MON-474 Dipeptidyl Peptidase-4 (DPP4) Inhibition Decreases Visceral Fat and Improves Glucose Metabolism in Overweight Women with Polycystic Ovarian Syndrome

Abstract

Background: Women with PCOS have decreased GH secretion.1 Diminished GH is associated with increased visceral adiposity and impaired vascular function. GH releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4 (DPP4).2 We tested the hypothesis that one month of DPP4 inhibition with sitagliptin increases GH secretion and improves glucose metabolism and vascular function in women with PCOS. Methods: Eighteen women with PCOS (BMI ≥ 25 kg/m2) participated in a randomized, double-blinded, cross-over study during which they received sitagliptin 100 mg p.o. vs. placebo daily for one month separated by a minimum eight-week wash-out. At two weeks, women underwent a 75 g oral glucose tolerance test (OGTT). At one month, women were admitted for fasting laboratories, assessment of conduit artery vascular function, and measurement of body composition via DEXA. Overnight GH secretion was assessed using an automated deconvolution algorithm (AutoDecon) previously validated for the analysis of endogenous pulsatile GH secretion from time-series data obtained via frequent venous sampling from an indwelling catheter every ten minutes for twelve hours. Results: Sitagliptin 100 mg daily decreased DPP4 activity (p<0.001 vs. placebo) and increased GLP-1 levels (p<0.001 vs. placebo) during OGTT. Glucose metabolism improved during sitagliptin, as demonstrated by mean decrease in blood glucose of 15.4 mg/dL (95% CI 8.7, 22.1; p<0.001) at 100 minutes as compared to placebo. Sitagliptin enhanced early insulin secretion (from mean insulinogenic index 1.9 ± SD 1.2 to 3.2 ± 3.1; p=0.01). At one month, sitagliptin decreased visceral adipose tissue (VAT) (from 1141.9 g ± 700.7 to 1055.1 ± 710.1; p=0.02) and total cholesterol (from 168.8 mg/dL ± 26.3 to 162.5 ± 22.2; p=0.02) but did not affect vascular function. Sitagliptin did not increase overnight GH secretion, as summarized by area over the curve (AUC) or mean GH, but did increase GH half-life (from 13.9 min ± 3.6 to 16.8 ± 6.2, N=16; p=0.04) and the interpulse interval (from 53.2 min ± 20.0 to 77.3 ± 38.4, N=16; p<0.05). DPP4 activity levels during sitagliptin were associated with overnight GH secretion (GH AUC: rs= -0.60, p=0.01; mean GH: rs= -0.57, p=0.02), VAT mass (rs= 0.66; p<0.01), and insulin resistance (HOMA-IR rs=0.54; p=0.04). Conclusions: Sitagliptin improved blood glucoses following 75 g OGTT in overweight women with PCOS and decreased VAT but did not enhance vascular function. While sitagliptin did not increase overnight GH secretion, it did enhance GH half-life and the interpulse interval. Moreover, the response to sitagliptin was directly related to overnight GH secretion and inversely to VAT and insulin resistance. In this pilot study, sitagliptin improved glucose metabolism and body composition in accordance with GH secretion. 1 deBoer et al., Hum. Reprod. 2004 19: 504. 2 Frohman et al., J Clin Invest. 1986 78:906.