Mechanisms of glucose hypersensitivity in beta-cells from normoglycemic, partially pancreatectomized mice

Increased beta-cell sensitivity to glucose precedes the loss of glucose-ind uced insulin secretion in diabetic animals. Changes at the level of beta-ce ll glucose sensor have been described in these situations, but it is not cl ear wether they fully account for the increased insulin secretion, Using a euglycemic-normolipidemic 60% pancreatectomized (60%-Px) mouse model, we ha ve studied the ionic mechanisms responsible for increased beta-cell glucose sensitivity. Two weeks after Px (Px14 group), Px mice maintained normoglyc emia with a reduced beta-cell mass (0.88 +/- 0.18 mg) compared with control mice (1.41 +/- 0.21 mg). At this stage, the dose-response curve for glucos e-induced insulin release showed a significant displacement to the left (P < 0.001). Islets from the Px14 group showed oscillatory electrical activity and cytosolic Ca2+ ([Ca2+](i)) oscillations in response to glucose concent rations of 5.6 mmol/l compared with islets from the control group at 11.1 m mol/l. All the above changes were fully reversible both in vitro (after 48- h culture of islets from the Px14 group) and in vivo (after regeneration of beta-cell mass in islets studied 60 days after Ps). No significant differe nces in the input resistance and ATP inhibition of ATP-sensitive K+ (K-ATP) channels were found between beta-cells from the Px14 and control groups. T he dose-response curve for glucose-induced MTT (C,N-diphenyl-N"-4,5-dimethy l thiazol 2 yl tetrazolium bromide) reduction showed a significant displace ment to the left in islets from the Px14 group (P < 0.001). These results i ndicate that increased glucose sensitivity in terms of insulin secretion an d Ca2+ signaling was not due to intrinsic modifications of K-ATP channel pr operties, and suggest that the changes are most likely to be found in the g lucose metabolism.