EXPRESSION OF HEPATIC INSULIN-LIKE GROWTH FACTOR-I AND INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-1 GENES IS TRANSCRIPTIONALLY REGULATED IN STREPTOZOTOCIN-DIABETIC RATS

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (BP-1) are critical cell regulators, with regulation and action in endocrine, paracrine, and autocrine modes. Although IGF-I and BP-1 are thought to be modulated mainly at the level of synthesis, underlying molecular mechanisms are poorly understood. To examine regulation by insulin, we used run-on assays to measure IGF-I and BP-1 gene transcription rates in nuclei isolated from the livers of normal and diabetic rats. Streptozotocin (STZ)-treated rats exhibited 20-25% weight loss, a 2.5- to 3-fold increase in serum glucose, and a 50-60% fall in circulating IGF-I levels (all P < 0.001). Diabetic animals also had a 45% reduction in hepatic IGF-I mRNA and over 400% increases in BP-1 mRNA (both P < 0.005); all parameters were restored toward normal after treatment with insulin. Metabolically responsive IGF-I gene transcription was evaluated effectively with a 3.2-kilobase BglII/EcoRI genomic probe located down-stream from all initiation sites in exon 1, while BP-1 gene transcription was studied with a cDNA probe. Animals treated with 144 mg/kg STZ exhibited 50-97% decreases in IGF-I gene transcription (P < 0.05), while insulin treatment raised IGF-I gene transcription to control levels (P < 0.02). IGF-I gene transcription appeared to be more sensitive to metabolic status than IGF-I mRNA levels, resulting in a modest correlation between transcription rates and mRNA levels (r = 0.68; P < 0.001). In contrast, changes in BP-1 mRNA and gene transcription appeared to be exquisitely sensitive to metabolic status. BP-1 gene transcription rose up to 10-fold in animals given 144 mg/kg STZ (P < 0.002) and was decreased 94% below control levels by treatment with insulin (P < 0.001). Hepatic levels of BP-1 mRNA were strongly correlated with gene transcription rates (r = 0.91; P < 0.001). These studies strongly suggest that insulin may play a critical role in the regulation of both IGF-I and BP-1 gene transcription.