Impaired growth in diabetic humans occurs despite increased growth hormone and normal insulinlike growth factor I (IGF-I). Because IGF-I circulates complexed to binding proteins (BPs), we asked whether diabetes-related changes in IGF BPs could be associated with alterations in free unbound IGF-I—presumably the active form. Rats were given streptozocin (STZ) in increasing doses to produce graded severity of diabetes. IGF BP-1 and BP-3 were measured by ligand blotting, total IGF-I was determined by radioimmunoassay after separation from BPs by isocratic high-performance liquid chromatography (HPLC) at pH 3.9, and free IGF-I was estimated operationally as immunoreactivity with molecular weight equal to native IGF-I after HPLC at pH 7. Animals given 36 mg/kg STZ exhibited a glucose level of 9.74 mM and impaired weight gain, with little alteration in IGF BPs or total or free IGF-I. In contrast, animals given 72 mg/kg STZ (glucose level 24.64 mM and weight loss) had insignificant changes in total IGF-I and BP-3 but a 300% increase in BP-1 and a 50% fall in free IGF-I (both P < 0.005). With 144 and 288 mg/kg STZ, animals had further metabolic decompensation and weight loss, with progressive fall in BP-3 and rise in BP-1; total and free IGF-I fell to 10–20% of control (both P < 0.001). High-STZ animals (288 mg/kg) given high doses of protamine zinc insulin (PZI; 10 U/100 g body wt) gained weight and had subnormal glucose, whereas animals given low doses (3 U/100 g body wt PZI) were modestly hyperglycemic and gained less weight. Although both high- and low-dose insulin raised total IGF-I to 70–90% of normal, free IGF-I was fully restored with high-dose insulin but raised to only 38% of control with low-dose insulin (P < 0.001); animals given low-dose insulin had BP-1 levels threefold higher than animals given high-dose insulin (P < 0.05). Across all groups, free IGF-I was inversely correlated with levels of BP-1 (r = –0.79, P < 0.001). We conclude that free IGF-I is more sensitive to metabolic status than total IGF-I; levels of free IGF-I appear to reflect underlying alterations in IGF BPs. Decreased free IGF-I may contribute to impaired growth in diabetes mellitus.

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