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Articles in PresS, published online ahead of print July 28, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00195.2002
Submitted on May 7, 2002
Accepted on July 24, 2002
1 Departments of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, CT, USA
2 Departments of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, CT, USA; The Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: robert.sherwin{at}yale.edu.
Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intra-islet 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 non-insulin glucose lowering agents 5-aminoimadazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and non-diabetic BB rats. The phlorizin-AICAR combination was able to induce moderate, and equivalent hypoglycemia to insulin in both diabetic and non-diabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with non-diabetic rats. In contrast, both glucagon (9-10 fold increase) and epinephrine (5-6-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 intra-islet hyperinsulinemia is prevented. This suggests exogenous insulin plays a pivotable role in the etiology of this defect.
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