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

Effects of Troglitazone in Young First-Degree Relatives of Patients With Type 2 Diabetes Klaus Levin , MD, PHD , Ole Hother-Nielsen , MD, PHD , Jan Erik Henriksen , MD, PHD and Henning Beck-Nielsen , MD, PHD From the Diabetes Research Centre, Department of Endocrinology M, Odense University Hospital, Odense, Denmark Address correspondence and reprint requests to Klaus Levin, MD, Department of Endocrinology M, Kloevervaenget 6, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: kl22{at}bbh.hosp.dk 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- 3 H 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/m 2 ; 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 sugges