Insulin-like growth factor binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic actions of the IGF peptides. Previous studies have established insulin as the major regulator of plasma IGFBP-1 in humans, acting to suppress hepatic IGFBP-1 synthesis. In this study, we investigated the regulation of plasma IGFBP-1 by cortisol in humans, independent of insulin. Following an overnight fast, six healthy adult volunteers received a euglycemic pancreatic clamp (somatostatin, 0.12 μg·kg−1·min−1; GH, 3 ng·kg−1·min−1; insulin, 0.05 mU·kg−1·min−1) to block endogenous insulin secretion and to control glucose and plasma hormone concentrations at desired levels. Three hours after the initiation of the pancreatic clamp, each subject received an additional 360 min infusion of either cortisol (2 μg·kg−1·min−1) or saline on separate occasions and in random order. Plasma cortisol concentrations increased from 220 to 970 nmol/1 during the cortisol infusion. Insulin concentrations were maintained at approximately 30 pmol/1 throughout saline and cortisol infusions. Plasma IGFBP-1 concentrations increased threefold in response to hypoinsulinemia, reaching plateau values of ∼ 140 μg/l with saline infusion. During cortisol infusion, IGFBP-1 levels increased to ∼300 μg/I. Over the 360 min study period, the integrated response of plasma IGFBP-1 to cortisol infusion was 314% greater than to saline infusion (p <0.01). Our data confirm that, under conditions of hypoinsulinemia, cortisol is a significant modulator of plasma IGFBP-1 in humans.
Cheryl A Conover, Gavin D Divertie and Phillip DK Lee
Ron G. Rosenfeld, Laura A. Dollar, Raymond L. Hintz and Cheryl Conover
Abstract. Growth retardation is a major manifestation of Turner syndrome (TS). Since plasma growth hormone and somatomedin-C/insulin-like growth factor I (SM-C/IGF-I) levels are generally normal, growth failure has been ascribed to peripheral defects in SM-C/IGF-I receptors or action. We have measured the binding of [125I]SM-C/IGF-I to cultured fibroblast monolayers derived from patients with Turner syndrome, and have evaluated SM-C/IGF-I stimulation of both [3H]thymidine incorporation and cell replication. When compared to fibroblasts from normal adults, newborns, and agematched children, no significant differences were observed in specific binding of [125I]SM-C/IGF-I to fibroblast monolayers, and displacement curves demonstrated similar receptor affinities for all groups. Similarly, equivalent SM-C/IGF-I stimulation of [3H]thymidine incorporation was seen in both Turner and control fibroblasts. In the absence of serum, SM-C/IGF-I, at a concentration of 10–25 ng/ml, stimulated thymidine incorporation 3.7–11.8-fold in Turner fibroblasts and 1.9–9.8-fold in control cells. In combination with 1.0% human hypopituitary serum (HHS), SM-C/IGF-I stimulated thymidine incorporation 20–70-fold in all cell lines. Cell replication in both TS and control cells was increased 90% by the combination of SM-C/IGF-I + 0.5% HHS, and 140% by SM-C/IGF-I + 0.5% HHS + dexamethasone. We conclude that TS fibroblasts have normal SM-C/IGF-I receptors and sensitivity, and are capable of enhanced DNA synthesis and replication following SM-C/IGF-I stimulation.