title: Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  METHODS
  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 (Ra) (P = .033) were reduced. During the clamp study, glucose infusion rates (P = .031) increased and glucose Ra (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.
authors.affiliation: Department of Paediatrics (A.T., P.H.T., C.A., D.E., R.M.W., D.B.D.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Wolfson Brain Imaging Centre (A.S.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Department of Paediatrics (P.H.T.), University of Oulu, 90029 OYS, Oulu, Finland; WellChild Laboratory (R.N.D.), King's College London, Evelina Children's Hospital, London SE1 7EH, United Kingdom; Diabetes and Metabolic Medicine (N.C.J., A.M.U.), Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, United Kingdom; and National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre (D.B.D.), Cambridge, CB2 0QQ, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Thankamony
authors.forename: P H
authors.initials: PH
authors.lastname: Tossavainen
authors.forename: A
authors.initials: A
authors.lastname: Sleigh
authors.forename: C
authors.initials: C
authors.lastname: Acerini
authors.forename: D
authors.initials: D
authors.lastname: Elleri
authors.forename: R N
authors.initials: RN
authors.lastname: Dalton
authors.forename: N C
authors.initials: NC
authors.lastname: Jackson
authors.forename: A M
authors.initials: AM
authors.lastname: Umpleby
authors.forename: R M
authors.initials: RM
authors.lastname: Williams
authors.forename: D B
authors.initials: DB
authors.lastname: Dunger
mesh_terms: D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007328:Insulin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C406545:pegvisomant