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


CONCLUSIONS
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.
Sun
Ying
Y
Department of Endocrinology, Shandong University, Jinan 250021, China.
Ren
Meng
M
Gao
Guan-qi
GQ
Gong
Bendi
B
Xin
Wei
W
Guo
Hua
H
Zhang
Xiu-juan
XJ
Gao
Ling
L
Zhao
Jia-jun
JJ
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D049449:Luminescence; D008163:Luminescent Measurements; D008297:Male; D047493:PPAR alpha / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D007328:Insulin; D047493:PPAR alpha; D010168:Palmitates; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D011345:Fenofibrate