CORTICOSTERONE REGULATION OF INSULIN-LIKE GROWTH-FACTOR-I, IGF-BINDING PROTEINS, AND GROWTH IN STREPTOZOTOCIN-INDUCED DIABETIC RATS

The experiments reported herein were conducted to determine how cortic osterone regulates growth and plasma insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP) concentrations in normal and strepto zotocin (STZ)-induced diabetic rats. IVIales were bilaterally adrenale ctomized (Ax) or sham Ax and given intravenous injections of 0, 30, or 65 mg STZ per kg body wt (0, 30, or 65 STZ) to induce varying degrees of insulin deficiency and implanted with 100-mg pellets containing 0, 40, or 80% corticosterone in cholesterol. Changes in plasma IGFBP con centrations were determined by Western ligand blotting or immunoblots. Neither IGFBP-5 nor IGFBP-6 was detected in any of the treatment grou ps. Plasma IGFBP-2 was elevated and IGF-I was reduced in the nondiabet ic Ax rats compared with sham Ax controls, but plasma IGFBP-3 and -4 w ere not significantly changed. Adrenalectomy had no affect on tibial g rowth or plasma IGFBP-1 in these animals. Plasma. IGF-I, IGFBP-1 and - 3, and tibial growth were equal among 0, 30, and 65 STZ Ax rats that d id not receive corticosterone. Plasma. IGFBP-4 was inversely related t o the amount of STZ injected in these animals, and IGFBP-2 was elevate d in those given the high dose of STZ. In the 0 STZ Ax rats, plasma IG F-I and IGFBP-3 increased in proportion to the corticosterone implant dose, but IGFBP-1 was unaffected. By contrast, IGF-I and IGFBP-3 were unaltered by corticosterone in the 30 STZ Ax rats, and IGFBP-1 increas ed in proportion with the dose of corticosterone. In the 65 STZ rats g iven 40% corticosterone, IGFBP-3 was elevated, but IGF-I was not chang ed. However, both of these parameters were reduced considerably in the 80% corticosterone rats. Plasma IGFBP-1 increased in direct proportio n to the corticosterone implant dose in the 30 and 65 STZ rats but was relatively unchanged in the 0 STZ rats. These results indicate that e levated corticosterone production is largely responsible for the reduc ed growth and changes in plasma concentrations of IGF-I and IGFBPs ass ociated with IDDM. Plasma IGF-I and tibial growth are normally correla ted in nondiabetic rats but were not in the corticosterone-treated ani mals; thus, corticosterone contributes to IGF-I resistance in vivo. Th e effect of corticosterone on the plasma IGFBPs was most striking in t he insulin-defiient rats, suggesting that the ability of corticosteron e to modify circulating concentrations of IGFBPs is enhanced by insuli n deficiency. The rise in plasma IGFBP-1 and the reduction in IGFBP-4 in rats with IDDM is due in part to corticosterone. However, IGFBP-2 w as reduced to nearly nondetectable levels by both doses of corticoster one. The rise in IGFBP-2 in the Ax 65 STZ rats and the decrease in IGF BP-4 in both groups of Sn-injected Ax rats not given corticosterone ap pears to be due to insulin deficiency per se, rather than to corticost erone. In all groups, plasma IGFBP-4 and tibial growth were inversely related to the corticosterone implant dose, suggesting that IGFBP-4 ma g have a growth-promoting role in vivo.