Effects of troglitazone in young first-degree relatives of patients with type 2 diabetes.
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.


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 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.
Levin
Klaus
K
Diabetes Research Centre, Department of Endocrinology M, Odense University Hospital, Odense, Denmark. kl22@bbh.hosp.dk
Hother-Nielsen
Ole
O
Henriksen
Jan Erik
JE
Beck-Nielsen
Henning
H
D001786:Blood Glucose / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005190:Family; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D009765:Obesity / Q000503:physiopathology; D010084:Oxidation-Reduction; D012307:Risk Factors; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D000077288:Troglitazone
D001786:Blood Glucose; D002839:Chromans; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D045162:Thiazolidinediones; D000077288:Troglitazone