Combined treatment with low-dose pioglitazone and beraprost sodium improves glucose intolerance without causing body weight gain

Abstract

Pioglitazone (PIO) is widely used as an insulin-sensitizing agent in the treatment of type 2 diabetes, but it also causes an increase in body weight in a dose-dependent manner. Beraprost sodium (BPS), a stable prostaglandin I2 analog, is used clinically for the treatment of peripheral arterial disease and primary pulmonary hypertension. BPS has recently been demonstrated to promote insulin-induced glucose uptake by skeletal muscle. In this study, we examined whether low-dose PIO (PIO-L; 3 mg/kg/day) plus BPS treatment might exert antidiabetic effects without causing body weight gain in obese/diabetic KKAy mice. Treatment with PIO-L plus BPS tended to improve the hepatic insulin resistance and significantly improved the skeletal muscle insulin resistance, yielding a similar degree of hyperglycemia improvement to that obtained with high-dose PIO (PIO-H; 30 mg/kg/day) treatment. Moreover, the increase in body weight observed following PIO-H treatment was not observed following PIO-L plus BPS treatment. An increase in plasma adiponectin levels, which have been shown to be negatively correlated with hepatic glucose production, but not with the glucose disappearance rate during hyperinsulinemic-euglycemic clamp, was observed in the animals treated with PIO-L, PIO-L plus BPS, and PIO-H. This suggests that the improvement in hepatic insulin resistance was associated, at least in part, with an increase in the plasma adiponectin levels observed during PIO treatment. In contrast, treatment with BPS, which failed to increase the plasma adiponectin levels, ameliorated skeletal, but not hepatic insulin resistance. PIO-L plus BPS treatment may represent efficacious treatment for insulin resistance and type 2 diabetes without causing body weight gain.