Pioglitazone improves insulin sensitivity, reduces visceral fat and stimulates lipolysis in non diabetic dialyzed patients

Abstract

Insulin resistance is common in dialyzed patients and is associated with increased mortality and protein-energy wasting. The aim of this study was to investigate the effect of pioglitazone (PIO), a powerful insulin sensitizer, on insulin sensitivity, body composition and adipose tissue metabolism, in dialyzed patients. A double blind randomized cross-over study was performed in non diabetic dialysis patients. Each patient followed 2 treatment phases of 16 weeks, starting either with oral PIO 45 mg/d or placebo (PL), and then switched to the other phase. At the end of each phase, patients underwent hyperinsulinemic euglycemic clamps, dual energy X-ray absorptiometry, an abdominal CT, and extensive plasma biochemical analysis. Twelve patients including 8 HD (59.6±4.4 y) and 4 PD patients (43.5±3.6 y) were recruited. Nine patients completed both phases and 3 patients dropped out (renal transplantation/2 HD and peritonitis/1 PD). PIO was safe and well tolerated. Under PIO, insulin sensitivity improved, as assessed by increased total glucose disposal rate (1.98±0.24 for PIO versus 1.58±0.12 umol/kg/min for PL, p<0.05), and reduced glucose endogenous hepatic production. PIO did not affect post-dialysis body weight, total fat and lean body mass, but significantly reduced visceral adipose tissue (VAT) area and the VAT/SAT (subcutaneous adipose tissue) ratio. HDL-cholesterol significantly increased. PIO decreased CRP (3.96±1.44 mg/l vs 7.88±2.56, p<0.05), plasma leptin, and dramatically reduced leptin/adiponectin ratio. Glycerol turnover, circulating glycerol and non esterified fatty acids were paradoxically increased. In conclusion, the improvement in insulin sensitivity by PIO, in non diabetic dialyzed patients, was associated with favorable metabolic effects, reduction in inflammation and body fat redistribution. The stimulation of systemic lipolysis was a surprising finding which may reflect adipose tissue remodeling and/or a paradoxical lypolitic effect of PIO in this population.