Metformin-induced stimulation of AMP-activated protein kinase in β-cells impairs their glucose responsiveness and can lead to apoptosis

Metformin is an anti-diabetic drug that increases glucose utilization in insulin-sensitive tissues. The effect is in part attributable to a stimulation of AMP-activated protein kinase (AMPK). The present study demonstrates that metformin (0.5-2 mM) also dose-dependently activates AMPK in insulin-producing MIN6 cells and in primary rat beta-cells, leading to increased phosphorylation of acetyl coA carboxylase (ACC). The maximal effect was reached within 12 h and sustained up to 48 h. After 24 h exposure to metformin (0.5-1 mM), rat P-cells exhibited a reduced secretory and synthetic responsiveness to 10 mM glucose, which was also the case following 24 h culture with the AMPK-activator 5-amino-imidazole-4-carboxamide riboside (AICAR; 1 mM). Longer metformin exposure (>24 h) resulted in a progressive increase in apoptotic beta-cells as was also reported for AICAR; metformin-induced apoptosis was reduced by compound C, an AMPK-inhibitor. As with AICAR, metformin activated c-Jun-N-terminal kinase (JNK) and caspase-3 prior to the appearance of apoptosis. It is concluded that metformin-induced AMPK-activation in beta-cells reduces their glucose responsiveness and may, following sustained exposure, result in apoptosis. (C) 2004 Elsevier Inc. All rights reserved.