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Chronic palmitate exposure inhibits AMPKalpha and decreases glucose-stimulated insulin secretion from beta-cells: modulation by fenofibrate.

Abstract：

AIM:Adenosine monophosphate-activated protein kinase (AMPK), a vital regulator of glucose metabolism, may affect insulin secretion in beta-cells. However, the role of AMPK in beta-cell lipotoxicity remains unclear. Fenofibrate has been reported to regulate lipid homeostasis and is involved in insulin secretion in pancreatic beta-cells. In the present study, we aimed to investigate the effect of palmitate on AMPK expression and glucose-stimulated insulin secretion (GSIS) in rat islets and INS-1 beta-cell, as well as the effect of fenofibrate on AMPK and GSIS in INS-1 cells treated with palmitate. METHODS:Isolated rat islets and INS-1 beta-cells were treated with and without palmitate or fenofibrate for 48 h. The mRNA levels of the AMPK alpha isoforms were measured by real-time PCR. Western blotting was used to detect the protein expression of total AMPKalpha (TAMPKalpha), phosphorylated AMPKalpha (P-AMPKalpha), and phosphorylated acetyl coenzyme A carboxylase (P-ACC). Insulin secretion was detected by radioimmunoassay induced by 20 mmol/L glucose as GSIS. RESULTS:The results showed that chronic exposure of beta-cells to palmitate for 48 h inhibited the expression of AMPK alpha1 mRNA and T-AMPK alpha protein levels, as well as P-AMPK alpha and PACC protein expressions in a dose-dependent manner. Accordingly, GSIS was inhibited by palmitate. Compared with the palmitate-treated cells, fenofibrate ameliorated these changes impaired by palmitate and exhibited a significant elevation in the expression of AMPK alpha and GSIS. CONCLUSION:Our findings suggest a role of AMPK alpha reduction in beta-cell lipotoxicity and a novel role of fenofibrate in improving GSIS associated with the AMPK alpha activation in beta-cells chronically exposed to palmitate.

journal_name

Acta Pharmacol Sin

journal_title

Acta pharmacologica Sinica

authors

Sun Y,Ren M,Gao GQ,Gong B,Xin W,Guo H,Zhang XJ,Gao L,Zhao JJ

doi

10.1111/j.1745-7254.2008.00717.x

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

443-50

issue

eissn

1671-4083

issn

1745-7254

journal_volume

pub_type

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Chronic palmitate exposure inhibits AMPKalpha and decreases glucose-stimulated insulin secretion from beta-cells: modulation by fenofibrate.