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Am J Physiol Endocrinol Metab 283: E1076-E1083, 2002. First published July 30, 2002; doi:10.1152/ajpendo.00195.2002
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Vol. 283, Issue 5, E1076-E1083, November 2002

AICAR and phlorizin reverse the hypoglycemia-specific defect in glucagon secretion in the diabetic BB rat

R. J. McCrimmon1, M. L. Evans1, R. J. Jacob1, X. Fan1, Y. Zhu1, G. I. Shulman1,2, and R. S. Sherwin1

1 Department of Internal Medicine and Endocrinology, and 2 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520

Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intraislet hyperinsulinemia plays a role in the genesis of this defect, glucagon-secretory responses to moderate hypoglycemia induced by either insulin or a novel combination of the noninsulin glucose-lowering agents 5-aminoimidazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and nondiabetic BB rats. The phlorizin-AICAR combination was able to induce moderate and equivalent hypoglycemia in both diabetic and nondiabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with nondiabetic rats. In contrast, both glucagon (9- to 10-fold increase) and epinephrine (5- to 6-fold increase) responses were markedly improved during phlorizin-AICAR hypoglycemia. Combining phlorizin, AICAR, and insulin attenuated the glucagon response to hypoglycemia by 70% in the diabetic BB rat. Phlorizin plus AICAR had no effect on counterregulatory hormones under euglycemic conditions. We conclude that alpha -cell glucagon secretion in response to hypoglycemia is not defective if intraislet hyperinsulinemia is prevented. This suggests that exogenous insulin plays a pivotal role in the etiology of this defect.

type 1 diabetes; counterregulation; epinephrine; insulin; 5-aminoimadazole-4-carboxamide; adenosine 5'-monophosphate-activated protein kinase


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