The agouti gene product stimulates pancreatic β-cell Ca2+ signaling and insulin release

1999 ◽  
Vol 1 (1) ◽  
pp. 11-19 ◽  
Author(s):  
B. Z. XUE ◽  
W. O. WILKISON ◽  
R. L. MYNATT ◽  
N. MOUSTAID ◽  
M. GOLDMAN ◽  
...  
Keyword(s):  
Gene Product ◽  
Insulin Release ◽  
Fold Increase ◽  
Cell Types ◽  
Human Pancreas ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Agouti Protein ◽  
Intracellular Ca ◽  
Agouti Gene

Xue, B. Z., W. O. Wilkison, R. L. Mynatt, N. Moustaid, M. Goldman, and M. B. Zemel. The agouti gene product stimulates pancreatic β-cell Ca2+ signaling and insulin release. Physiol. Genomics 1: 11-19, 1999.—Ubiquitous expression of the mouse agouti gene results in obesity and hyperinsulinemia. Human agouti is expressed in adipose tissue, and we found recombinant agouti protein to stimulate lipogenesis in adipocytes in a Ca2+-dependent fashion. However, adipocyte-specific agouti transgenic mice only became obese in the presence of hyperinsulinemia. Because intracellular Ca2+ concentration ([Ca2+]i) is a primary signal for insulin release, and we have shown agouti protein to increase [Ca2+]i in several cell types, we examined the effects of agouti on [Ca2+]i and insulin release. We demonstrated the expression of agouti in human pancreas and generated recombinant agouti to study its effects on Ca2+ signaling and insulin release. Agouti (100 nM) stimulated Ca2+ influx, [Ca2+]i increase, and a marked stimulation of insulin release in two β-cell lines (RIN-5F and HIT-T15; P < 0.05). Agouti exerted comparable effects in isolated human pancreatic islets and β-cells, with a 5-fold increase in Ca2+ influx ( P < 0.001) and a 2.2-fold increase in insulin release ( P < 0.01). These data suggest a potential role for agouti in the development of hyperinsulinemia in humans.

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.

scholarly journals Inhibition of Forkhead Box O1 Protects Pancreatic β-Cells against Dexamethasone-Induced Dysfunction

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4065-4073 ◽  
Author(s):  
Xiongfei Zhang ◽  
Wei Yong ◽  
Jinghuan Lv ◽  
Yunxia Zhu ◽  
Jingjing Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Types ◽  
Pancreatic Β Cell ◽  
Rinm5f Cells ◽  
Β Cells ◽  
Β Cell ◽  
Rat Islets ◽  
Cell Dysfunction ◽  
Forkhead Box ◽  
Glucose Stimulated Insulin Secretion

Abstract Forkhead Box O1 (FoxO1) is a key transcription regulator of insulin/IGF-I signaling pathway, and its activity can be increased by dexamethasone (DEX) in several cell types. However, the role of FoxO1 in DEX-induced pancreatic β-cell dysfunction has not been fully understood. Therefore, in this study, we investigated whether FoxO1 could mediate DEX-induced β-cell dysfunction and the possible underlying mechanisms in pancreatic β-cell line RINm5F cells and primary rat islet. We found that DEX markedly increased FoxO1 mRNA and protein expression and decreased FoxO1 phosphorylation through the Akt pathway, which resulted in an increase in active FoxO1 in RINm5F cells and isolated rat islets. Activated FoxO1 subsequently inhibited pancreatic duodenal homeobox-1 expression and induced nuclear exclusion of pancreatic duodenal homeobox-1. Knockdown of FoxO1 by RNA interference restored the expression of pancreatic duodenal homeobox-1 and prevented DEX-induced dysfunction of glucose-stimulated insulin secretion in rat islets. Together, the results of present study demonstrate that FoxO1 is integrally involved in DEX-induced inhibition of pancreatic duodenal homeobox-1 and glucose-stimulated insulin secretion dysfunction in pancreatic islet β-cells. Inhibition of FoxO1 can effectively protect β-cells against DEX-induced dysfunction.

scholarly journals Exosome microRNAs in Metabolic Syndrome as Tools for the Early Monitoring of Diabetes and Possible Therapeutic Options

2021 ◽  
Vol 14 (12) ◽  
pp. 1257
Author(s):  
Erika Cione ◽  
Roberto Cannataro ◽  
Luca Gallelli ◽  
Giovambattista De Sarro ◽  
Maria Cristina Caroleo
Keyword(s):  
Essential Role ◽  
Cell Injury ◽  
Cell Types ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Pathological Conditions ◽  
Novel Approach ◽  
Almost All

Exosomes are nano-sized extracellular vesicles produced and released by almost all cell types. They play an essential role in cell–cell communications by delivering cellular bioactive compounds such as functional proteins, metabolites, and nucleic acids, including microRNA, to recipient cells. Thus, they are involved in various physio-pathological conditions. Exosome-miRNAs are associated with numerous diseases, including type 2 diabetes, a complex multifactorial metabolic disorder linked to obesity. In addition, exosome-miRNAs are emerging as essential regulators in the progression of diabetes, principally for pancreatic β-cell injury and insulin resistance. Here, we have clustered the recent findings concerning exosome-miRNAs associated with β-cell dysfunction to provide a novel approach for the early diagnosis and therapy of diabetes.

scholarly journals Loss of Secretory Pathway Ca2+ ATPase (SPCA1) Impairs Insulin Secretion and Reduces Autophagy in the Pancreatic Islet

2021 ◽  
Author(s):  
Robert N. Bone ◽  
Xin Tong ◽  
Staci A. Weaver ◽  
Charanya Muralidharan ◽  
Preethi Krishnan ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Secretory Pathway ◽  
Cell Types ◽  
Β Cell ◽  
Human Organ ◽  
Altered Glucose ◽  
Intracellular Ca ◽  
Insulin Granule ◽  
Granule Maturation ◽  
Glucose Stimulated Insulin Secretion

AbstractThe β cell Golgi apparatus serves as a significant store of intracellular Ca2+ and an important site of proinsulin maturation. However, the contribution of Golgi Ca2+ to diabetes pathophysiology is unknown. The Golgi primarily utilizes the Secretory Pathway Ca2+ ATPase (SPCA1) to maintain intraluminal Ca2+ stores, and loss of SPCA1 has been linked to impaired Golgi function in other cell types. Here, we demonstrated that SPCA1 expression is decreased in islets from diabetic mice and human organ donors with type 2 diabetes, suggesting SPCA1 may impact diabetes development. INS-1 β cells lacking SPCA1 (SPCA1KO) showed reduced intraluminal Golgi Ca2+ levels, reduced glucose-stimulated insulin secretion (GSIS), and increased insulin content. Islets from SPCA1 haploinsufficient mice (SPCA1+/-) exhibited reduced GSIS, altered glucose-induced Ca2+ oscillations, and altered insulin granule maturation. Autophagy can regulate granule homeostasis, therefore we induced autophagy with Torin1 and found that SPCA1KO cells and SPCA1+/- islets had reduced levels of the autophagosome marker LC3-II. Furthermore, SPCA1KO LC3-II were unchanged after blocking autophagy initiation or autophagolysosome fusion and acidification. Thus, we concluded that β cell SPCA1 plays an important role in the maintenance of Golgi Ca2+ homeostasis and reduced Golgi Ca2+ impairs autophagy initiation and may impact insulin granule homeostasis.

scholarly journals XPR1 mediates the pancreatic β-cell phosphate flush

2020 ◽  
Author(s):  
Ada Admin ◽  
Christopher J. Barker ◽  
Fernando Henrique Galvão Tessaro ◽  
Sabrina de Souza Ferreira ◽  
Rafael Simas ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Inorganic Phosphate ◽  
Blood Glucose Concentration ◽  
Cell Types ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Inositol Pyrophosphate ◽  
Inositol Pyrophosphates ◽  
Potential Impact ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion is the hallmark of the pancreatic β-cell, a critical player in the regulation of blood glucose concentration. In 1974 Dawson, Freinkel and co-workers made the remarkable observation that an efflux of intracellular inorganic phosphate (P<sub>i</sub>) accompanied the events of stimulated insulin secretion. The mechanism behind this ‘phosphate flush’, its association with insulin secretion and its regulation have since then remained a mystery. We recapitulated the phosphate flush in the MIN6m9 β-cell line and pseudoislets. We demonstrated that knockdown of XPR1, a phosphate transporter present in MIN6m9 cells and pancreatic islets, prevented this flush. Concomitantly, XPR1 silencing led to intracellular P<sub>i</sub> accumulation and a potential impact on Ca<sup>2+</sup> signaling. XPR1 knockdown slightly blunted first phase glucose-stimulated insulin secretion in MIN6m9 cells, but had no significant impact on pseudoislet secretion. In keeping with other cell types, basal P<sub>i</sub> efflux was stimulated by inositol pyrophosphates and basal intracellular P<sub>i</sub> accumulated following knockdown of inositol hexakisphosphate kinases. However, the glucose-driven phosphate flush occurred despite inositol pyrophosphate depletion. Finally, whilst it is unlikely that XPR1 directly affects exocytosis, it may protect Ca<sup>2+ </sup>signaling. Thus we have revealed XPR1 as the missing mediator of the phosphate flush, shedding light on a 45-year-old mystery.

scholarly journals Piezo1 channel activation mimics high glucose as a stimulator of insulin release

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Vijayalakshmi Deivasikamani ◽  
Savitha Dhayalan ◽  
Yilizila Abudushalamu ◽  
Romana Mughal ◽  
Asjad Visnagri ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
Cell Lines ◽  
High Glucose ◽  
Mammalian Cells ◽  
Cell Swelling ◽  
Β Cells ◽  
Β Cell ◽  
Intracellular Ca ◽  
Mouse Pancreatic Islets

AbstractGlucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic β-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca2+ permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca2+ permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release. Two rat β-cell lines (INS-1 and BRIN-BD11) and freshly-isolated mouse pancreatic islets were studied. Intracellular Ca2+ measurements were performed using the fura-2 Ca2+ indicator dye and ionic current was recorded by whole cell patch-clamp. Piezo1 agonist Yoda1, a competitive antagonist of Yoda1 (Dooku1) and an inactive analogue of Yoda1 (2e) were used as chemical probes. Piezo1 mRNA and insulin secretion were measured by RT-PCR and ELISA respectively. Piezo1 mRNA was detected in both β-cell lines and mouse islets. Yoda1 evoked Ca2+ entry was inhibited by Yoda1 antagonist Dooku1 as well as other Piezo1 inhibitors gadolinium and ruthenium red, and not mimicked by 2e. Yoda1, but not 2e, stimulated Dooku1-sensitive insulin release from β-cells and pancreatic islets. Hypotonicity and high glucose increased intracellular Ca2+ and enhanced Yoda1 Ca2+ influx responses. Yoda1 and hypotonicity induced insulin release were significantly inhibited by Piezo1 specific siRNA. Pancreatic islets from mice with haploinsufficiency of Piezo1 released less insulin upon exposure to Yoda1. The data show that Piezo1 channel agonist induces insulin release from β-cell lines and mouse pancreatic islets suggesting a role for Piezo1 in cell swelling induced insulin release. Hence Piezo1 agonists have the potential to be used as enhancers of insulin release.

Role of mitochondria in metabolism-secretion coupling of insulin release in the pancreatic β-cell

BioFactors ◽  
1998 ◽  
Vol 8 (3-4) ◽  
pp. 255-262 ◽  
Author(s):  
Pierre Maechler ◽  
Claes B. Wollheim
Keyword(s):  
Insulin Release ◽  
Pancreatic Β Cell ◽  
Β Cell

Acute and long-term effects of metformin on the function and insulin secretory responsiveness of clonal β-cells

2010 ◽  
Vol 391 (12) ◽  
Author(s):  
Joan M. McKiney ◽  
Nigel Irwin ◽  
Peter R. Flatt ◽  
Clifford J. Bailey ◽  
Neville H. McClenaghan
Keyword(s):  
Insulin Secretion ◽  
Cell Viability ◽  
Palmitic Acid ◽  
Insulin Release ◽  
Prolonged Exposure ◽  
Long Term Effects ◽  
Β Cell ◽  
Beneficial Effects ◽  
Intracellular Ca ◽  
Glucose Stimulated Insulin Secretion

Abstract Functional effects of acute and prolonged (48 h) exposure to the biguanide drug metformin were examined in the clonal pancreatic β-cell line, BRIN-BD11. Effects of metformin on prolonged exposure to excessive increased concentrations of glucose and palmitic acid were also assessed. In acute 20-min incubations, 12.5–50 μm metformin did not alter basal (1.1 mm glucose) or glucose-stimulated (16.7 mm glucose) insulin secretion. However, higher concentrations of metformin (100–1000 μm) increased (1.3–1.5-fold; p<0.001) insulin release at basal glucose concentrations, but had no effect on glucose-stimulated insulin secretion. There were no apparent acute effects of metformin on intracellular Ca2+ concentrations, but metformin enhanced (p<0.05 to p<0.01) the acute insulinotropic actions of GIP and GLP-1. Exposure for 48 h to 200 μm metformin improved aspects of β-cell insulin secretory function, whereas these benefits were lost at 1 mm metformin. Prolonged glucotoxic and lipotoxic conditions impaired β-cell viability and insulin release in response to glucose and to a broad range of insulin secretagogues. Concomitant culture with 200 μm metformin partially reversed many of the adverse effects of prolonged glucotoxic conditions. However, there were no beneficial effects of metformin under prolonged culture with elevated concentrations of palmitic acid. The results suggest that metformin exerts direct effects on β-cell viability, function and survival that could contribute to the use of this agent in the treatment of type 2 diabetes.

scholarly journals Cystine accumulation attenuates insulin release from the pancreatic β-cell due to elevated oxidative stress and decreased ATP levels

2015 ◽  
Vol 593 (23) ◽  
pp. 5167-5182 ◽  
Author(s):  
Bernadette McEvoy ◽  
Rodolfo Sumayao ◽  
Craig Slattery ◽  
Tara McMorrow ◽  
Philip Newsholme
Keyword(s):  
Oxidative Stress ◽  
Insulin Release ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Atp Levels
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