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

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 Ca 2+ . 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.

Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin

“…To confirm the activity of AMPK in the N-43/5 neurons, we also measured the phosphorylation of ACC, a downstream substrate of pAMPK (Minokoshi et al 2002, Yamashita et al 2004, Targonsky et al 2006. Decreased phosphorylation of ACC indicates increased activity leading to an increase in malonyl-CoA, a potential regulatory component of the energy-sensing system (Wolfgang & Lane 2006).…”

Activation of the AMP-activated protein kinase enhances glucose-stimulated insulin secretion in mouse β-cells

“…[14][15][16] Others did not find any acute effects of AICAR on insulin secretion and conclude that the AMPK does not play a decisive role for b-cell function. 17,18 These discrepancies can neither be explained by different glucose or AICAR concentrations nor by species differences. Experiments with AMPK knockout mice bearing an inactivated subunit of either the alpha 1 -or alpha 2 -isoform, 10 do not help to unravel the confusion.…”

Mitochondria and Antioxidants: The Active Players in Islet Oxidative Stress

“…Discrepancies in the effective concentration ranges reported in these studies may lie in different nature of oxidative stress stimuli and in www.intechopen.com different protective mechanisms by which ALA acted in each case. Concentration of 2 mM, which is not physiologically relevant, impaired functions of isolated rat islets and MIN6 cells (Targonsky et al 2006). …”