diabetes mellitus, and a chronically high glucose (HG) level causes β-cell glucolipotoxicity, which is characterized by lipid accumulation, impaired β-cell function, and apoptosis. TXNIP (Thioredoxin-interacting protein) is a key mediator of diabetic β-cell apoptosis and dysfunction in diabetes, and thus, its regulation represents a therapeutic target. Recent studies have reported that p90RSK is implicated in the pathogenesis of diabetic cardiomyopathy and nephropathy. In this study, we used FMK (a p90RSK inhibitor) to determine whether inhibition of p90RSK protects β-cells from chronic HG-induced TXNIP expression and to investigate the molecular mechanisms underlying the effect of FMK on its expression. In INS-1 pancreatic β-cells, HG-induced β-cell dysfunction, apoptosis, and ROS generation were significantly diminished by FMK. In contrast BI-D1870 (another p90RSK inhibitor) did not attenuate HG-induced TXNIP promoter activity or TXNIP expression. In addition, HG-induced nuclear translocation of ChREBP and its transcriptional target molecules were found to be regulated by FMK. These results demonstrate that HG-induced pancreatic β-cell dysfunction resulting in HG conditions is associated with TXNIP expression, and that FMK is responsible for HG-stimulated TXNIP gene expression by inactivating the regulation of ChREBP in pancreatic β-cells. Taken together, these findings suggest FMK may protect against HG-induced β-cell dysfunction and TXNIP expression by ChREBP regulation in pancreatic β-cells, and that FMK is a potential therapeutic reagent for the drug development of diabetes and its complications.

scholarly journals Selenoprotein P as a significant regulator of pancreatic β cell function

2019 ◽  
Author(s):  
Yoshiro Saito
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Insulin Signalling ◽  
Selenoprotein P ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Abstract Selenoprotein P (SeP; encoded by SELENOP) is selenium (Se)-rich plasma protein that is mainly produced in the liver. SeP functions as a Se-transport protein to deliver Se from the liver to other tissues, such as the brain and testis. The protein plays a pivotal role in Se metabolism and antioxidative defense, and it has been identified as a ‘hepatokine’ that causes insulin resistance in type 2 diabetes. SeP levels are increased in type 2 diabetes patients, and excess SeP impairs insulin signalling, promoting insulin resistance. Furthermore, increased levels of SeP disturb the functioning of pancreatic β cells and inhibit insulin secretion. This review focuses on the biological function of SeP and the molecular mechanisms associated with the adverse effects of excess SeP on pancreatic β cells’ function, particularly with respect to redox reactions. Interactions between the liver and pancreas are also discussed.

scholarly journals Optical control of GPR40 signalling in pancreatic β-cells

2017 ◽  
Vol 8 (11) ◽  
pp. 7604-7610 ◽  
Author(s):  
James Allen Frank ◽  
Dmytro A. Yushchenko ◽  
Nicholas H. F. Fine ◽  
Margherita Duca ◽  
Mevlut Citir ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Function ◽  
Optical Control ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Fatty acids activate GPR40 and K+ channels to modulate β-cell function.

scholarly journals Oxytocin signal contributes to the adaptative growth of islets during gestation

2021 ◽  
Author(s):  
Ping Gu ◽  
Yuege Lin ◽  
Qi Wan ◽  
Dongming Su ◽  
Qun Shu
Keyword(s):  
Insulin Secretion ◽  
Pregnant Women ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Adaptation ◽  
Β Cell Function ◽  
Insulinoma Cells

Background: Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or in gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy. Methods: The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells. Results: The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A three-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells. Conclusions: These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and lack of oxytocin could be associated with the risk of GDM.

Calcium and pancreatic β-cell function. 12. Modification of 45Ca fluxes by excess of K+

1981 ◽  
Vol 96 (1) ◽  
pp. 87-92 ◽  
Author(s):  
T. Andersson ◽  
C. Betsholtz ◽  
B. Hellman
Keyword(s):  
Cell Function ◽  
Secretory Granules ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Deficient Medium ◽  
Β Cell Function ◽  
Cell Handling ◽  
Stimulation Of ◽  
Glucose Effects

Abstract. Glucose stimulation of insulin release is supposed to result from depolarization of the pancreatic β-cells with subsequent influx of Ca2+. Isolated islets from non-inbred ob/ob-mice were employed for elucidating whether the glucose effects on the β-cell handling of Ca2+ could be simulated by the depolarization evoked by excess of K+. Addition of 25 mm K+ was as effective as 20 mm glucose in stimulating the intracellular uptake of 45Ca. In both instances the additional amounts of incorporated 45Ca appeared in the mitochondria and the secretory granules. When analysing the washout pattern for 45Ca it was evident that the effects of raising K+ differed from those evoked by glucose. Whereas glucose inhibited 45Ca efflux during perifusion with Ca2+-deficient medium the addition of K+ resulted in a slight stimulation. Furthermore, the 45Ca incorporated in response to K+ was more readily mobilised.

Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

2018 ◽  
Vol 460 ◽  
pp. 47-56 ◽  
Author(s):  
Marie Balslev Backe ◽  
Jan Legaard Andersson ◽  
Karl Bacos ◽  
Dan Ploug Christensen ◽  
Jakob Bondo Hansen ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function ◽  
Lysine Demethylase

scholarly journals A Putative Prohibitin-Calcium Nexus in β-Cell Mitochondria and Diabetes

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Gaurav Verma ◽  
Aparna Dixit ◽  
Craig S. Nunemaker
Keyword(s):  
Cell Function ◽  
Mitochondrial Protein ◽  
Active Role ◽  
Targeted Drugs ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function ◽  
Significant Attention

The role of mitochondria in apoptosis is well known; however, the mechanisms linking mitochondria to the proapoptotic effects of proinflammatory cytokines, hyperglycemia, and glucolipotoxicity are not completely understood. Complex Ca2+ signaling has emerged as a critical contributor to these proapoptotic effects and has gained significant attention in regulating the signaling processes of mitochondria. In pancreatic β-cells, Ca2+ plays an active role in β-cell function and survival. Prohibitin (PHB), a mitochondrial chaperone, is actively involved in maintaining the architecture of mitochondria. However, its possible interaction with Ca2+-activated signaling pathways has not been explored. The present review aims to examine potential crosstalk between Ca2+ signaling and PHB function in pancreatic β-cells. Moreover, this review will focus on the effects of cytokines and glucolipotoxicity on Ca2+ signaling and its possible interaction with PHB. Improved understanding of this important mitochondrial protein may aid in the design of more targeted drugs to identify specific pathways involved with stress-induced dysfunction in the β-cell.

scholarly journals Over-expression of AMP-activated protein kinase impairs pancreatic β-cell function in vivo

2005 ◽  
Vol 187 (2) ◽  
pp. 225-235 ◽  
Author(s):  
S K Richards ◽  
L E Parton ◽  
I Leclerc ◽  
G A Rutter ◽  
R M Smith
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Islet Transplantation ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Over Expression ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

Treatment of type 1 diabetes by islet transplantation is currently limited by loss of functional β-cell mass after transplantation. We investigated here whether adenovirus-mediated changes in AMP-activated protein kinase (AMPK) activity, previously shown to affect insulin secretion in vitro, might affect islet graft function in vivo. In isolated mouse and rat islets, insulin secretion stimulated by 17 (vs 3) mmol/l glucose was inhibited by 36.5% (P<0.01) and 43% (P<0.02) respectively after over-expression of constitutively-active AMPK- (AMPK CA) versus null (eGFP-expressing) viruses, and glucose oxidation was decreased by 38% (P<0.05) and 26.6% (P<0.05) respectively. Increases in apoptotic index (terminal deoxynucleotide transferase-mediated deoxyuridine trisphosphate biotin nick end-labelling) (TUNEL)) were also observed in AMPK CA- (22.8 ± 3.6% TUNEL-positive cells, P<0.001), but not AMPK DN- (2.72 ± 3.9%, positive cells, P=0.05) infected islets, versus null adenovirus-treated islets (0.68 ± 0.36% positive cells). Correspondingly, transplantation of islets expressing AMPK CA into streptozotocin-diabetic C57 BL/6 mice improved glycaemic control less effectively than transplantation with either null (P<0.02) or AMPK-DN-infected (P<0.01) islets. We conclude that activation of AMPK inhibits β-cell function in vivo and may represent a target for therapeutic intervention during islet transplantation.

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