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

Abstract

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. 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. We conducted two randomized crossover studies. Sixteen healthy males participated. 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. 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. 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. 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.