ALTERATIONS IN HEPATIC PRODUCTION AND PERIPHERAL CLEARANCE OF IGF-I AFTER ENDOTOXIN

Lipopolysaccharide (LPS) produces a rapid and sustained reduction in t he circulating concentration of insulin-like growth factor I (IGF-I), which may be responsible, in part, for the alterations in protein meta bolism observed in these animals. The purpose of the present study was to determine whether this drop was due to a decreased hepatic product ion of IGF-I and/or an increased clearance of the peptide from the blo od. Four hours after intravenous injection of LPS the plasma IGF-I con centration was decreased 50%. IGF-I release by in situ perfused livers from control rats was constant throughout the 60-min perfusion period and averaged 111 +/- 3 ng/min. In contrast, hepatic IGF-I output was decreased 46% by in vivo LPS. In contrast, livers from LPS-injected ra ts released more IGF binding proteins-1, -2 and -4 than did control li vers. Hepatic cell isolation indicated that LPS decreased the IGF-I co ntent in Kupffer and parenchymal cells, but not endothelial cells, by similar to 45%. Pharmacokinetic analysis of blood I-125-IGF-I decay cu rves indicated that the half-life for whole body clearance of I-125-IG F-I from the circulation was not altered by LPS. However, LPS increase d I-125-IGF-I uptake by spleen, liver, lung, and kidney while decreasi ng uptake by the pancreas and gastrointestinal tract. These results in dicate that the LPS-induced decrease in blood IGF-I concentration is p rimarily due to a reduction in hepatic production, not a change in who le body peptide clearance, and that a decreased production by both par enchymal and Kupffer cells contributes to this alteration.