Previous studies have documented an age-related decline in glucose and protein tolerance which appears to be related to tissue insensitivity to insulin. The present studies will further examine the site(s) and mechanism(s) of this insulin resistance. I. Hepatic Glucose Metabolism: a) suppression of hepatic glucose production and hepatic glucose uptake following oral glucose will be examined with a double tracer technique (3-H-3-glucose and 14-C-glucose); b) suppression of hepatic glucose production following small doses of intravenous insulin will be examined with the insulin clamp in combination with 3-H-3-glucose; c) glucose oxidation and glucose storage during insulin and/or glucose administration will be assessed using indirect calorimetry; d) alanine turnover and hepatic gluconeogenesis will be studied with 14-C-alanine and 3-H-3-glucose; e) the effect of oral protein on hepatic glucose production will be examined with 3-H-3-glucose. II. Insulin Resistance--Receptor versus Postreceptor Defect: a) insulin binding to human monocytes will be determined and correlated with changes in tissue sensitivity to insulin as determined by the insulin clamp technique; b) insulin binding, glucose transport, and glucose metabolism by soleus muscle in young and old Fisher 344 rats will be quantitated and compared with tissue sensitivity to insulin as measured in vivo with the insulin clamp technique. III. Amino Acid Metabolism: a) leucine turnover and oxidation will be determined with 14-C-leucine; b) uptake of amino acids by human leg muscle following oral protein ingestion will be examined; c) the ability of insulin to stimulate amino acid uptake by leg muscle in young and old subjects will be examined.
