Combination Therapy with Pparα and Pparγ Agonists in Type 2 Diabetes Blunts the Reduction in Intra-Organ Triglyceride Content Seen with Pparγ Monotherapy.

Balasubramanian, Ravikumar; Gerrard, Jean; English, Philip T.; Firbank, Michael F.; Taylor, Roy

PPARγ monotherapy in type 2 diabetes (T2DM) is characterized by significant reduction in intra-organ triglyceride content. It was hypothesized that combined PPARγ and PPARα therapy in T2DM may achieve a greater decrease. 9 diet-controlled T2DM subjects (5M;4F; age 52.7 ± 2.7 years; HbA1c 6.5 ± 0.2 %) were studied before and after 4 months treatment with pioglitazone 45mg and bezafibrate 400mg. Changes in liver, muscle and abdominal fat content was measured by magnetic resonance spectroscopy and MRI and postprandial metabolism studied following a mixed meal. Mean fasting (7.5 ± 0.5 vs. 6.5 ± 0.2 mmol/L, p<0.001), fasting insulin (94.9 ± 25.9 vs. 55.7 ± 11.3 pmol/L, p=0.11) and postprandial glucose (13.9 ± 1.1 vs. 11.3 ±0.7 mmol/L at 120 min, p=0.001) were reduced following combination therapy. Despite a mean weight gain of 3.4 kg, fasting plasma triglyceride improved [2.15 ± 0.51 to 1.31 ± 0.39 mmol/L (p=0.01] and HOMA-IR improved [2.14 ± 0.49 to 0.76 ± 0.3 (p =0.03)]. No significant change was observed in liver (129 ± 53.3 vs. 138.8 ± 53.6 mmol/L, p=NS) or muscle triglyceride (7.3 ± 1.9 vs. 5.4 ± 1.7 mmol/L, p=NS) content. Fasting NEFA improved from 0.55 ± 0.05 to 0.41 ± 0.07 mmol/L (p =0.08). Both subcutaneous fat content (9.36 ± 1.82 vs. 7.82 ± 1.55 L, p=0.01) and visceral fat content (4.83 ± 0.58 vs. 4.44 ± 0.68 L, p=0.03) increased significantly. Combination of PPARα therapy with PPARγ is not additive and blunts the reduction in liver and muscle triglyceride content we and others have previously reported for PPARγ monotherapy.

COMBINATION drug therapy; INSULIN agonists; TYPE 2 diabetes; TRIGLYCERIDES; DRUG therapy

Diabetes, 2007, Vol 56, pA163

0012-1797

Academic Journal