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Rosiglitazone Reduces Liver Fat and Insulin Requirements and Improves Hepatic Insulin Sensitivity and Glycemic Control in Patients with Type 2 Diabetes Requiring High Insulin Doses

Department of Medicine (L.J., A.K., H.Y.-J.), Division of Diabetes, University of Helsinki, Minerva Medical Research Institute (L.J., A.K.), and Department of Internal Medicine (M.G.), Division of Cardiology, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland

Address all correspondence and requests for reprints to: Anna Kotronen, M.B., Department of Medicine, Division of Diabetes, University of Helsinki, P.O. Box 700, Room C418B, FIN-00029 HUCH Helsinki, Finland. E-mail: anna.kotronen{at}helsinki.fi.

Background: Liver fat is an important determinant of insulin requirements during insulin therapy. Peroxisome proliferator-activated receptor (PPAR)- agonists reduce liver fat. We therefore hypothesized that type 2 diabetic patients using exceptionally high doses of insulin might respond well to addition of a PPAR agonist.

Methods: We determined the effect of the PPAR agonist rosiglitazone on liver fat and directly measured hepatic insulin sensitivity in 14 patients with type 2 diabetes (aged 51 ± 3 yr, body mass index 36.7 ± 1.1 kg/m²), who were poorly controlled (glycosylated hemoglobin A_1c (HbA_1c) 8.9 ± 0.4%) despite using high doses of insulin (218 ± 22 IU/d) in combination with metformin. Liver fat content (¹H-magnetic resonance spectroscopy), hepatic insulin sensitivity [6 h hyperinsulinemic euglycemic clamp (insulin 0.3 mU/kg·min) combined with [3-³H]glucose], body composition (magnetic resonance imaging), substrate oxidation rates (indirect calorimetry), clinical parameters, and liver enzymes were measured before and after rosiglitazone treatment (8 mg/d) for 8 months.

Results: During rosiglitazone, HbA_1c decreased from 8.9 ± 0.4% to 7.8 ± 0.3% (P = 0.007) and insulin requirements from 218 ± 22 to 129 ± 20 IU/d (P = 0.002). Liver fat content decreased by 46 ± 9% from 20 ± 3% to 11 ± 3% (P = 0.0002). Hepatic insulin sensitivity, measured from the percent suppression of endogenous glucose production by insulin, increased from –40 ± 7% to –89 ± 12% (P = 0.001). The percent change in liver fat correlated with the percent decrease in HbA_1c (r = 0.53, P = 0.06), insulin dose (r = 0.66, P = 0.014), and suppression of endogenous glucose production (r = 0.76, P = 0.003).

Conclusions: Our results suggest that rosiglitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses. The mechanism is likely to involve reduced liver fat and enhanced hepatic insulin sensitivity.

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