Nutrition and somatomedin. XIX. molecular regulation of insulin-like growth factor-1 in streptozotocin-diabetic rats

Abstract

Poor growth in diabetes involves low circulating levels of somatomedins/insulin-like growth factors (IGFs), largely reflecting decreased growth factor release by the liver. To define regulatory mechanisms, circulating IGF-1 was compared with levels of a high mol wt putative hepatic IGF-1 precursor and hepatic IGF-1 mRNA in a model of progressive severity of diabetes in rats. Streptozotocin administered at 36, 72, 144, and 288 mg/kg produced graded metabolic decompensation 2 days later, from minimal hyperglycemia with continued weight gain at 36 mg/kg, to marked hyperglycemia, ketonemia, and weight loss at 288 mg/kg (all P < 0.001). Total serum IGF-1 measured by RIA was unchanged with the 36 and 72 mg/kg doses of streptozotocin (471 ± 19 and 439 ± 27 ng/ml, respectively, vs. 517 ± 27 ng/ml in controls) despite serum glucose > 400 mg/dl. With streptozotocin 144 and 288 mg/kg, serum IGF-1 fell to 131 ± 27 and 142 ± 10 ng/ml, respectively (both P < 0.005 vs. controls). Serum IGF-1 was correlated strongly with serum 0-hydroxybutyrate and body weight (r = -0.88 and 0.91, respectively, P < 0.0001), and less strongly with serum glucose (r = -0.59, P < 0.0002). Extractable hepatic content of a high mol wt form of immunoreactive IGF-1 (a putative precursor) was unchanged at the two lowest doses of streptozotocin (68 ± 4 and 83 ± 9 ngeq/g vs. 67 ± 4 in controls), but decreased to 16 ± 3 and 29 ± 4 ng/g at the two highest doses (both P < 0.001 vs. controls). Hepatic IGF-1 content was correlated strongly with serum IGF-1 (r = 0.85, P < 0.0001). Levels of hepatic IGF- 1 mRNA paralleled serum and hepatic IGF-1, unchanged at the two lowest doses of streptozotocin (9.8 ±1.1 and 9.4 ± 0.7 ngeq vs. 9.4 ± 2 in controls), and falling with the two highest doses of streptozotocin (3.4 ±1.1 and 1.1 ± 0.4 ngeq, respectively, both P < 0.05 vs. controls). Levels of IGF-1 mRNA were correlated both with serum IGF-1 (r = 0.70), and with hepatic content of IGF-1 (r = 0.59), both P < 0.001. In contrast, there was no change in hepatic levels of mRNA for the structural protein β-actin. The strong correlations between hepatic IGF-1 content and circulating IGF-1 levels buttress older evidence supporting the liver as a major source of IGF-1 in the circulation. The close relationship between levels of hepatic IGF-1 mRNA and levels of IGF-1 in both liver and serum is consistent with the hypothesis of metabolic regulation of IGF-1 at the messenger RNA level. © 1988 by The Endocrine Society.