Insulin restores GH responsiveness during lactation-induced negative energy balance in dairy cattle: effects on expression of IGF-I and GH receptor 1A

Abstract

Early lactation in dairy cattle is a period of severe negative energy balance (NEB) characterized by reduced blood glucose and insulin concentrations and elevated blood growth hormone (GH) concentrations. The liver is refractory to GH during NEB and this uncoupling of the GH-insulin-like growth factor (IGF) axis results in diminished plasma concentrations of IGF-I. Our objectives were to examine the effects of insulin administration during the immediate postpartum period on plasma IGF-I and GH concentrations and to examine the hepatic expression of total GH receptor (all GH receptor transcripts), GH receptor 1A (GHR 1A) and IGF-I. In addition, we examined adipose tissue for total GH receptor and IGF-I mRNA levels to establish the effects of chronic hyperinsulinemia on an insulin-responsive peripheral tissue. Holstein cows (n = 14) were subjected to either a hyperinsulinemic-euglycemic clamp (insulin; INS) or saline infusion (control; CTL) for 96 hours starting on day 10 postpartum. Insulin was infused intravenously (1µg • kg BW-1 • h-1), blood samples were collected hourly, and euglycemia was maintained by infusion of glucose. Insulin concentrations during the infusions were increased 8-fold in INS cows compared with CTL cows (2.33 ± 0.14 vs. 0.27 ± 0.14 ng/ml; P < 0.001) while blood glucose concentrations were not different between treatments (45.3 ± 2.2 vs. 42.5 ± 2.2 mg/dl; P > 0.1). Plasma IGF-I increased continuously during the insulin infusion, and reached the highest concentrations at the end of the clamp, being almost four-fold higher in INS compared with CTL cows (117 ± 4 vs. 30 ± 4 ng/ml; P < 0.001). Hepatic expression of GHR 1A and IGF-I mRNA was low in CTL cows, but was increased 3.6-fold (P < 0.05) and 6.3-fold (P < 0.001) respectively in INS cows. By contrast, in adipose tissue the changes in gene expression in response to insulin were reversed with decreases in both total GHR and IGF-I mRNA. The expression of GHR 1A and IGF-I mRNA in liver tissue were correlated in INS (r = 0.86; P < 0.05), but not CTL cows (r = 0.43; P > 0.1). Insulin appears to be a key metabolic signal in coupling the GH-IGF axis, thus orchestrating a marked elevation in circulating IGF-I concentrations.