Growth Hormone (GH)-Induced Insulin Resistance Is Rapidly Reversible: An Experimental Study in GH-Deficient Adults

Context: It is clinically relevant and of physiological interest to investigate whether GH-induced insulin resistance depends on the timing of GH exposure relative to when insulin sensitivity is assessed. Hypothesis: GH-induced insulin resistance is rapidly reversible. Design and Participants: Eight male GH-deficient patients underwent a 6-h euglycemic-hyperinsulinemic glucose clamp thrice in a randomized crossover design receiving either no GH (study 0), a 7-h GH infusion (0.2-0.3 mg in total) that terminated 5 h before the clamp (study 1), or a similar GH infusion timed to continue during the first hour of the clamp (study 2). A muscle biopsy was obtained 30 min into the clamp. The patients were compared with eight healthy untreated control subjects (study c). Main Outcome Measures: The glucose infusion rate, indirect calorimetry, and free fatty acid metabolism were assessed. In muscle biopsies, protein phosphorylation of signal transducer and activator of transcription 5, Akt, and Akt substrate 160 (phospho-Akt substrate signal) and gene expression of IGF-I and SOCS1-3 were assessed. Results: Insulin sensitivity differed significantly between the GH-deficiency studies (P = 0.005) with distinct insulin resistance in study 2 and increased insulin sensitivity in study 0 [area under the glucose infusion rate curve (mg/kg . min): 1663 +/- 151 (study 0) vs. 1482 +/- 166 (study 1) vs. 1123 +/- 136 (study 2) vs. 1492 +/- 229 (control group)]. Free fatty acid levels and lipid oxidation were elevated in response to GH exposure but became suppressed during the clamp. IGF-I and SOCS3 gene expression was increased in study 2. Conclusions: Very-low-dose GH exposure evokes acute insulin resistance that subsides after 5h. This time-dependent reversibility should be considered when assessing the impact of GH on glucose homeostasis. (J Clin Endocrinol Metab 96: 2548-2557, 2011)