Combination peroxisome proliferator-activated receptor gamma and alpha agonist treatment in Type 2 diabetes prevents the beneficial pioglitazone effect on liver fat content.

Aims  Peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-α agonists individually reduce intra-organ triglyceride content and improve insulin sensitivity. However, the precise effects of combined PPAR-γ and PPAR-α therapy on intra-organ triglyceride content and insulin sensitivity in subjects with Type 2 diabetes have not yet been determined. Methods  Diet-controlled Type 2 subjects (n = 9) were studied before and after 16 weeks of combined PPAR-γ [pioglitazone (PIO), 45 mg daily] and PPAR-α [bezafibrate (BEZA), modified release 400 mg daily] agonist therapy. Glucose metabolism and endogenous glucose production were measured following a standard liquid test meal. Liver and muscle triglyceride levels were measured by 1H magnetic resonance spectroscopy. Results  Combined PIO and BEZA therapy reduced mean fasting (7.5 ± 0.5 vs. 6.5 ± 0.2 mmol/l, P = 0.04) and peak postprandial plasma glucose (15.3 ± 1.1 vs. 11.7 ± 0.6 mmol/l, P = 0.007). No significant change in hepatic or muscle triglyceride content was observed. Postprandial suppression of endogenous glucose production remained similar on both study days. Both subcutaneous and visceral fat content increased following therapy. Conclusions  Combined PIO and BEZA therapy in Type 2 diabetes does not decrease intrahepatic triglyceride content or postprandial endogenous glucose production. This study demonstrates an unexpected adverse interaction of PPAR-α with PPAR-γ agonist therapy.