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

Biochem Pharmacol. 2004 Aug 1;68(3):409-16. doi: 10.1016/j.bcp.2004.04.003.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Apoptosis*
  • Enzyme Activation / drug effects
  • Female
  • Glucose / metabolism*
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • JNK Mitogen-Activated Protein Kinases
  • Metformin / pharmacology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Multienzyme Complexes / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Wistar

Substances

  • Hypoglycemic Agents
  • Insulin
  • Multienzyme Complexes
  • Metformin
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • Glucose