King's College London

Context: Data on the metabolic effects of GH derived from studies using GH suppression by pharmacological agents may not reflect selective actions.

Objective: The purpose of this study was to evaluate the effects of GH antagonism on glucose and lipid metabolism using pegvisomant, a selective GH receptor antagonist in patients with type 1 diabetes (T1D).

Design and Participants: In a randomized, placebo-controlled, crossover study, 10 young adults with T1D were evaluated at baseline and after 4 weeks of treatment with either 10 mg of pegvisomant or placebo. The assessments included an overnight euglycemic steady state followed by a hyperinsulinemic euglycemic clamp and used glucose and glycerol cold stable isotopes.

Outcome Measures: Hepatic and peripheral insulin sensitivity (IS), lipid turnover, and intramyocellular lipid (IMCL) were measured.

Results: Compared with placebo, pegvisomant treatment resulted in lower IGF-I levels (P <.001). During the overnight steady state, insulin requirements for euglycemia (P = .019), insulin levels (P = .008), and glucose production rates (R-a) (P = .033) were reduced. During the clamp study, glucose infusion rates (P = .031) increased and glucose R-a (P = .015) decreased whereas glucose disposal rates were unchanged. Free fatty acid levels were similar during the steady state but were lower during the clamp (P = .040) after pegvisomant. Soleus muscle IMCL decreased after treatment (P = .024); however, no change in tibialis anterior muscle was observed.

Conclusions: The study demonstrates that GH antagonism in T1D results in improved hepatic insulin sensitivity. Lack of consistent changes in free fatty acid levels may suggest a direct effect of GH on IS. Unchanged peripheral IS despite reductions in IMCL indicate that GH-induced alterations in IMCL may not be causally linked to glucose metabolism.