Effects of streptozotocin-induced diabetes mellitus on growth and hepatic insulin-like growth factor I gene expression in the rat

Abstract

Poorly controlled diabetes mellitus in humans and animals is often accompanied by impaired growth. We undertook this study in young rats to determine whether the reduction in growth rate associated with streptozotocin (STZ)-induced diabetes might be related to changes in both serum insulin-like growth factor I (IGF-I) and IGF-II levels, and, if so, whether these changes reflect alterations in serum growth hormone (GH) and in hepatic IGF-I and IGF-II gene expression. Serum rat GH (rGH) levels were variable during the first 4 days after STZ administration, but during the subsequent 5- to 11-day period the mean (±SEM) levels in insulin-treated (DI) (21.4 ± 4.9 ng/mL) and untreated (D) (8.5 ± 1.5 ng/ml) diabetic rats were significantly ( P < .001) lower than in controls (C) (117.8 ± 22.9 ng/mL). Multiple transcripts of IGF-I (7.0, 4.0, 1.9, 1.0 kb), but barely detectable amounts of IGF-II mRNA, were found in the livers of normal and diabetic rats by Northern blot analysis. Using dot blot analysis, we have shown that the abundance of total hepatic IGF-I mRNA in untreated, growth-retarded diabetic animals decreases rapidly over a period of 3 days after STZ administration. Both serum IGF-I and IGF-II levels are also diminished during this interval in these markedly hyperglycemic rats. Insulin treatment for 3 to 4 days, started either immediately (6 hours) or within 3 days after administering STZ, blunts diabetes-induced impairment of growth and restores mean hepatic IGF-I mRNA abundance to control levels, but does not normalize serum IGF-I and IGF-II concentrations. In insulin-treated and untreated diabetic rats and their controls, blood glucose levels are negatively correlated with steady-state hepatic IFG-I mRNA abundance ( r = −.53), serum IGF-I ( r = −.53), and IGF-II ( r = −.48) concentrations, and growth rates ( r = −.62). In contrast, their growth rates are positively correlated with the abundance of hepatic IGF-I mRNA ( r = .63) and with serum concentrations of IGF-I ( r = .60) and IGF-II ( r = .57). These data suggest that impaired growth in the rat associated with poorly controlled diabetes, and its correction by insulin administration, may be mediated in part through the regulation of serum rGH levels and hepatic IGF-I gene expression.