Role of the Liver in Regulating Somatomedin Activity: Effects of Streptozotocin Diabetes and Starvation on the Synthesis and Release of Insulin-Like Growth Factor and Its Carrier Protein by the Isolated Perfused Rat Liver*

This report describes the use of 12-h isolated liver perfusions to examine the effects of experimental diabetes mellitus or starvation on the synthesis/release of somatomedin activity, insulin-like growth factor (IGF), by the liver of the adult male Sprague-Dawley rat. Diabetes was induced by the iv injection of streptozotocin (80 mg/kg BW). One group of diabetic liver donors was untreated for 6–8 weeks; a second and third groups of diabetic rats were treated with protamine zinc insulin (2–3 U daily) for periods of 6–8 weeks and 8–9 months, respectively. At the close of these time periods after the onset of diabetes, livers were perfused, and the net cumulative release of IGF and its carrier protein (CP) into perfusates was calculated from analyses of the perfusates by competitive protein-binding assay. The net cumulative synthesis/release of IGF (mean ± SEM, expressed as microunits per 300 cm2 body surface area of donor rat) by livers from untreated diabetic rats (116 ± 94) was profoundly decreased to less than 5% of normal 6280 ± 630, and in two experiments did not respond to insulin plus cortisol added continuously during the 12 h of the perfusion. Livers from insulin-treated diabetic rats showed significant decreases in IGF production to 57% (6–8 weeks) and about 15% (at 8–9 months) of normal. In contrast, the synthesis/release of CP was relatively unaffected by diabetes; a small but significant difference from normal became apparent only at 12 h. For the purpose of comparison, livers from otherwise normal 2- to 6-day-starved rats were perfused, and their production of IGF and CP was measured; impairment of IGF production was already as severe at 2 days as that in livers from untreated diabetics, while the production of CP was impaired only in livers of rats starved from 3–6 days. The severity of diabetes in the liver donors, expressed in terms of weight loss or less than normal weight gain, was significantly orrelated (P < 0.01) with the net cumulative 12-h production of IGF by the isolated livers. These studies demonstrate that both decreased hepatic production and serum levels of IGF and its CP in the rat result from diabetes mellitus, and that these changes can be corrected, at least in part, by in vivo insulin administration.