miR-25 and miR-92b Regulate Insulin Biosynthesis and Pancreatic β-Cell Apoptosis

Abstract Purpose. - Pancreatic β-cell failure is a central hallmark of the pathogenesis of diabetes mellitus; however, the molecular basis underlying chronic inflammation-caused β-cell failure remains unclear. This study reported here specifically assessed the association between miR-25/miR-92b family and β-cell failure in diabetes.Methods. - IL-1β and two additional ER stress activators, palmitate and tunicamycin were applied to evaluate the expression level miR-25 by Taqman® RT-PCR. Glucose- and potassium-stimulated insulin secretion assays were performed to assess β-cell function. Dual luciferase activity, and western blotting assays were utilized for miR-25 target gene verification. CCK-8 and TUNEL staining were used to evaluate β-cell viability and apoptosis.Results. – miRNA ChIP identified the increased level of miR-25 in INS-1 cells by IL-1β treatment. Expression levels of miR-25 were significantly upregulated with the treatment of IL-1β, palmitate or tunicamycin in both INS-1 cells and human islets. Ectopic elevation of miR-25 recapitulated most featured β-cell defects caused by IL-1β, including inhibition of insulin biosynthesis and increased β-cell apoptosis. These detrimental effects of miR-25 relied on its seed sequence recognition and repressed expression of its target genes Neurod1 and Mcl1. The miR-25/NEUROD1 axis reduced insulin biosynthesis via transcriptional regulation of β-cell specific genes. The miR-25/MCL1 axis caused β-cell apoptosis in a caspase 3/PARP1-dependent manner. Comparable impairments were generated by miR-92b and miR-25, emphasizing the redundant biological roles of miRNA family members with the same seed sequence. Conclusion. - MiR-25/miR-92b family plays a major role in β-cell failure occurring under inflammation and diabetes states.

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Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

International Journal of Molecular Sciences ◽

10.3390/ijms22157917 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7917

Author(s):

Hideaki Kaneto ◽

Tomohiko Kimura ◽

Masashi Shimoda ◽

Atsushi Obata ◽

Junpei Sanada ◽

...

Keyword(s):

Large Scale ◽

Cell Function ◽

Apoptotic Cell ◽

Early Stage ◽

Insulin Biosynthesis ◽

Protective Effects ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Toxicity

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

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Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity

Journal of Endocrinology ◽

10.1530/joe-14-0335 ◽

2014 ◽

Vol 223 (2) ◽

pp. 107-117 ◽

Cited By ~ 53

Author(s):

Michael Rouse ◽

Antoine Younès ◽

Josephine M Egan

Keyword(s):

Insulin Secretion ◽

Cell Lines ◽

Cell Function ◽

Human Islets ◽

Dependent Manner ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Pde Inhibitors ◽

Β Cell Function

Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against β-cell dysfunction, we studied their mechanism(s) of action in β-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic β-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic β-cells. In our current study, we found that both RES (0.1–10 μmol/l) and CUR (1–100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating β-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in β-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic β-cell function.

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Induction of core circadian clock transcription factor Bmal1 enhances β cell function and protects against obesity-induced glucose intolerance

10.2337/figshare.13103045 ◽

2020 ◽

Author(s):

Ada Admin ◽

Kuntol Rakshit ◽

Aleksey V. Matveyenko

Keyword(s):

Transcription Factor ◽

Insulin Secretion ◽

Circadian Clock ◽

Glucose Intolerance ◽

Target Genes ◽

Cell Function ◽

Dependent Manner ◽

Β Cell ◽

Cell Dysfunction

Type 2 diabetes mellitus (T2DM) is characterized by β cell dysfunction due to impaired glucose-stimulated insulin secretion (GSIS). Studies show that β cell circadian clocks are important regulators of GSIS and glucose homeostasis. These observations raise the question whether enhancement of the circadian clock in β cells will confer protection against β cell dysfunction under diabetogenic conditions. To test this we employed an approach by first generating mice with β cell-specific inducible overexpression of Bmal1 (core circadian transcription factor; β-Bmal1OV). We subsequently examined the effects of β-Bmal1OV on the circadian clock, GSIS, islet transcriptome, and glucose metabolism in context of diet-induced obesity. We additionally tested the effects of circadian clock-enhancing small molecule Nobiletin on GSIS in mouse and human control and T2DM islets. We report that β-Bmal1OV mice display enhanced islet circadian clock amplitude, augmented in vivo and in vitro GSIS and are protected against obesity-induced glucose intolerance. These effects were associated with increased expression of purported BMAL1-target genes mediating insulin secretion, processing, and lipid metabolism. Furthermore, exposure of isolated islets to Nobiletin enhanced β cell secretory function in Bmal1-dependent manner. This work suggests therapeutic targeting of the circadian system as a potential strategy to counteract β cell failure under diabetogenic conditions.

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Induction of core circadian clock transcription factor Bmal1 enhances β cell function and protects against obesity-induced glucose intolerance

10.2337/figshare.13103045.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Kuntol Rakshit ◽

Aleksey V. Matveyenko

Keyword(s):

Transcription Factor ◽

Insulin Secretion ◽

Circadian Clock ◽

Glucose Intolerance ◽

Target Genes ◽

Cell Function ◽

Dependent Manner ◽

Β Cell ◽

Cell Dysfunction

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Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model

10.1101/2021.03.02.433645 ◽

2021 ◽

Author(s):

Hung Tae Kim ◽

Arnaldo H. de Souza ◽

Heidi Umhoefer ◽

JeeYoung Han ◽

Lucille Anzia ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Survival ◽

Cell Apoptosis ◽

Cell Mass ◽

Human Islets ◽

Dependent Manner ◽

Pancreatic Β Cell ◽

Β Cell

AbstractLoss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of both type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. Now, we demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.One Sentence SummaryCholecystokinin ameliorates pancreatic β-cell death under models of stress and after transplant of human islets.

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Pax6 Is Crucial for β-Cell Function, Insulin Biosynthesis, and Glucose-Induced Insulin Secretion

Molecular Endocrinology ◽

10.1210/me.2011-1256 ◽

2012 ◽

Vol 26 (4) ◽

pp. 696-709 ◽

Cited By ~ 58

Author(s):

Yvan Gosmain ◽

Liora S. Katz ◽

Mounia Heddad Masson ◽

Claire Cheyssac ◽

Caroline Poisson ◽

...

Keyword(s):

Insulin Secretion ◽

Target Genes ◽

Cell Function ◽

Insulin Biosynthesis ◽

Candidate Gene Approach ◽

Mrna Levels ◽

Β Cells ◽

Β Cell ◽

Cell Content ◽

Β Cell Function

Abstract The Pax6 transcription factor is crucial for endocrine cell differentiation and function. Indeed, mutations of Pax6 are associated with a diabetic phenotype and a drastic decrease of insulin-positive cell number. Our aim was to better define the β-cell Pax6 transcriptional network and thus provide further information concerning the role of Pax6 in β-cell function. We developed a Pax6-deficient model in rat primary β-cells with specific small interfering RNA leading to a 75% knockdown of Pax6 expression. Through candidate gene approach, we confirmed that Pax6 controls the mRNA levels of the insulin 1 and 2, Pdx1, MafA, GLUT2, and PC1/3 genes in β-cells. Importantly, we identified new Pax6 target genes coding for GK, Nkx6.1, cMaf, PC2, GLP-1R and GIPR which are all involved in β-cell function. Furthermore, we demonstrated that Pax6 directly binds and activates specific elements on the promoter region of these genes. We also demonstrated that Pax6 knockdown led to decreases in insulin cell content, in insulin processing, and a specific defect of glucose-induced insulin secretion as well as a significant reduction of GLP-1 action in primary β-cells. Our results strongly suggest that Pax6 is crucial for β-cells through transcriptional control of key genes coding for proteins that are involved in insulin biosynthesis and secretion as well as glucose and incretin actions on β-cells. We provide further evidence that Pax6 represents a key element of mature β-cell function.

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Adipokines as key players in β cell function and failure

Clinical Science ◽

10.1042/cs20190523 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2317-2327 ◽

Cited By ~ 3

Author(s):

Nicolás Gómez-Banoy ◽

James C. Lo

Keyword(s):

Metabolic Diseases ◽

Cell Function ◽

Whole Body ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Axis ◽

Β Cell Function ◽

Prevalence Of Obesity ◽

Specific Factors ◽

Whole Body Metabolism

Abstract The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the “classic” adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose–pancreatic β cell axis.

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