scholarly journals Long-term inhibition of protein tyrosine kinase impairs electrophysiologic activity and a rapid component of exocytosis in pancreatic β-cells

2005 ◽  
Vol 35 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Yu-Feng Zhao ◽  
Damien J Keating ◽  
Maria Hernandez ◽  
Dan Dan Feng ◽  
Yulong Zhu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Protein Tyrosine ◽  
Cell Dysfunction ◽  
Genistein Treatment

Dysfunction of pancreatic β-cells is a fundamental feature in the pathogenesis of type 2 diabetes. As insulin receptor signaling occurs via protein tyrosine kinase (PTK), we investigated the role of PTK activity in the etiology of β-cell dysfunction by inhibiting PTK activity in primary cultured mouse pancreatic β-cells and INS-1 cells with genistein treatment over 24 h. Electrophysiologic recordings showed genistein treatment significantly attenuated ATP-sensitive K+ (KATP) and voltage-dependent Ca2+ currents, and depolarized the resting membrane potential in primary β-cells. When stimulated by high glucose, genistein-treated β-cells exhibited a time delay of both depolarization and Ca2+ influx, and were unable to fire action potentials, as well as displaying a reduced level of Ca2+ influx and a loss of Ca2+ oscillations. Semiquantitative PCR analysis revealed decreased expression of KATP and L-type Ca2+ channel mRNA in genistein-treated islets. PTK inhibition also significantly reduced the rapid component of secretory vesicle exocytosis, as indicated by membrane capacitance measurements, and this is likely to be due to the reduced Ca2+ current amplitude in these cells. These results illustrate that compromised PTK activity contributes to pancreatic β-cell dysfunction and may be involved in the etiology of type 2 diabetes.

Arachidonic acid fights palmitate: new insights into fatty acid toxicity in β-cells

2010 ◽  
Vol 120 (5) ◽  
pp. 179-181 ◽  
Author(s):  
Henrik Ortsäter
Keyword(s):  
Type 2 Diabetes ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Saturated Fatty Acids ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Self Protection

Saturated fatty acids are toxic to pancreatic β-cells. By inducing apoptosis, they contribute to a decrease in β-cell mass, a hallmark of Type 2 diabetes. In the present issue of Clinical Science, Keane and co-workers show that the polyunsaturated fatty acid arachidonic acid protects the β-cell against the toxic effects of palmitate. As Type 2 diabetes is characterized by subclinical inflammation, and arachidonic acid and metabolites thereof are produced during states of inflammation, it is possible that pancreatic β-cells use arachidonic acid as a compound for self-protection.

scholarly journals Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1682
Author(s):  
Jeanne Guitton ◽  
Cécile L. Bandet ◽  
Mohamed L. Mariko ◽  
Sophie Tan-Chen ◽  
Olivier Bourron ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Current Knowledge ◽  
Sphingolipid Metabolism ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Sphingosine 1 Phosphate

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway.

scholarly journals Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

2015 ◽  
Vol 93 (5) ◽  
pp. 511-521 ◽  
Author(s):  
Tasnim Dayeh ◽  
Charlotte Ling
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin Secretion ◽  
Expression Of Genes ◽  
Impaired Insulin

β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

Novel roles of SUMO in pancreatic β-cells: thinking outside the nucleus

2012 ◽  
Vol 90 (6) ◽  
pp. 765-770 ◽  
Author(s):  
Jocelyn E. Manning Fox ◽  
Catherine Hajmrle ◽  
Patrick E. MacDonald
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Endocrine Pancreas ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cellular Processes ◽  
Wide Range ◽  
Cell Gene

The endocrine pancreas is critically important in the regulation of energy metabolism, with defective insulin secretion from pancreatic islet β-cells a major contributing factor to the development of type 2 diabetes. Small ubiquitin-like modifier (SUMO) proteins have been demonstrated to covalently modify a wide range of target proteins, mediating a broad range of cellular processes. While the effects of SUMOylation on β-cell gene transcription have been previously reviewed, recent reports indicate roles for SUMO outside of the nucleus. In this review we shall focus on the reported non-nuclear roles of SUMOylation in the regulation of β-cells, including SUMOylation as a novel signaling pathway in the acute regulation of insulin secretion.

GLP-1 Analog Liraglutide Enhances Proinsulin Processing in Pancreatic β-Cells via a PKA-Dependent Pathway

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3817-3828 ◽  
Author(s):  
Liang Wang ◽  
Ye Liu ◽  
Jin Yang ◽  
Hejun Zhao ◽  
Jing Ke ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Proinsulin Processing ◽  
Kinase A

Abstract Hyperproinsulinemia has gained increasing attention in the development of type 2 diabetes. Clinical studies have demonstrated that glucagon-like peptide-1 (GLP-1)-based therapies significantly decrease plasma proinsulin/insulin ratio in patients with type 2 diabetes. However, the underlying mechanism remains unclear. Prohormone convertase (PC)-1/3 and PC2 are primarily responsible for processing proinsulin to insulin in pancreatic β-cells. We have recently reported that Pax6 mutation down-regulated PC1/3 and PC2 expression, resulting in defective proinsulin processing in Pax6 heterozygous mutant (Pax6m/+) mice. In this study, we investigated whether and how liraglutide, a novel GLP-1 analog, modulated proinsulin processing. Our results showed that liraglutide significantly up-regulated PC1/3 expression and decreased the proinsulin to insulin ratio in both Pax6m/+ and db/db diabetic mice. In the cultured mouse pancreatic β-cell line, Min6, liraglutide stimulated PC1/3 and PC2 expression and lowered the proinsulin to insulin ratio in a dose- and time-dependent manner. Moreover, the beneficial effects of liraglutide on PC1/3 and PC2 expression and proinsulin processing were dependent on the GLP-1 receptor-mediated cAMP/protein kinase A signaling pathway. The same mechanism was recapitulated in isolated mouse islets. In conclusion, liraglutide enhanced PC1/3- and PC2-dependent proinsulin processing in pancreatic β-cells through the activation of the GLP-1 receptor/cAMP/protein kinase A signaling pathway. Our study provides a new mechanism for improvement of pancreatic β-cell function by the GLP-1-based therapy.

scholarly journals Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion

2015 ◽  
Vol 112 (9) ◽  
pp. 2888-2893 ◽  
Author(s):  
Miles Berger ◽  
David W. Scheel ◽  
Hector Macias ◽  
Takeshi Miyatsuka ◽  
Hail Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Perinatal Period ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Gpcr Signaling

Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

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 β-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 226
Author(s):  
Ahmad Al-Mrabeh
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lipid Metabolism ◽  
Cardiovascular Health ◽  
Lipoprotein Metabolism ◽  
Hepatic Lipid Metabolism ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction

Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of β-cell dysfunction and recovery in T2DM are discussed in the context of abnormal hepatic lipid metabolism and cardiovascular health. (i) In normal health, continuous exposure of the pancreas to nutrient stimulus increases the demand on β-cells. In the long term, this will not only stress β-cells and decrease their insulin secretory capacity, but also will blunt the cellular response to insulin. (ii) At the pre-diabetes stage, β-cells compensate for insulin resistance through hypersecretion of insulin. This increases the metabolic burden on the stressed β-cells and changes hepatic lipoprotein metabolism and adipose tissue function. (iii) If this lipotoxic hyperinsulinemic environment is not removed, β-cells start to lose function, and CVD risk rises due to lower lipoprotein clearance. (iv) Once developed, T2DM can be reversed by weight loss, a process described recently as remission. However, the precise mechanism(s) by which calorie restriction causes normalization of lipoprotein metabolism and restores β-cell function are not fully established. Understanding the pathophysiological and molecular basis of β-cell failure and recovery during remission is critical to reduce β-cell burden and loss of function. The aim of this review is to highlight the link between lipoprotein export and lipid-driven β-cell dysfunction in T2DM and how this is related to cardiovascular health. A second aim is to understand the mechanisms of β-cell recovery after weight loss, and to explore new areas of research for developing more targeted future therapies to prevent T2DM and the associated CVD events.

scholarly journals Overexpression of Galectin 3 in Pancreatic β Cells Amplifies β-Cell Apoptosis and Islet Inflammation in Type-2 Diabetes in Mice

2020 ◽  
Vol 11 ◽  
Author(s):  
Ivica Petrovic ◽  
Nada Pejnovic ◽  
Biljana Ljujic ◽  
Sladjana Pavlovic ◽  
Marina Miletic Kovacevic ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Diabetes In Mice ◽  
Galectin 3 ◽  
Islet Inflammation

Oxidative stress: the vulnerable β-cell

2008 ◽  
Vol 36 (3) ◽  
pp. 343-347 ◽  
Author(s):  
Sigurd Lenzen
Keyword(s):  
Type 2 Diabetes ◽  
Reactive Oxygen ◽  
Reactive Species ◽  
Β Cells ◽  
Β Cell ◽  
Subsequent Formation ◽  
Redox Imbalance ◽  
Cell Dysfunction

Antioxidative defence mechanisms of pancreatic β-cells are particularly weak and can be overwhelmed by redox imbalance arising from overproduction of reactive oxygen and reactive nitrogen species. The consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage and interference of reactive species with signal transduction pathways, which contribute significantly to β-cell dysfunction and death in Type 1 and Type 2 diabetes mellitus. Reactive oxygen species, superoxide radicals (O2•−), hydrogen peroxide (H2O2) and, in a final iron-catalysed reaction step, the most reactive and toxic hydroxyl radicals (OH•) are produced during both pro-inflammatory cytokine-mediated β-cell attack in Type 1 diabetes and glucolipotoxicity-mediated β-cell dysfunction in Type 2 diabetes. In combination with NO•, which is toxic in itself, as well as through its reaction with the O2•− and subsequent formation of peroxynitrite, reactive species play a central role in β-cell death during the deterioration of glucose tolerance in the development of diabetes.

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