Troglitazone ameliorates insulin resistance in patients with Werner's syndrome.

Abstract

Insulin resistance in Werner's syndrome (WS) is probably due to defective signaling distal to the insulin receptor. To analyze the metabolic effects of troglitazone (TRO) in these patients, we performed frequently sampled iv glucose tolerance tests. Glucose kinetics were analyzed by the minimal model. Five patients with WS (mean age, 41.2 yr; body mass index, 17.0 kg/m2) were treated with TRO (400 mg/day) for 4 weeks. Each subject underwent a 75-g OGTT and frequently sampled iv glucose tolerance tests. Treatment reduced the area under the curve of glucose and insulin in the OGTT by 26% and 43%, respectively. Glucose tolerance, as manifested by the glucose disappearance rate improved significantly (1.36 +/- 0.16 to 1.94 +/- 0.30%/min; P < 0.05). Although the first phase insulin secretion was unchanged, insulin sensitivity and glucose effectiveness increased significantly [0.47 +/- 0.11 to 1.38 +/- 0.37 x 10(-4) min/pmol.L (P < 0.05) and 1.72 +/- 0.17 to 2.52 +/- 0.24 x 10(-2) min-1 (P < 0.05), respectively]. However, treatment did not change glucose effectiveness at zero insulin. In patients with WS, TRO ameliorates glucose intolerance mediated by increased insulin sensitivity as well as glucose effectiveness, as assessed by minimal model analysis. TRO may modulate the postreceptor signaling component and be a clinically useful regimen for the treatment of patients with the intracellular insulin signaling defect.