Although poor growth in diabetes and malnutrition is attributed to decreased utilization of nutrients, the mechanism of the defect is not known. Skeletal growth is attributed to stimulation of cartilage by somatomedins, circulating factors with broad anabolic effects. Other circulating factors, inhibitors, limit the actions of somatomedins; both are reflected in bioassay measurements of net somatomedin activity, and both appear to be generated by the liver according to insulin and nutritional status. While alterations in somatomedins and inhibitors might direct utilization of nutrients toward or away from growth, control processes are poorly understood. To elucidate mechanisms, we propose: 1. To examine the nature of the circulating somatomedin inhibitors, a) the high-MW inhibitor in human plasma and the low-MW inhibitor in rat serum will be isolated and characterized; and b) attempts made to raise antibodies which can be used to enhance purification, elucidate biological actions, and refine assessment of regulation in vivo. 2. To define potential modulation of nutrient utilization according to the balance of somatomedins and inhibitors, a) inhibitor effects on somatomedin and insulin action will be examined in models of skeletal elongation and calorie storage; b) interactions characterized in terms of reversibility, kinetics, and temporal sequence of impact on somatomedin and insulin action; and c) effects on binding tested as a possible locus of antagonism of insulin action. 3. To assess metabolic determinants of hepatic contributions of somatomedins and somatomedins and somatomedin inhibitors, a perfusion model will be used to quantify formation (content and release) of somatomedins and inhibitors a) in response to changes in donor metabolic status; b) as related to hepatic glycogen, gluconeogenesis, and ketogenesis; and c) as potentially affected by enzymatic regulatory factors which could control both fuel metabolism and somatomedin/inhibitor formation in concert. 4. To evaluate metabolic regulation in vivo, fuel- and/or insulin-limited modulation will be delineated in terms of a) """"""""native"""""""" (carrier-bound) somatomedins and inhibitors fractionated by HPLC and quantitated by bioassay; b) """"""""total"""""""" serum IGF-1 extracted and measured by RIA; and c) """"""""free"""""""" somatomedins as reflected by IGF-1 in urine. These studies should provide improved understanding of the regulation of normal growth, insight into the pathophysiology of impaired growth, and new concepts for therapy of growth failure in diabetes and malnutrition.
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