HYPOGLYCEMIA COUNTERREGULATION IN DIABETES

In type 1 diabetes, impaired counterregulatory mechanisms play important and sometimes dominant roles in the pathogenesis of severe hypoglycemia. Defective counterregulation appears to be due, in part, to altered glycemic thresholds for activation of hormones and symptoms which, in turn, may result from alteration in blood brain barrier (BBB) glucose transport. This is important because under conditions of hypoglycemia glucose transport becomes rate-limiting for brain glucose metabolism. During intensive insulin treatment, loss of awareness of hypoglycemia may be related to altered brain glucose transport. The major BBB glucose transport molecule is GLUT 1 which has been shown to be upregulated in certain experimental hypoglycemic conditions. These conditions, however, are of chronic, nonphysiologic hypoglycemia. The question remains whether insulin-induced hypoglycemia of the sort to which patients with diabetes are prone is also associated with alterations in glucose transport. Whole-brain glucose uptake studies suggest that chronic adaptation to glucose levels in type 1 diabetes (e.g., during intensive treatment) may indeed occur, but this is quite controversial. Troglitazone is an insulin sensitizer not chemically related to either sulfonylurea or biguanide agents. Thiazolidinedione agents have been shown to enhance GLUT 1 activity in vitro and in vivo. Troglitazone increases basal glucose transport while insulin-stimulated transport is unaffected. We hypothesize that troglitazone may improve hypoglycemia awareness and/or counterregulation by enhancing BBB glucose transporter activity. In addition, as an "insulin sensitizer," troglitazone could influence the plasma insulin concentrations required to lower plasma glucose; we and others have shown that prevailing plasma insulin may be an important variable in the counterregulatory response to hypoglycemia in humans. The current study is a comparison of the hormonal, metabolic, and symptomatic responses to experimental hypoglycemia using a stepped clamp technique with prior treatment with either troglitazone or placebo for one week.