Effect of Rosiglitazone on Glucose and Non-esterified Fatty Acid Metabolism in Type II Diabetic Patients

Aims/hypothesis: We aimed to examine the mechanisms by which rosiglitazone improves glycaemic control in Type II (non-insulin-dependent) diabetic patients.

Methods: Altogether 29 diet-treated diabetic patients were assigned at random to rosiglitazone, 8 mg/day (n = 15), or placebo (n = 14) for 12 weeks. Patients received 75 g OGTT and two-step euglycaemic insulin (40 and 160 mU/m(2)min) clamp with 3-(3)H-glucose, (14)C-palmitate and indirect calorimetry.

Results: After 12 weeks, rosiglitazone reduced fasting plasma glucose (195 +/- 11 to 150 +/- 7 mg/dl, p < 0.01), mean plasma glucose (PG) during OGTT (293 +/- 12 to 236 +/- 9 mg/dl, p < 0.01), and HbA1 c (8.7 +/- 0.4 to 7.4 +/- 0.3 %, p < 0.01) without changes in plasma insulin concentration. Basal endogenous glucose production (EGP) declined (3.3 +/- 0.1 to 2.9 +/- 0.1 mg/kg FFM. min, p < 0.05) and whole body glucose metabolic clearance rate increased after rosiglitazone (first clamp step: 2.8 +/- 0.2 to 3.5 +/- 0.2 ml/kg FFM. min, p < 0.01; second clamp step: 6.7 +/- 0.6 to 9.2 +/- 0.8, p < 0.05) despite increased body weight (86 +/- 4 to 90 +/- 4 kg, p < 0.01) and fat mass (33 +/- 3 to 37 +/- 3 kg, p < 0.01). Fasting plasma non-esterified fatty acid (NEFA) (735 +/- 52 to 579 +/- 49 microEq/l, p < 0.01), mean plasma NEFA during OGTT (561 +/- 33 to 424 +/- 35, p < 0.01), and basal NEFA turnover (18.3 +/- 1.5 to 15.5 +/- 1.2 microEq/kg FM. min, p < 0.05) decreased after rosiglitazone. Changes in EPG and mean plasma glucose (PG) during OGTT correlated with changes in basal EGP (r = 0.54; r = 0.58), first EGP (r = 0.36; r = 0.41), first MCR (r = -0.66; r = -0.68), second MCR (r = -0.49; r = -0.54), fasting plasma NEFA (r = 0.53; r = 0.49), and NEFA during OGTT (r = 0.66; r = 0.66).

Conclusion/interpretation: Rosiglitazone increases hepatic and peripheral (muscle) tissue insulin sensitivity and reduces NEFA turnover despite increased total body fat mass. These results suggest that the beneficial effects of rosiglitazone on glycaemic control are mediated, in part, by the drug's effect on NEFA metabolism.