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Pioglitazone is a member of the thiazolidinediones (TZDs), insulin-sensitizing agents used to treat type 2 diabetes. The aim of this study was to define the effect of pioglitazone on the expression of genes related to carbohydrate and lipid metabolism in subcutaneous fat obtained from type 2 diabetic patients.Forty-eight volunteers with type 2 diabetes were divided into two groups treated for 12 weeks with placebo or pioglitazone (30 mg/day). The expression of several genes was quantified by real-time RT-PCR.Pioglitazone treatment increased the expression of genes involved in glycerol-3-phosphate synthesis. The mRNA expression of PEPCK-C and glycerol-3-phosphate dehydrogenase (GPDH) increased (P < 0.01) in patients treated with pioglitazone. There was no difference in glycerol kinase (GyK) mRNA levels. The expression of genes that regulate fatty acid availability in adipocytes, including lipoprotein lipase (LPL) and acetyl-CoA synthetase (ACS), was higher (P < 0.01) in pioglitazone-treated patients. Pioglitazone stimulated (P < 0.0001) expression of c-Cbl-associated protein (CAP), whereas tumor necrosis factor-α, leptin, resistin, angiopoietin like-4, and 11-β-hydroxysteroid dehydrogenase type 1 (11β HSD 1) were not affected by pioglitazone. The baseline peroxisome proliferator-activated receptor (PPAR)-γ1 mRNA was significantly correlated with mRNA for LPL, CAP, ACS, 11β HSD 1, GyK, fatty acid synthase, leptin, and GPDH, whereas PPAR-γ2 mRNA was correlated with CAP, PEPCK-C, leptin, and GPDH.Treatment with pioglitazone increased body weight, and this is associated with upregulation of some, but not all, genes previously demonstrated as "TZD responsive" in subcutaneous fat. The results suggest that TZDs might increase body weight through the upregulation of genes facilitating adipocyte lipid storage in vivo.