α-Lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells
E. D. Targonsky1, F. Dai1, V. Koshkin1, G. T. Karaman1, A. V. Gyulkhandanyan1, Y. Zhang1, C. B. Chan3 and M. B. Wheeler1, 2 Contact Information
(1) Department of Physiology, University of Toronto, 1 Kings College Circle, Toronto, ON, Canada, M5S 1A8
(2) Department of Medicine, University of Toronto, Toronto, ON, Canada
(3) Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, PE, Canada
Received: 15 October 2005 Accepted: 27 February 2006 Published online: 13 May 2006
Aims/hypothesis The antioxidant compound α-lipoic acid (α-LA) possesses antidiabetic and anti-obesity properties. In the hypothalamus, α-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK). Given the therapeutic potential of α-LA for the treatment of type 2 diabetes and obesity, and the importance of AMPK in beta cells, we examined the effect of α-LA on pancreatic beta cell function.
Materials and methods Isolated rat islets and MIN6 beta cells were treated acutely (1590 min) or chronically (1824 h) with α-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 α-LA led to dose-dependent rises in phosphorylation of the AMPK α-subunit and acetyl CoA carboxylase. Chronic exposure to α-LA, AICAR or metformin caused a reduction in insulin secretion. α-LA inhibited the p70 s6 kinase translational control pathway, and inhibited MIN6 growth in a manner similar to rapamycin. Unlike AICAR and metformin, α-LA also acutely inhibited insulin secretion. Examination of the effect of α-LA on mitochondrial function showed that acute treatment with this compound elevated reactive oxygen species (ROS) production and mitochondrial depolarisation induced by Ca2+.
Conclusions/interpretation This study is the first to demonstrate that α-LA directly affects beta cell function. The chronic effects of α-LA include AMPK activation and reductions in insulin secretion and content, and cell growth. Acutely, α-LA also inhibits insulin secretion, an effect probably involving the ROS-induced impairment of mitochondrial function.
Keywords AMPK - Insulin secretion - α-Lipoic acid - Mitochondrial permeability transition - mTOR - Pancreatic beta cell - Reactive oxygen species