Activation of GPR40 attenuates chronic inflammation induced impact on pancreatic β-cells health and functionReportar como inadecuado




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BMC Cell Biology

, 15:24

Cell signaling pathways and networks

Abstract

BackgroundChronic inflammation-mediated β-cell apoptosis is known to decrease β-cell mass in diabetes leading to reduced insulin secretion. Exposure to pro-inflammatory cytokines can stimulate apoptosis in pancreatic β-cells. The G protein coupled receptor 40 GPR40 is implicated for glucose induced insulin secretion. We hypothesized that GPR40 activation can protect β-cells from inflammation-induced apoptosis and restore glucose stimulated insulin secretion.

ResultsBy exposing NIT1 insulinoma cells and rat islets to a cocktail of pro-inflammatory cytokines TNFα and IL1β, we mimicked inflammatory signaling as seen by JNK and NFκB activation and increased mRNA levels of TNFα, IL1β and NOS2a. These changes were reversed by pharmacological activation of GPR40 by a specific, small molecule, CNX-011-67. Further, GPR40 activation reduced inflammation-mediated oxidative and endoplasmic reticulum ER stresses. Importantly, GPR40 activation decreased inflammation-induced apoptosis as measured by key markers. These impacts of GPR40 were mediated through activation of PLC, CaMKII, calcineurin and cAMP. Cell survival was also enhanced by GPR40 activation as seen from the increased phosphorylation of Akt-PKB and enhanced expression of BCL2 and PDX1 genes. Interestingly, GPR40 activation restored both, inflammation-mediated inhibition on insulin secretion and intracellular insulin content.

ConclusionsIn this study, we provide evidences that CNX-011-67, a GPR40 agonist, reduces inflammatory signaling and apoptosis in pancreatic β-cells while promoting insulin secretion and synthesis. Activation of GPR40 leads to attenuation of β-cell dysfunction caused by chronic inflammation and thus could be of immense clinical value to improve insulin secretion and β-cell survival.

KeywordsGPR40 β-cell apoptosis β-cell survival Inflammation cAMP ATP Ca Insulin content Insulin secretion Electronic supplementary materialThe online version of this article doi:10.1186-1471-2121-15-24 contains supplementary material, which is available to authorized users.

Mahesh Kumar Verma, Manoj Kumar Sadasivuni contributed equally to this work.

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Autor: Mahesh Kumar Verma - Manoj Kumar Sadasivuni - Aggunda N Yateesh - Korrapati Neelima - Srikanth Mrudula - Madhusudhan Redd

Fuente: https://link.springer.com/







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