Context: GH induces insulin resistance in muscle and fat and in vitro data indicate that this may involve crosstalk between the signaling pathways of the two hormones.

Objective: 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: 2 randomized cross-over studies.

Participants: 16 healthy males.

Intervention: Administration of GH as a bolus (n=8) and constant infusion (n=8). The bolus study included 3 arms: 1) control (saline), 2) GH (0.5 mg i.v.), and 3) GH blockade (pegvisomant 30 mg s.c.) each combined with a hyperinsulinemic glucose clamp. The infusion study included 2 arms: 1) GH infusion (45 ng|b1kg^-1|b1min^-1, 5 h) and 2) saline infusion (5 h) combined with a hyperinsulinemic glucose clamp during the final 2 h.

Main Outcome Measures: Muscle and fat biopsies were subjected to western blotting for expression of Stat5/p-Stat5, Akt/p-Akt and ERK 1/2/p-ERK 1/2 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 expressions increased after GH infusion. Hyperinsulinemia induced Akt phosphorylation in both tissues, irrespective of GH status. In muscle ERK 1/2 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 crosstalk with insulin signaling pathways. The molecular mechanisms subserving GH-induced insulin resistance in humans remain unclarified.