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1 Henry Wellcome Laboratories for Integrated Cell Signalling and Department of Biochemistry, University of Bristol, Bristol, United Kingdom
2 Academic Renal Unit, Southmead Hospital, University of Bristol, Bristol, United Kingdom
3 Department of Surgery, Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada
* To whom correspondence should be addressed. E-mail: i.leclerc{at}bristol.ac.uk.
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, regulate 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 et al, Biochem. J 371:761-774,
2003). Here, we explore whether (a) glucose, metformin or leptin regulate AMPK
activity in isolated islets from rodent and human, and (b) whether changes in AMPK
activity modulate insulin secretion from human islets. Increases in glucose
concentration from 0 to 3 and 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 in respect to the use of this drug for the treatment of Type 2 diabetes.
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