The kidney plays an important role in the metabolism of insulin, proinsulin, and C-peptide. However, uncertainty exists as to the nature of the intrarenal route of insulin, for although it is accepted that glomerular filtration accounts for a significant proportion of the insulin extracted, the contribution of peritubular uptake is ill-defined. Furthermore, it is not clear whether the anatomical localization of insulin in the proximal tubule is related to a biological effect on renal function or whether this is merely a site of non-specific localization of a low molecular weight (LMW) protein. Impaired insulin catabolism is a well recognized but incompletely understood disturbance that occurs in uremia. In particular the role of hepatic dysfunction, secondary to uremia, in the production of this disturbance has not been fully evaluated. The overall objectives of this proposed study are (a) to gain a deeper understanding of the physiology of the renal handling of insulin, proinsulin and C-peptide, (b) to determine what action these peptides might have on renal function and (c) to assess the role of the liver in the pathogenesis of impaired insulin catabolism seen in uremia. Renal handling of insulin, proinsulin and C-peptide will be studied using the isolated perfused rat kidney. These peptides will be measured by radioimmunoassay. The impaired insulin degradation of uremia will be studied using isolated perfused rat livers. This study has particular significance because of the major role played by the kidney in regulating plasma insulin, proinsulin and C-peptide levels. Furthermore, the renal handling of these peptides serves as a model for low molecular weight proteins of similar size. A fuller understanding of the renal handling of insulin and proinsulin and the effects of uremia on hepatic insulin degradation should contribute to a better understanding of the disturbances in plasma levels of these as well as other low molecular weight proteins that occur in renal failure.