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1 Metabolism, Joslin Diabetes Center, Boston, MA, USA; Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), University Hospital of Aarhus, Aarhus, Denmark
2 Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), University Hospital of Aarhus, Aarhus, Denmark
3 Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), University Hospital of Aarhus, Aarhus, Denmark; Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: Niels.Jessen{at}Joslin.Harvard.edu.
Prolonged growth hormone (GH) excess is known to be associated with insulin resistance but the underlying mechanisms remain unknown. The aim of this study was to assess the impact of GH on insulin stimulated glucose metabolism and insulin signaling in human skeletal muscle. In a cross-over design, eight healthy male subjects (age 26.0±0.8 years and BMI 24.1±0.5 kg/m2) were infused for 360 min with either GH (Norditropin 45 ng/kg per min) or saline. During the final 180 min of the infusion a hyperinsulinemic euglycemic clamp was performed (insulin infusion rate: 1.2 mU/kg/min). Muscle biopsies from vastus lateralis were taken before GH/saline administration and after 60 min of hyperinsulinemia. GLUT4 content and insulin signaling, as assessed by IRS1 associated PI3-kinase and Akt activity were determined. GH levels increased to a mean±SE level of 20.0 µg/L ± 2.3 µg/L compared to 0.5 µg/L ± 0.2 µg/L after saline infusion (p<0.01). During GH infusion, the glucose infusion rate during hyperinsulinemia was reduced by 38% (p<0.01). In both conditions FFAs were markedly suppressed during hyperinsulinemia. Despite skeletal muscle insulin resistance, insulin still induced a similar ~3 fold rise in IRS1 associated PI3-kinase activity (269±105% and 311±71% compared to baseline, GH vs. saline). GH infusion did not change Akt protein expression and insulin caused a ~13 fold increase in Akt activity (1309±327% and 1287±173%) after both GH and saline infusion. No difference in total GLUT4 content was noted (114.7 ± 7.4 and 107.6 ± 16.7 arb. units, GH vs. saline compared to baseline). In conclusion, insulin resistance in skeletal muscle induced by short-term GH administration is not associated with detectable changes in the upstream insulin signaling cascade or reduction in total GLUT4. Yet unknown mechanisms in insulin signaling downstream of Akt may be responsible.
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