scholarly journals Mitochondrial Calcium Signaling in Pancreatic β-Cell

2021 ◽  
Vol 22 (5) ◽  
pp. 2515
Author(s):  
Anna Weiser ◽  
Jerome N. Feige ◽  
Umberto De Marchi
Keyword(s):  
Calcium Signaling ◽  
Cell Function ◽  
Intervention Strategies ◽  
Mitochondrial Calcium ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Accumulation of calcium in energized mitochondria of pancreatic β-cells is emerging as a crucial process for pancreatic β-cell function. β-cell mitochondria sense and shape calcium signals, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion during nutrient stimulation. Here, we describe the role of mitochondrial calcium signaling in pancreatic β-cell function. We report the latest pharmacological and genetic findings, including the first mitochondrial calcium-targeted intervention strategies developed to modulate pancreatic β-cell function and their potential relevance in the context of diabetes.

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.

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.

miR-124-3p Down-Regulation Influences Pancreatic-β-Cell Function by Targeting Secreted Frizzled-Related Protein 5 (SFRP5) in Diabetes Mellitus

2021 ◽  
Vol 11 (4) ◽  
pp. 711-717
Author(s):  
Zhenhuan Jiang ◽  
Min Yang ◽  
Jianming Jin ◽  
Zhenqiang Song ◽  
Chenguang Li ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Luciferase Reporter ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Down Regulation ◽  
Β Cell Function ◽  
Direct Target

Diabetes mellitus (DM) is a complex metabolic disease characterized by hyperglycemia, insulin resistance and pancreatic β-cell dysfunction. There are evidences showed that microRNAs (miRNAs) play important roles in DM. The purpose of our study was to determine the role of miR-124-3p in DM. Quantitative reverse transcription PCR (qRT-PCR) was applied to measure the level of miR- 124-3p in peripheral blood from healthy control patients and DM patients. Then we explored the effects of miR-124-3p inhibitor on the secretion of insulin of pancreatic β-cells. Moreover, we determined the effects of miR-124-3p inhibitor on the apoptosis and viability of pancreatic β-cells through flow cytometry and MTT assay. And we also used western blotting to detect the protein expression of cleaved-caspase3/pro-caspase3, and the activity of caspase3 was detected. In addition, we confirmed the direct target of miR-124-3p using Dual luciferase reporter assay. Our data showed that in the blood of DM patients, SFRP5 was significantly reduced, while miR-124-3p was increased significantly. Furthermore, we found that down-regulation of miR-124-3p increased total insulin content in INS-1 cells, enhanced insulin secretion in INS-1 cells. Furthermore, we revealed that miR-124-3p inhibitor enhanced INS-1 cell viability, decreased apoptosis of INS-1 cells, increased pro-caspase3 expression, decreased cleaved-caspase3 expression and caspase3 activity. In addition, we proved SFRP5 was a direct target of miR-124-3p in pancreatic β-cells. Moreover, SFRP5-siRNA reversed all the effects of miR-124-3p knockdown on pancreatic β-cells.

CALCIUM AND PANCREATIC β-CELL FUNCTION

1979 ◽  
Vol 90 (4) ◽  
pp. 624-636 ◽  
Author(s):  
Bo Hellman
Keyword(s):  
Cell Function ◽  
Secretory Granules ◽  
Metabolic Inhibitors ◽  
Antimycin A ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
A 23187 ◽  
Β Cell Function

ABSTRACT Glucose is believed to stimulate incorporation of calcium into the secretory granules of the pancreatic β-cells. The mechanism of the glucose-stimulated accumulation of calcium in the granule pool was evaluated by measuring fluxes of 45Ca in β-cell-rich pancreatic islets microdissected from ob/ob-mice. The incorporation of lanthanum-nondisplaceable 45Ca in response to glucose differed from both the basal uptake and that seen in response to phosphate in being suppressed by 10 μm antimycin A, 0.3 mm 2,4-dinitrophenol or 1 mm N-ethylmaleimide. Exposure to each of these metabolic inhibitors also resulted in a protracted efflux of the glucose-sensitive 45Ca under conditions when neither the 45Ca incorporated in the presence of 3 mm glucose nor in response to phosphate was significantly affected. The glucose-stimulated intracellular 45Ca existed in a state allowing it to be washed out with the ionophore A-23187. The results suggest that the glucose-stimulated incorporation of calcium into the secretory granules is mediated by transport against a concentration gradient into the granule sac.

scholarly journals NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Idil I. Aigha ◽  
Essam M. Abdelalim
Keyword(s):  
Transcription Factor ◽  
Cell Function ◽  
Disease Modeling ◽  
Critical Role ◽  
Cell Mass ◽  
Cell Development ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

scholarly journals Biphasic Response of Pancreatic β-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice

2008 ◽  
Vol 28 (9) ◽  
pp. 2971-2979 ◽  
Author(s):  
Yutaka Shigeyama ◽  
Toshiyuki Kobayashi ◽  
Yoshiaki Kido ◽  
Naoko Hashimoto ◽  
Shun-ichiro Asahara ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cell Function ◽  
Cell Mass ◽  
Mammalian Target Of Rapamycin ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass ◽  
Β Cell Function

ABSTRACT Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic β-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on β-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic β cells (βTSC2−/− mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual β cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the βTSC2−/− mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of β cells. These results thus indicate that TSC2 regulates pancreatic β-cell mass in a biphasic manner.

Life and death decisions of the pancreatic β-cell: the role of fatty acids

2006 ◽  
Vol 112 (1) ◽  
pp. 27-42 ◽  
Author(s):  
Philip Newsholme ◽  
Deirdre Keane ◽  
Hannah J. Welters ◽  
Noel G. Morgan
Keyword(s):  
Fatty Acids ◽  
Insulin Release ◽  
Chronic Exposure ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Endogenous Fatty Acid ◽  
Gene And Protein Expression ◽  
Β Cell Function

Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion, followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. Therefore changes in the levels of NEFAs are likely to be important for the regulation of β-cell function and viability under physiological conditions. In addition, the switching between endogenous fatty acid synthesis or oxidation in the β-cell, together with alterations in neutral lipid accumulation, may have critical implications for β-cell function and integrity. Long-chain acyl-CoA (formed from either endogenously synthesized or exogenous fatty acids) controls several aspects of β-cell function, including activation of specific isoenzymes of PKC (protein kinase C), modulation of ion channels, protein acylation, ceramide formation and/or NO-mediated apoptosis, and transcription factor activity. In this review, we describe the effects of exogenous and endogenous fatty acids on β-cell metabolism and gene and protein expression, and have explored the outcomes with respect to insulin secretion and β-cell integrity.

The role of aging and senescence on pancreatic β-cell function and proliferation

2017 ◽  
Vol 108 ◽  
pp. S71
Author(s):  
Richard Kehm ◽  
Oliver Kluth ◽  
Annette Schürmann ◽  
Tilman Grune ◽  
Annika Höhn
Keyword(s):  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function

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

2014 ◽  
Vol 223 (2) ◽  
pp. 107-117 ◽  
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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