Even though hyperglucagonemia coexists with insulin deficiency in a variety of clinical conditions with accelerated urinary nitrogen excretion, and even though hypoaminoacidemia is characteristic of patients with glucagonoma, glucagon's effect on protein synthesis and degradation remains incompletely defined. The major objective of the present proposal is to gain better understanding of the effect of glucagon on protein synthesis and degradation in man, and to define its action on protein balance in relation to insulin. Recent evidence indicates that insulin causes positive protein balance in the postabsorptive state by inhibiting proteolysis and not by stimulating protein synthesis. Contrary to the conventional belief, plasma amino acids seem to modulate insulin's effect on protein synthesis. Experiments will be performed in normal volunteers with infusion of somatostatin and varying concentrations of insulin and glucagon to more clearly define the effects of these hormones on protein synthesis and degradation. Intra- arterial infusion of glucagon and insulin will be performed to determine whether an increase in the local concentrations of these hormones in forearm without any systemic changes affects protein turnover. We will also study the effect of insulin and glucagon on peripheral tissue- protein synthesis in postabsorptive man during the infusion of essential amino acids. These studies will more clearly define the role of plasma amino acids on insulin and glucagon's action on protein synthesis. Studies will also be performed in diabetic patients to determine the effect of somatostatin infusion on fractional mixed skeletal muscle protein synthesis rate (FMPS) and leucine oxidation. Protein synthesis and degradation in the peripheral tissues will be measured from the dilution of [2H5} phenylalanine and phenylalanine balance across leg or forearm during a continuous infusion of L-[ring 2H5] phenylalanine. Whole body leucine flux will be estimated from plasma [13 C]KIC abundance at plateau, and FMPS will be estimated from the increment in [13C] leucine in mixed muscle protein obtained by serial muscle biopsies during a continuous infusion of L-[1-13C] leucine. Results of proteins synthesis estimated from various techniques will be compared to check the validity of the conclusions. these investigations will provide new insight into the control of protein turnover in vivo and the cause of protein catabolism in diabetes and other catabolic conditions. A greater understanding of the mechanism of catabolic state resulting from these studies is likely to stimulate therapeutic research in many catabolic conditions.
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