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

ABSTRACT:

Background

Chronic inflammation-mediated ?-cell apoptosis is known to decrease ?-cell mass in diabetes leading to reduced insulin secretion. Exposure to pro-inflammatory cytokines can stimulate apoptosis in pancreatic ?-cells. The G protein coupled receptor 40 (GPR40) is implicated for glucose induced insulin secretion. We hypothesized that GPR40 activation can protect ?-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 (TNF? and IL1?), we mimicked inflammatory signaling as seen by JNK and NF?B activation and increased mRNA levels of TNF?, IL1? 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 ?-cells while promoting insulin secretion and synthesis. Activation of GPR40 leads to attenuation of ?-cell dysfunction caused by chronic inflammation and thus could be of immense clinical value to improve insulin secretion and ?-cell survival.

SUBMITTER: Verma MK

PROVIDER: S-EPMC4083038 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Verma Mahesh Kumar MK Sadasivuni Manoj Kumar MK Yateesh Aggunda N AN Neelima Korrapati K Mrudula Srikanth S Reddy Madhusudhan M Smitha Rachapalli R Biswas Sanghamitra S Chandravanshi Bhawna B Pallavi Puttrevana M PM Oommen Anup M AM Jagannath Madanahalli R MR Somesh Baggavalli B BB

BMC cell biology 20140630

<h4>Background</h4>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.<h4>Results</h4>By exposing ...[more]

PMID: 24974801

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