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

• Published in: Diabetologia 2006-07, Vol.49 (7), p.1587-1598
• Main Authors: TARGONSKY, E. D, DAI, F, KOSHKIN, V, KARAMAN, G. T, GYULKHANDANYAN, A. V, ZHANG, Y, CHAN, C. B, WHEELER, M. B
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases; Animals; Biological and medical sciences; Cells, Cultured; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Models, Biological; Multienzyme Complexes - metabolism; Multienzyme Complexes - physiology; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Sirolimus - pharmacology; Thioctic Acid - pharmacology; TOR Serine-Threonine Kinases
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0265-9

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. 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. 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+). 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.