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Diabetologia. 2006 Jul;49(7):1587-98. Epub 2006 May 13.

alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells.

Author information

1
Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada, M5S 1A8.

Abstract

AIMS/HYPOTHESIS:

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.

MATERIALS AND 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/INTERPRETATION:

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.

PMID:
16752177
DOI:
10.1007/s00125-006-0265-9
[Indexed for MEDLINE]

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