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Open Access Highly Accessed Research article

Activation of GPR40 attenuates chronic inflammation induced impact on pancreatic β-cells health and function

Mahesh Kumar Verma, Manoj Kumar Sadasivuni, Aggunda N Yateesh, Korrapati Neelima, Srikanth Mrudula, Madhusudhan Reddy, Rachapalli Smitha, Sanghamitra Biswas, Bhawna Chandravanshi, Puttrevana M Pallavi, Anup M Oommen, Madanahalli R Jagannath* and Baggavalli P Somesh

Author Affiliations

Connexios Life Sciences Pvt Ltd, Bangalore, India

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BMC Cell Biology 2014, 15:24  doi:10.1186/1471-2121-15-24

Published: 30 June 2014

Abstract

Background

Chronic 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.

Results

By 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.

Conclusions

In 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.

Keywords:
GPR40; β-cell apoptosis; β-cell survival; Inflammation; cAMP; ATP; Ca+2; Insulin content; Insulin secretion