scholarly journals Glucose Regulates m6A Methylation of RNA in Pancreatic Islets

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 291
Author(s):  
Florine Bornaque ◽  
Clément Philippe Delannoy ◽  
Emilie Courty ◽  
Nabil Rabhi ◽  
Charlène Carney ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Control Of Gene Expression ◽  
Altered Expression ◽  
Chronic Hyperglycemia

Type 2 diabetes is characterized by chronic hyperglycemia associated with impaired insulin action and secretion. Although the heritability of type 2 diabetes is high, the environment, including blood components, could play a major role in the development of the disease. Amongst environmental effects, epitranscriptomic modifications have been recently shown to affect gene expression and glucose homeostasis. The epitranscriptome is characterized by reversible chemical changes in RNA, with one of the most prevalent being the m6A methylation of RNA. Since pancreatic β cells fine tune glucose levels and play a major role in type 2 diabetes physiopathology, we hypothesized that the environment, through variations in blood glucose or blood free fatty acid concentrations, could induce changes in m6A methylation of RNAs in pancreatic β cells. Here we observe a significant decrease in m6A methylation upon high glucose concentration, both in mice and human islets, associated with altered expression levels of m6A demethylases. In addition, the use of siRNA and/or specific inhibitors against selected m6A enzymes demonstrate that these enzymes modulate the expression of genes involved in pancreatic β-cell identity and glucose-stimulated insulin secretion. Our data suggest that environmental variations, such as glucose, control m6A methylation in pancreatic β cells, playing a key role in the control of gene expression and pancreatic β-cell functions. Our results highlight novel causes and new mechanisms potentially involved in type 2 diabetes physiopathology and may contribute to a better understanding of the etiology of this disease.

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.

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.

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.

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.

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 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

Mouse models of insulin resistance

2002 ◽  
Vol 282 (5) ◽  
pp. E977-E981 ◽  
Author(s):  
Marta Letizia Hribal ◽  
Francesco Oriente ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Impaired Insulin

The hallmarks of type 2 diabetes are impaired insulin action in peripheral tissues and decreased pancreatic β-cell function. Classically, the two defects have been viewed as separate entities, with insulin resistance arising primarily from impaired insulin-dependent glucose uptake in skeletal muscle, and β-cell dysfunction arising from impaired coupling of glucose sensing to insulin secretion. Targeted mutagenesis and transgenesis involving components of the insulin action pathway have changed our understanding of these phenomena. It appears that the role of insulin signaling in the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been overlooked in liver, pancreatic β-cells, and brain, which had been thought not to be primary insulin targets. We review recent progress and try to reconcile areas of apparent controversy surrounding insulin signaling in skeletal muscle and pancreatic β-cells.

scholarly journals Diazoxide Prevents Diabetes through Inhibiting Pancreatic β-Cells from Apoptosis via Bcl-2/Bax Rate and p38-β Mitogen-Activated Protein Kinase

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 81-91 ◽  
Author(s):  
Qin Huang ◽  
Shizhong Bu ◽  
Yongwei Yu ◽  
Zhiyong Guo ◽  
Gautam Ghatnekar ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Critical Role ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Oletf Rats ◽  
Insulin Secretory Capacity ◽  
Secretory Capacity

Increased apoptosis of pancreatic β-cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic β-cell apoptosis and its potential mechanism in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes, at the prediabetic and diabetic stages. We found a significant increase with age in the frequency of apoptosis, the sequential enlargement of islets, and the proliferation of the connective tissue surrounding islets, accompanied with defective insulin secretory capacity and increased blood glucose in untreated OLETF rats. In contrast, diazoxide treatment (25 mg·kg−1·d−1, administered ip) inhibited β-cell apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet β-cells whether diazoxide was used at the prediabetic or diabetic stage. Linear regression showed the close correlation between the frequency of apoptosis and hyperglycemia (r = 0.913; P < 0.0001). Further study demonstrated that diazoxide up-regulated Bcl-2 expression and p38β MAPK, which expressed at very low levels due to the high glucose, but not c-jun N-terminal kinase and ERK. Hence, diazoxide may play a critical role in protection from apoptosis. In this study, we demonstrate that diazoxide prevents the onset and development of diabetes in OLETF rats by inhibiting β-cell apoptosis via increasing p38β MAPK, elevating Bcl-2/Bax ratio, and ameliorating insulin secretory capacity and action.

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.

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