The biguanides metformin and phenformin enhance insulin sensitivity and improve glycaemic control in type 2 diabetes. Metformin is the most prescribed oral agent for type 2 diabetes but phenformin has been withdrawn because of its propensity to cause lactic acidosis. Metformin has a major effect in the liver where it reduces glucose output via AMPK activation. As the adipocyte is now considered to be a critical participant in whole-organism metabolic homeostasis we investigated metformin action in the murine 3T3-L1 adipocyte model. Treatment of cells with metformin for 2 h had no effect on subsequent basal or insulin-stimulated glucose uptake or on basal or isoproterenol-stimulated lipolysis, although phenformin significantly reduced insulin-stimulated glucose uptake and isoproterenol-induced lipolysis. AMPK activity was more strongly activated by phenformin than metformin. Moreover, phenformin markedly inhibited differentiation of preadipocytes, while metformin had no significant effect. To determine whether metformin might affect adipocyte functions not captured by targeted biochemical assays we undertook a global transcriptomic analysis of metformin-treated adipocytes. While 2 h metformin treatment did not induce any significant changes in mRNA expression, 12 h incubation significantly altered the abundance of 44 transcripts, including mRNAs encoding key enzymes involved in metabolism and protection from oxidative stress, and several transcription factors and transcriptional co-regulators. We conclude that, acute treatment with metformin has little impact on adipocyte function, but prolonged treatment results in significant changes in gene expression, including induction of genes implicated in response to cellular stress, suggesting that some of metformins beneficial effects may be mediated through the modification of the stress response. In contrast, the striking effects of phenformin in adipocytes may contribute to its adverse metabolic profile.
03 - 07 May 2008
European Society of Endocrinology