Growth hormone signaling in vivo in human muscle and adipose tissue: Impact of insulin, substrate background, and growth hormone receptor blockade

Context: GH induces insulin resistance in muscle and fat, and in vitro data indicate that this may involve cross-talk between the signaling pathways of the two hormones. Objective: Our objective was to investigate GH and insulin signaling in vivo in human muscle and fat tissue in response to GH, GH receptor blockade, and insulin stimulation. Design: We conducted two randomized crossover studies. Participants: Sixteen healthy males participated. Intervention: GH was administered as a bolus (n = 8) and constant infusion ( n = 8). The bolus study included three arms: 1) control ( saline), 2) GH (0.5 mg iv), and 3) GH blockade (pegvisomant 30 mg sc), each combined with a hyperinsulinemic glucose clamp. The infusion study included two arms: 1) GH infusion (45 ng/.kg.min, 5.5 h) and 2) saline infusion ( 5.5 h) combined with a hyperinsulinemic glucose clamp during the final 2.5 h. Main Outcome Measures: Muscle and fat biopsies were subjected to Western blotting for expression of Stat5/p-Stat5, Akt/p-Akt, and ERK1/2/p-ERK1/2 and to real-time RT-PCR for expression of SOCS1-3 and IGF-I mRNA. Results: GH significantly reduced insulin sensitivity. The GH bolus as well as GH infusion induced phosphorylation of Stat5 in muscle and fat, and SOCS3 and IGF-I mRNA expression increased after GH infusion. Hyperinsulinemia induced Akt phosphorylation in both tissues, irrespective of GH status. In muscle, ERK1/2 phosphorylation was increased by insulin, but insulin per se did not induce phosphorylation of Stat5. Conclusions: GH exposure associated with insulin resistance acutely translates into GH receptor signaling in human muscle and fat without evidence of cross-talk with insulin signaling pathways. The molecular mechanisms subserving GH-induced insulin resistance in humans remain unclarified.