Troglitazone amplifies counterregulatory responses to hypoglycemia in nondiabetic subjects

As insulin sensitizers, thiazolidinediones could affect the hormonal counte rregulatory response to hypoglycemia via the modulatory effect of insulin o n counterregulation. In addition, recent studies suggest that thiazolidined iones may influence key steps in glucose sensing and glucoregulatory hormon e secretion. We therefore evaluated the effects of a short course of trogli tazone on counter-regulatory hormones in response to mild hypoglycemia in e ight lean nondiabetic subjects. Subjects received either troglitazone (400 mg/day) or placebo for 7 days before stepped hypoglycemia clamp studies (5. 0, 4.4, 3.9, and 3.3 mmol/L target plasma glucose steps, 50 min each). The glycemic thresholds for secretion of epinephrine (3.77 +/- 0.05 mmol/L) and glucagon (3.83 +/- 0.11 mmol/L) were reset to a higher plasma glucose conc entration after troglitazone [4.05 +/- 0.05 mmol/L (P = 0.003) and 4.10 +/- 0.05 mmol/L (P = 0.03), respectively]. In addition, the magnitude of the r ise in epinephrine and glucagon concentrations was higher with troglitazone (28% and 11%, respectively; P < 0.05 for both), whereas plasma norepinephr ine, GH, and cortisol were comparable in both sets of studies. Endogenous g lucose production, measured with [3-H-3]glucose, rose by 33% (P < 0.05) in the troglitazone studies compared with 17% (P = NS) after placebo. We concl ude that thiazolidinediones may induce an amplification of the counterregul atory response to hypoglycemia characterized by a shift in the glycemic thr eshold for and an increase in the magnitude of glucagon and epinephrine sec retion, and subsequent activation of glucose production.