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01.07.2006 | Article

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

verfasst von: E. D. Targonsky, F. Dai, V. Koshkin, G. T. Karaman, A. V. Gyulkhandanyan, Y. Zhang, C. B. Chan, M. B. Wheeler

Erschienen in: Diabetologia | Ausgabe 7/2006

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Abstract

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 (15–90 min) or chronically (18–24 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 enhanced 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.

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Titel: α-Lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells
verfasst von: E. D. Targonsky
F. Dai
V. Koshkin
G. T. Karaman
A. V. Gyulkhandanyan
Y. Zhang
C. B. Chan
M. B. Wheeler
Publikationsdatum: 01.07.2006
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 7/2006
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0265-9

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Abstract

Aims/hypothesis

Materials and methods

Results

Conclusions/interpretation

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