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

BMC Cell Biology

Baggavalli P Somesh¹  Madanahalli R Jagannath¹  Anup M Oommen¹  Puttrevana M Pallavi¹  Bhawna Chandravanshi¹  Sanghamitra Biswas¹  Rachapalli Smitha¹  Madhusudhan Reddy¹  Srikanth Mrudula¹  Korrapati Neelima¹  Aggunda N Yateesh¹  Manoj Kumar Sadasivuni¹  Mahesh Kumar Verma¹ 

[1] Connexios Life Sciences Pvt Ltd, Bangalore, India

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

Others  :  852063
DOI  :  10.1186/1471-2121-15-24

 received in 2014-01-14, accepted in 2014-06-24,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Verma et al.; licensee BioMed Central Ltd.

【 图 表 】

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