alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells.
OBJECTIVE
The antioxidant compound alpha-lipoic acid (alpha-LA) possesses antidiabetic and anti-obesity properties. In the hypothalamus, alpha-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK). Given the therapeutic potential of alpha-LA for the treatment of type 2 diabetes and obesity, and the importance of AMPK in beta cells, we examined the effect of alpha-LA on pancreatic beta cell function.


METHODS
Isolated rat islets and MIN6 beta cells were treated acutely (15-90 min) or chronically (18-24 h) with alpha-LA or the known AMPK-activating compounds 5'-amino-imidazole-4-carboxamide ribonucleoside (AICAR) and metformin. Insulin secretion, the AMPK-signalling pathway, mitochondrial function and cell growth were assessed.


RESULTS
Acute or chronic treatment of islets and MIN6 cells with alpha-LA led to dose-dependent rises in phosphorylation of the AMPK alpha-subunit and acetyl CoA carboxylase. Chronic exposure to alpha-LA, AICAR or metformin caused a reduction in insulin secretion. alpha-LA inhibited the p70 s6 kinase translational control pathway, and inhibited MIN6 growth in a manner similar to rapamycin. Unlike AICAR and metformin, alpha-LA also acutely inhibited insulin secretion. Examination of the effect of alpha-LA on mitochondrial function showed that acute treatment with this compound elevated reactive oxygen species (ROS) production and enhanced mitochondrial depolarisation induced by Ca(2+).


CONCLUSIONS
This study is the first to demonstrate that alpha-LA directly affects beta cell function. The chronic effects of alpha-LA include AMPK activation and reductions in insulin secretion and content, and cell growth. Acutely, alpha-LA also inhibits insulin secretion, an effect probably involving the ROS-induced impairment of mitochondrial function.
Targonsky
E D
ED
Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada, M5S 1A8.
Dai
F
F
Koshkin
V
V
Karaman
G T
GT
Gyulkhandanyan
A V
AV
Zhang
Y
Y
Chan
C B
CB
Wheeler
M B
MB
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002478:Cells, Cultured; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism* / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D008063:Thioctic Acid / Q000494:pharmacology*
D007328:Insulin; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D008063:Thioctic Acid; D011494:Protein Kinases; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus