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Biochem Pharmacol. 2004 Aug 1;68(3):409-16.

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

Author information

1
Diabetes Research Center, Partner of the Juvenile Diabetes Research Center for Beta-cell Therapy in Europe, Brussels Free University-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium.

Abstract

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 (0.5-2mM) 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 12h and sustained up to 48h. After 24h exposure to metformin (0.5-1mM), rat beta-cells exhibited a reduced secretory and synthetic responsiveness to 10mM glucose, which was also the case following 24h culture with the AMPK-activator 5-amino-imidazole-4-carboxamide riboside (AICAR; 1mM). Longer metformin exposure (>24h) 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.

PMID:
15242807
DOI:
10.1016/j.bcp.2004.04.003
[Indexed for MEDLINE]

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