REGULATION OF INSULIN-LIKE GROWTH FACTOR-BINDING PROTEINS IN RATS WITH INSULIN-DEPENDENT DIABETES-MELLITUS

As previously reported, activation of the adrenocorticotropic hormone (ACTH)-adrenal cortical axis in rats with insulin-dependent diabetes m ellitus (IDDM) reduces their growth and circulating insulin-like growt h factor-I (IGF-I) levels and induces a resistance to growth hormone ( GH) and IGF-I, The studies reported herein were conducted to determine whether the pituitary and/or adrenal gland influence the changes in b asal and GH-stimulated serum concentrations of IGF-binding proteins (I GFBPs) in rats with IDDM. Male rats were made diabetic by injections o f streptozotocin, Intact nondiabetic (NonDb), diabetic (Db), hypophyse ctomized diabetic (HxDb), and adrenalectomized diabetic (AxDb) rats we re injected twice daily with 50 mu g porcine (p) OH or with 0.9% salin e for 2 weeks following the surgeries, Changes in serum IGFBP concentr ations were determined by Western ligand- or immune-blot analysis, Nei ther IGFBP-5 nor -6 was detected in any of the treatment groups, Induc tion of IDDM increased serum concentrations of IGFBP-1 and -2 and redu ced those of IGFBP-3 and -4, Although serum IGFBP-1 and -2 concentrati ons remained elevated in the HxDb rats compared with the NonDb control s, IGFBP-1 levels were reduced compared with those in the Db controls, Serum IGFBP-3 and -4 were reduced to levels below those in Db control s, Although IGFBP-3 and -4 concentrations were elevated to normal in A xDb rats, the IGFBP-5 concentration was increased above those in both NonDb and Db rats and the IGFBP-1 concentration was reduced, Administr ation of pGH increased serum IGFBP-4 concentrations in all groups and IGFBP-3 concentrations in all groups except the Db, In addition, pGH r educed the concentration of IGFBP-1 in HxDb rats and nearly abolished it in AxDb rats, but had no effect on IGFBP-1 concentration in NonDb o r Db rats. Administration of corticosterone (B; 25 mu g/ml of 0.9% sal ine drinking water) to AxDb rats restored Db-like profiles of all IGFB Ps. The refractoriness of Db rats to pGH is associated with a failure of the hormone to elevate IGFBP-2 and -3 titers and to reduce those of IGFBP-1, Adrenal B production appears to be responsible for this resi stance to GH, However, the elevated IGFBP-2 concentration in Db rats d oes not appear to be due to B or any other pituitary-controlled or -de rived factors, Impaired growth was associated with substantially reduc ed IGFBP-3 concentrations and elevated IGFBP-1, whereas growth restora tion was associated with the opposite changes.