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
Tg. Unterman et al., 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, Endocrinology, 133(6), 1993, pp. 2531-2539
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.