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It is proposed that the impaired counterregulatory response (CRR) to hypoglycemia in insulin deficient diabetes may be due to chronic brain insulin deficiency. To test this hypothesis, streptozotocin-diabetic Sprague-Dawley rats were infused with either insulin (3mU/day) or artificial cerebrospinal fluid (aCSF) bilaterally into the ventromedial hypothalamus (VMH) for 2 weeks and compared to nondiabetic rats. Rats underwent hyperinsulinemic (50 mU.kg.min) hypoglycemic (~45 mg/dl) clamps. Diabetic rats demonstrated an impaired CRR to hypoglycemia noted by an high glucose infusion rate (GIR) and blunted epinephrine and glucagon responses. The defective sympathoadrenal response was restored with chronic infusion of insulin into the VMH. Diabetic rats had decreased VMH Akt phosphorylation and decreased VMH glucose transporter 4 (GLUT4) content, which was also restored with chronic infusion of insulin into the VMH. Separate experiments in non-diabetic rats in which VMH GLUT4 translocation was inhibited with an infusion of indinavir was notable for an impaired CRR to hypoglycemia indicated by increased GIR and diminished epinephrine and glucagon responses. Results suggest that in this model of diabetes, VMH insulin deficiency impairs the sympathoadrenal response to hypoglycemia and chronic VMH insulin infusion is sufficient to normalize the sympathoadrenal response to hypoglycemia, via restoration of VMH GLUT4 expression.

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