Porcine somatotropin alters insulin response in growing pigs by reducing insulin sensitivity rather than changing responsiveness

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Abstract

Exogenous porcine somatotropin (pST) treatment consistently improves growth performance and reduces fat deposition in pigs, and it is hypothesized that one component of the mechanism is through altering the sensitivity and/or responsiveness to insulin. Therefore, a study was conducted to investigate the effect of pST treatment on whole-body glucose metabolism in response to varying doses of insulin. Eight barrows were surgically prepared with indwelling catheters and randomly assigned to one of two treatment groups (0 or 120 μg pST/kg BW · d) for 13 d. Whole-body glucose kinetics were measured during infusion of [6-3H]-glucose under basal conditions and during hyperinsulinemic-euglycemic clamps at various insulin infusion rates (7, 28, and 140, and 14, 70, and 280 ng insulin/kg BW · min) and alterations in the dose–response parameters were calculated with nonlinear regression. Treatment with pST increased basal plasma concentrations of glucose (36%; P = 0.005), insulin (276%; P = 0.001), and NEFAs (177%; P = 0.01) and decreased the rate of glucose disappearance (−59%; P = 0.001). The responsiveness (maximum response) for steady state glucose infusion rate to maintain glycemia was not altered by pST (112 vs 106 μmol/min · kg; P = 0.78), whereas the sensitivity (effective dose at 50% of maximum response) was increased almost 7-fold (1.3 vs 8.7 ng/mL; P = 0.027). Similar responses were observed for rate of glucose disappearance and insulin-dependent glucose utilization. Therefore, pST-induced insulin resistance with regard to whole-body glucose uptake is due to a reduced sensitivity to insulin, rather than a change in responsiveness.

Introduction

Exogenous porcine somatotropin (pST) treatment consistently improves average daily gain, feed conversion efficiency, and protein deposition and reduces fat deposition in pigs [1], [2], [3], [4], [5], [6]. Dose-dependent increases in lean deposition and reductions in feed intake, fat deposition, and carcass fat have been observed [1], [3], [7], [8]. It appears that the pST-induced shift in nutrient partitioning is mediated, in part, through inducing insulin resistance in adipose tissue. Treatment with pST induces insulin resistance with resultant hyperglycemia and hyperinsulinemia in growing pigs [9], [10], [11], [12], [13]. Unlike for bovine ST, which is delivered via an implant, under commercial conditions pST is delivered as either a daily, every other day, or thrice weekly injection (approximately 5 mg/d) administered with a propane-powered applicator [14], [15]. Apart from issues related to dissolution and aggregation of the pST molecule [16], a main impediment to the development of a slow-release pST implant is the degree of insulin resistance induced by pST in pigs. The pST implants investigated to date display first-order kinetics with a declining release over time [17], and this presents a challenge in developing a prolonged-release system that would maintain effective circulating dose of pST without inducing severe insulin resistance. Likewise, the degree of insulin resistance may limit the amount of pST incorporated into an alternative injection regime [15]. Knowledge of the nature of the pST-induced insulin resistance will assist in developing alternative strategies, as well as further elucidating the mode of action of pST.

We previously have shown that ST treatment reduces whole-body glucose clearance and adipose tissue and hind limb glucose uptake in response to elevated levels of insulin in the growing pig [18] and steer [19]. The change in whole-body and tissue response to insulin could be due to a decrease in responsiveness and (or) a decrease in sensitivity [20] and can occur in several tissues. Walton et al [21] reported that in vitro examination of lipogenic rates indicated that both responsiveness and sensitivity to insulin were reduced in explants of adipose tissue from pST-treated pigs. By contrast, in vivo hyperinsulinemic-euglycemic clamp studies have indicated that at least for glucose utilization, pST reduced the amount of exogenous glucose needed to maintain glycemia during infusion of a low [9], [18] but not a high [12], [13], [18] dose of insulin. These in vivo studies suggest a lowered sensitivity to insulin without altering responsiveness. Evaluation of the effect of pST on insulin sensitivity and responsiveness requires insulin dose–response curves to properly determine the effects of pST administration on the maximum response (Rmax) and the effective dose to achieve 50% maximum response (ED50). Our objective was to define insulin dose–response curves for whole-body glucose utilization and endogenous glucose entry rate in the growing pig and to determine the effect of pST on these parameters.

Section snippets

Animals and treatments

All procedures were approved by the Cornell University Animal Use and Care Committee. Eight crossbred (Large White × Landrace × Duroc × Hampshire) barrows were housed in individual metabolism crates in an environmentally controlled (20 ±1°C; 16:8 h light/dark cycle, lights on at 6:00 AM) room for at least 5 d before commencement of the study. Pigs (67 ±6.0 kg) were stratified into pairs on age and live weight and then within each pair randomly assigned to one of two treatment groups (daily pST

Results

Treatment with exogenous pST increased basal plasma concentrations of glucose (36%; P = 0.005), insulin (276%; P = 0.001), and NEFAs (177%; P = 0.01) and decreased glucose Rd (−59%, P = 0.001) (Table 1). Animals that received pST also consumed approximately 36% less feed (data not shown), consistent with similar studies in this class of animal [11].

In general, insulin infusion increased plasma insulin concentrations in a dose-dependent manner (Fig. 1). Across the range of insulin infusion

Discussion

Basal plasma glucose, insulin, and NEFAs were all increased by pST in the present study. This is consistent with the insulin resistance as reported by others [9], [10], [11], [12], [13], [30]. The hyperglycemia and hyperinsulinemia that occurs within hours of the first injection of pST [11] is clear evidence that the pST-induced alterations in glucose metabolism occur rapidly. Hyperglycemia could occur because of increased glucose production and (or) decreased utilization of glucose. A review

Acknowledgments

Funding for this study was provided by the Cornell University Agricultural Experiment Station (Ithaca, NY). We thank Cornell University staff members, in particular Dottie Ceurter, Bill English, Karl Roneker, and Regina Tobin, for their assistance in the conduct of this investigation.

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  • 1

    Present address: USDA, Foreign Agricultural Service, Office of Agreements and Scientific Affairs/New Technologies and Production Methods Division, Washington, DC 20250, USA.

    2

    Present address: Melbourne School of Land and Environment, The University of Melbourne, Parkville, Victoria, 3010, Australia.

    3

    Present address: The Hanor Company, Franklin, KY 42134, USA.

    4

    Present address: CSIRO Livestock Industries, St Lucia, QLD 4067, Australia.

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