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1Henry Wellcome Laboratories for Integrated Cell Signalling and Department of Biochemistry, School of Medical Sciences, University of Bristol, BS8 1TD Bristol; 2Academic Renal Unit, Southmead Hospital, University of Bristol, BS10 5NB Bristol, United Kingdom; and 3Department of Surgery, Surgical-Medical Research Institute, University of Alberta, Edmonton, Canada T6G 2N8
Submitted 21 November 2003 ; accepted in final form 3 February 2004
Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761–774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2–1 mM) activated AMPK in both human islets and MIN6 
-cells in parallel with an inhibition of insulin secretion, whereas leptin (10–100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal -cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.
5'-adenosine monophosphate-activated protein kinase; human islets of Langerhans; MIN6 cells
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