EFFECTS OF GLUCOCORTICOIDS ON CIRCULATING LEVELS AND HEPATIC EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR (IGF)-BINDING PROTEINS AND IGF-I IN THE ADRENALECTOMIZED STREPTOZOTOCIN-DIABETIC RAT

Circulating levels and hepatic expression of insulin-like growth facto r-binding protein-1 (IGFBP-1) are increased in insulin-deficient strep tozotocin (STZ)-diabetic rats. Glucocorticoids stimulate and insulin s uppresses hepatocellular expression of IGFBP-1 in vitro. We asked whet her increased IGFBP-1 expression in STZ-diabetic animals is due to an effect of insulin deficiency per se or whether insulin deficiency repr esents a permissive state where glucocorticoids may play an important role in the regulation of IGFBP-1 and other circulating peptides invol ved in the modulation of IGF bioactivity. Intact female Sprague-Dawley -derived rats and rats undergoing bilateral adrenalectomy (ADNX) were injected with STZ (140 mg/kg) or buffer. Corticosterone acetate (50 mg /kg) or vehicle was administered to diabetic and nondiabetic animals i mmediately after ADNX and 24 h later. All rats were killed 48 h after surgery and/or STZ administration. Serum [I-125]IGF-I-binding activity was increased 4-fold (P < 0.01), and Western ligand and immunoblottin g demonstrated that levels of IGFBP-1 were high in intact STZ-diabetic animals. ADNX prevented these effects of STZ-diabetes, and corticoste rone treatment restored serum IGF-binding activity and IGFBP-1 to inta ct diabetic levels. Similarly, Northern analysis demonstrated that the abundance of hepatic IGFBP-1 mRNA was increased 6-fold in intact STZ- diabetic animals (P < 0.01), but not in adrenalectomized diabetic anim als. Corticosterone treatment restored hepatic IGFBP-1 mRNA to intact diabetic levels, and serum concentrations of corticosterone correlated with the abundance of IGFBP-1 mRNA (r = 0.475; P < 0.01), indicating that glucocorticoids play an important role in the regulation of expre ssion of IGFBP-1 in insulin-deficient animals. In contrast, neither AD NX nor corticosterone altered the abundance of hepatic IGFBP-1 mRNA le vels in nondiabetic animals. This pattern of regulation appeared to be specific; serum levels of immunoreactive IGFBP-2 and -4 tended to ris e in adrenalectomized animals, and levels of IGFBP-3 were not affected by either ADNX or corticosterone treatment. Of note, serum levels of IGF-I by RIA were reduced in STZ-diabetic animals compared to control values (168 +/- 16 vs. 587 +/- 55 ng/ml, respectively; P < 0.01), were partially restored toward control values with ADNX (320 +/- 22 ng/ml) , and were reduced again by corticosterone treatment (195 +/- 26 ng/ml ), indicating that glucocorticoids also contribute to the regulation o f IGF-I levels in insulin-deficient animals. The abundance of IGF-I mR NA was reduced in STZ-diabetic animals, and ADNX also partially preven ted this effect of diabetes. In summary, these studies demonstrate tha t glucocorticoids play an important role in the regulation of circulat ing IGF-binding activity and serum levels and hepatic expression of IG FBP-1 in the STZ-diabetic rat. Glucocorticoids also contribute to the regulation of serum levels of IGF-1. Glucocorticoids and other counter regulatory factors may be important modulators of IGF bioactivity in c onditions where insulin levels are low.