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Chronic Treatment with Pioglitazone Does Not Protect Obese Patients with Diabetes Mellitus Type II from Free Fatty Acid-Induced Insulin Resistance

Departments of Endocrinology and Metabolism (M.J.S., G.A., H.P.S.), Medical Biochemistry (J.E.G., J.M.A., A.J.M.), and Clinical Chemistry, Laboratory of Endocrinology (M.T.A., B.C.V.), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; and Department of Internal Medicine, Hospital Gelderse Vallei (R.H.), 6710 HN Ede, The Netherlands

Address all correspondence and requests for reprints to: M. J. M. Serlie, Academic Medical Center, F5-169, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: m.j.serlie{at}amc.uva.nl.

Context: Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated.

Objective: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids.

Design: We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids.

Patients: Patients were obese with poorly controlled type 2 diabetes mellitus.

Intervention: Patients were treated with 30 mg pioglitazone once daily.

Main Outcome Measure: The change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion was the main outcome measure.

Results: Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change.

Conclusions: Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with type 2 diabetes mellitus from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids.

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