title: Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle.
abstract: The effects of GH replacement therapy on energy metabolism are still uncertain, and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects. This study was designed to address this issue by examining both short-term (1 wk) and long-term (6 months) effects of a low-dose (9.6 micro g/kg body weight.d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism (oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[(3)H]glucose) and on muscle composition and muscle enzymes/metabolites, as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects. GH therapy resulted in impaired insulin-stimulated glucose uptake at 1 wk (-52%; P = 0.008) and 6 months (-39%; P = 0.008), which correlated with deterioration of glucose tolerance (r = -0.481; P = 0.003). The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk (60%; P = 0.008) and 6 months (60%; P = 0.008) and a concomitant decrease in glucose oxidation. The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation (r = -0.508; P = 0.0002). In addition, there was a shift toward more glycolytic type II fibers during GH therapy. In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy.
authors.affiliation: Department of Endocrinology, University Hospital, S-205 02 Malmö, Sweden. margareta.bramnert@skane.se
authors.forename: Margareta
authors.initials: M
authors.lastname: Bramnert
authors.forename: Mikael
authors.initials: M
authors.lastname: Segerlantz
authors.forename: Esa
authors.initials: E
authors.lastname: Laurila
authors.forename: Jens R
authors.initials: JR
authors.lastname: Daugaard
authors.forename: Per
authors.initials: P
authors.lastname: Manhem
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition; D015992:Body Mass Index; D004311:Double-Blind Method; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006006:Glycogen Synthase / Q000378:metabolism; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D019382:Human Growth Hormone / Q000009:adverse effects* / Q000172:deficiency* / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects; D008066:Lipolysis; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000737:chemistry / Q000648:ultrastructure; D010919:Placebos; D011506:Proteins / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D010919:Placebos; D011506:Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D006006:Glycogen Synthase; D005947:Glucose