NUTRITION AND SOMATOMEDIN .21. INSULIN-LIKE GROWTH FACTOR-I AND SOMATOMEDIN INHIBITOR IN STREPTOZOTOCIN-DIABETIC RATS - RELATION TO KETOGENESIS AND GLUCONEOGENESIS

Diabetes is associated with a fall in serum insulin-like growth factor-I (IGF-1) and a rise in somatomedin inhibitor, a circulating factor(s) of ∼30,000 MW that is released by the liver and can antagonize both somatomedin and insulin action. Levels of inhibitor correlate with levels of glucose, β-hydroxybutyrate, and weight loss. To study pathways that could underlie the fall in IGF-1 and rise in inhibitor, the effects of metabolic inhibitors on circulating metabolic fuels, serum IGF-1, and serum somatomedin inhibitor activity were studied. Rats given streptozotocin exhibited weight loss of 14% ± 0.1%, glucose 457 ± 26 mg/dL, and β-hydroxybutyrate (BOHB) 6.3 ± 0.5 mmol/L. Somatomedin inhibitor was separated from IGF-1 by size exclusion HPLC at pH 3; IGF-1 was measured by RIA, and somatomedin inhibitor by cartilage bioassay. Diabetic animals exhibited a fall in IGF-1 to 76% of normal (P < .02) and a rise in inhibitor to 270% of normal (P < .01). 3-Mercaptopicolinic (3-MPA) acid, an inhibitor of gluconeogenesis, lowered glucose to 68 ± 2 mg/dL and BOHB to 0.96 ± 0.09 mmol/L (both P < .01 v diabetic), but levels of inhibitor did not fall. Nicotinic acid, an inhibitor of lipolysis, did not affect glucose but reduced BOHB to 0.42 ± 0.02 mmol/L; somatomedin inhibitor fell 19% below diabetic levels (NS) but remained above normal (P < .01). In contrast, inhibition of fatty acid oxidationwith methyl-2-tetradecylglycidate reduced glucose to 191 ± 18 mg/dL but lowered BOHB to normal, 0.16 ± 0.02 mmol/L, accompanied by normalization of somatomedin inhibitor levels (152% ± 33% of normal, NS). Below 1.0 mmol/L BOHB, somatomedin inhibitor and BOHB were strongly correlated (r = .67, P < .001); no comparable relation was found with glucose. Despite the highly significant fluctuations in levels of somatomedin inhibitor, circulating IGF-1 was unchanged by inhibition of gluconeogenesis, lipolysis, or fatty acid oxidation. These results are consistent with the hypothesis that ketogenesis and somatomedin inhibitor production are associated via common regulatory factors. © 1990.