Thalidomide impairs insulin action on glucose uptake and glycogen synthesis in patients with type 2 diabetes

OBJECTIVE - To investigate the effect of thalidomide on glucose turnover (g lucose production and uptake), on intracellular pathways of glucose utiliza tion (glycogen synthesis [GS], glycolysis [GLS], carbohydrate oxidation, an d nonoxidative GLS), and on free fatty acid (FFA) turnover (lipolysis, FFA oxidation, and FFA reesterification). RESEARCH DESIGN AND METHODS - A total of 6 patients with type 2 diabetes we re studied with 4-h isoglycemic-hyperinsulinemic clamps (similar to 8 mmol/ l and 500-600 pmol/l, respectively) before treatment (Prestudy), after 3 we eks of thalidomide (1SO mg orally at bedtime), and after 3 weeks of placebo . RESULTS - Thalidomide reduced insulin-stimulated glucose uptake by 31% (fro m 27.7 to 19.2 mu mol . kg(-1) min(-1), P < 0.05) compared with the prestud y and by 21% (from 24.2 to 19.2 mu mol kg(-1) . min(-1), P < 0.05) compared with placebo. Thalidomide also reduced insulinstimulated GS by 48% (from 1 4.1 to 8.2 mu mol . kg(-1) min(-1), P < 0.05) compared with the prestudy an d by 40% (from 13.6 to 8.2 mu mol . kg(-1) . min(-1), P < 0.5) compared wit h placebo. Thalidomide had no effect on rates of GLS, carbohydrate oxidatio n, nonoxidative GLS, lipolysis, FFA oxidation, and reesterification. CONCLUSIONS - We conclude that thalidomide increased insulin resistance in obese patients with type 2 diabetes by inhibiting insulin-stimulated GS and that patients taking thalidomide should be monitored for possible deterior ation in their glucose tolerance.