Recent studies have documented that the MCRI plays a major role in determining the plasma insulin response to ingested glucose. We evaluated the long-term effect of pioglitazone (PIO) on MCRI in 441 IGT subjects (ACT NOW study) who were randomized to PIO (45 mg/day) or placebo and followed for an average of 2.4 years. OGTT was performed at baseline and study end. 50 placebo-treated subjects developed type 2 diabetes versus 15 PIO-treated subjects (p<0.005). Insulin secretion rate (ISR) was measured from deconvolution of plasma C-peptide curve. MCRI was measured as ISR/mean insulin conc during OGTT. Data were correlated with changes in liver enzymes and peripheral insulin sensitivity measured with the Matsuda index (MI).

Results: PIO improved MI from to 3.9 ±1 to 7.5 ±3 (p<0.0001), glucose tolerance (mean glucose OGTT from 172±2to 148±1mg/dl, p<0.0001) and reduced ALT(from 30±1 to 24±1, p<0.0001). Fasting insulin secretion increased in the placebo group (420 ±14 to 558 ±21 pmol/min, p < 0.0001 vs. baseline) and did not change in the PIO group (411 ±14 to 446 ± 19; p <0.0001, PIO vs. placebo). During the OGTT (0- 120 min) ISR increased in both groups (PIO, 165 ±3 to 189 ± 5 nmol; placebo, 167 ±3 to 202 ±6; p < 0.0001 vs. baseline in both groups; p = NS, PIO vs. placebo).The MCRI increased in both groups but the increase was much greater in PIO (3.5 ± 0.2 to 6.0±0.2 ml/min; placebo, 3.5 ± 0.1 to 4.7±0.2; p < 0.0001 vs. baseline in both groups; p <0.0001, PIO vs. placebo). In the whole dataset the improvement in insulin clearance was associated with improvement in peripheral insulin sensitivity (r=0.62, p<0.0001), the reduction in mean plasma glucose concentration during OGTT (r=-0.31, p<0.0001) and decrease in ALT (r=-0.14, p<0.009).

Conclusion: PIO treatment results in an increase in MCRI that is associated with improved hepatic function, glucose metabolism and peripheral insulin sensitivity.

Disclosure

A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. D. Tripathy: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.

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