Pegvisomant Improves Insulin Sensitivity and Reduces Overnight Free Fatty Acid Concentrations in Patients with Acromegaly

Introduction: Acromegaly is complicated by an increased incidence of diabetes mellitus caused by impaired insulin sensitivity and reduced β-cell function. Pegvisomant blocks activity at GH receptors, normalizing IGF-I in over 90% of patients and improving insulin sensitivity. The mechanisms for this increase in insulin sensitivity are not fully determined. We used stable isotope techniques to investigate the effects of pegvisomant on glucose and lipid metabolism in acromegaly. Methods: Five patients (age, 43 yr ± sd) with active acromegaly were studied on two occasions: before pegvisomant and after 4 wk of pegvisomant (20 mg daily sc). 2H5-glycerol was infused overnight to measure overnight and early morning (basal) glycerol production rate (Ra). The next morning 2H2-glucose was infused for 2 h before and throughout a hyperinsulinemic euglycemic (1.5 mU/kg · min insulin) clamp to measure basal glucose Ra and insulin-stimulated peripheral glucose disposal (Rd). Results: Mean IGF-I was significantly reduced after pegvisomant treatment (mean, 539 ± 176 vs. 198 ± 168 μg/ml; P = 0.001). The insulin sensitivity of endogenous glucose production was significantly increased after pegvisomant [mean glucose Ra∗insulin, 118.5 ± 28 vs. 69.2 ± 22 μmol/kg · min∗(mU/liter); P = 0.04]. No differences in glucose Rd were seen after pegvisomant. All patients showed a reduction in glycerol Ra adjusted for insulin [mean, 18.12 ± 1.75 vs. 14.4 ± 4.75 μmol/kg · min∗(mU/liter); P = 0.08] and overnight FFA concentrations (mean area under the curve, 278 ± 84 vs. 203 ± 71; P < 0.05) after pegvisomant. Conclusion: Short-term administration of pegvisomant leads to a reduction in overnight endogenous glucose production, and this may be related to reduced levels of FFA. This stable isotope study in acromegaly demonstrates improvement in insulin sensitivity of endogenous glucose production and glycerol Ra and a reduction in free fatty acid concentrations following pegvisomant.