Effects of Troglitazone in Young First-Degree Relatives of Patients With Type 2 Diabetes

Abstract

OBJECTIVE—Insulin resistance is a key characteristic of first-degree relatives of patients with type 2 diabetes. We therefore treated young, glucose-tolerant relatives with the insulin action enhancer troglitazone in order to determine the effects on insulin sensitivity, glucose metabolism, and glycogen synthase activity.

RESEARCH DESIGN AND METHODS—Relatives were randomized in a double-blind manner and treated for 12 weeks with either 200 mg troglitazone or placebo. Before and after treatment, an oral glucose tolerance test (OGTT) and a euglycemic-hyperinsulinemic clamp (40 mU · m⁻² · min⁻¹) were performed, including 3-³H glucose infusion, glycolytic flux calculations, indirect calorimetry, and muscle biopsies.

RESULTS—Twelve relatives received troglitazone and 12 placebo (aged 30.8 ± 2.0 vs. 30.3 ± 1.6 years, BMI 29.6 ± 0.8 vs. 30.5 ± 1.3 kg/m²; means ± SE). Area under the curve (AUC) for plasma glucose at the second OGTT was unchanged after troglitazone. In contrast, troglitazone reduced fasting (from 70.3 ± 6.9 to 52.2 ± 5.8 vs. 73.6 ± 11.0 to 73.3 ± 6.5 pmol/l, P < 0.02) and AUC plasma insulin (mean [CI] from 335.7 [230.9–488.1] to 277.4 [179.4–428.8] vs. 313.8 [218.2–451.2] to 353.9 [208.3–601.3] pmol/l, P < 0.05). Additionally, fasting plasma triglycerides were reduced by troglitazone (from 1.86 ± 0.33 to 1.38 ± 0.27 vs. 2.22 ± 0.44 to 2.35 ± 0.46 mmol/l, P < 0.01). Insulin-stimulated glucose disposal increased in the troglitazone group (from 208.3 ± 23.7 to 263.5 ± 30.4 vs. 197.1 ± 20.0 to 200.8 ± 20.8 mg · m⁻² · min⁻¹, P < 0.02) mainly due to increased glucose storage (from 99.9 ± 17.9 to 146.0 ± 25.3 vs. 87.1 ± 16.7 to 87.9 ± 15.7 mg · m⁻² · min⁻¹, P < 0.02), which took place without altering insulin-stimulated glycogen synthase activity.

CONCLUSIONS—In glucose-tolerant first-degree relatives, treatment with troglitazone improved insulin sensitivity almost 50%, primarily due to increased glucose storage. It is suggested that the use of insulin action enhancers can be especially valuable in this group of subjects with a known high risk for developing type 2 diabetes.