DEFECTS OF INSULIN ACTION AND SKELETAL-MUSCLE GLUCOSE-METABOLISM IN GROWTH HORMONE-DEFICIENT ADULTS PERSIST AFTER 24 MONTHS OF RECOMBINANT HUMAN GROWTH-HORMONE THERAPY

We have previously reported that GH-deficient (GHD) adults are severel y insulin resistant. In the present study, we determined the effects o f 6 months (n = 7) and 24 months (long-term; n = 11) of recombinant hu man GH (rhGH) therapy (similar to 0.22 IU/kg.week) on body composition and fasting biochemical (including lipid) parameters, and baseline an d insulin-stimulated: 1) rates of hepatic glucose production, total gl ucose disposal (Rd), total glycolysis (GF) and glucose storage (GS); a nd 2) skeletal muscle glucose processing [using the euglycemic-hyperin sulinemic (similar to 60 mU/L) clamp technique with tritiated glucose infusion coupled with skeletal muscle biopsies]. To allow baseline com parison, these measurements were also obtained from 10 control subject s matched to the pretreated GHD adults for age, sex, and body mass ind ex. Long-term rhGH therapy in GHD adults induced significant improveme nts in fat mass, abdominal fat mass and fat free mass, and reductions in fasting cholesterol and low-density lipoprotein-cholesterol levels (P < 0.05-0.01 vs, pretreatment values). However, there was a signific ant increase in fasting insulin (13.1 +/- 0.9 vs. 8.6 +/- 1.1 mU/L; P < 0.01) and connecting peptide (0.56 +/- 0.05 vs. 0.41 +/- 0.06 nmol/L ; P < 0.05). Although rates of baseline hepatic glucose production, GF , and GS were unchanged, the insulin-stimulated increment (Delta) in R d, GF, and GS remained markedly attenuated in the long-term rhGH-treat ed GHD adults [pretreatment: Delta Rd 16.6 +/- 3.4, Delta GF 3.0 +/- 1 .2 Delta GS 13.6 +/- 3.0 vs. 24 months of rhGH: Delta Rd 17.2 +/- 3.3, Delta GF 3.1 +/- 0.9, Delta GS 14.1 +/- 2.5 vs. controls: Delta Rd 42 .6 +/- 4.3, Delta GF 9.2 +/- 1.9, Delta GS 35.9 +/- 4.5 mu mol/kg fat free mass min; P < 0.05-0.01 vs, controls]. Additionally, there was a sustained reduction in the insulin-stimulated skeletal muscle glycogen synthase fractional velocity (pretreatment: 0.29 +/- 0.03 vs. 24 mont hs of rhGH: 0.24 +/- 0.03 vs. controls: 0.48 +/- 0.04; both P < 0.05 v s. controls), which was accompanied by a sustained 44% decrease in bas eline glycogen content and a 70% increase in baseline im glucose conce ntrations in the presence of low-to-normal glucose 6-phosphate levels and persisting euglycemia. Stepwise regression analysis revealed that body weight and fasting free fatty acid and high-density lipoprotein ( HDL)-cholesterol accounted for 82% of the variance in the insulin sens itivity index in long-term rhGH-treated adults, and that the 24-month fasting insulin-like growth factor 1 was a negative predictor of the c hange in insulin sensitivity (r = -0.82; P < 0.01). In conclusion, des pite improvements in body composition and lipid profiles, the severe d efects of in vivo insulin sensitivity and skeletal muscle intracellula r glucose phosphorylation and glycogen synthase activity, which are as sociated with modestly elevated insulin-like growth factor 1 levels, n ormal free fatty acid levels, and the development of hyperinsulinemia, persist with long-term rhGH therapy.