The renal metabolism of insulin

Abstract

The kidney plays a pivotal role in the clearance and degradation of circulating insulin and is also an important site of insulin action. The kidney clears insulin via two distinct routes. The first route entails glomerular filtration and subsequent luminal reabsorption of insulin by proximal tubular cells by means of endocytosis. The second involves diffusion of insulin from peritubular capillaries and subsequent binding of insulin to the contraluminal membranes of tubular cells, especially those lining the distal half of the nephron. Insulin delivered to the latter sites stimulates several important processes, including reabsorption of sodium, phosphate, and glucose. In contrast, insulin delivered to proximal tubular cells is degraded to oligopeptides and amino-acids by one of two poorly delineated enzymatic pathways. One pathway probably involves the sequential action of insulin protease and either GIT or non-specific proteases; the other probably involves the sequential action of GIT and lysosomal proteases. The products of insulin degradation are reabsorbed into the peritubular capillaries, apparently via simple diffusion. Impairment of the renal clearance of insulin prolongs the half-life of circulating insulin by a number of mechanisms and often results in a decrease in the insulin requirement of diabetic patients. Much needs to be learned about these metabolic events at the subcellular level and how they are affected by disease states. Owing to the heterogeneity of cell types within the kidney and to their anatomical and functional polarity, investigation of these areas will be challenging indeed.

Impaired Glucose and Insulin Homeostasis in Moderate-Severe CKD

“…[18][19][20] Insulin taken into renal tubules via either route is then catabolized by insulin-degrading enzyme. 21,22 In our study, participants with versus without CKD had a difference in mean eGFR of 51 ml/min per 1.73 m 2 and an adjusted difference in mean insulin clearance of 77 ml/min. This mean difference in insulin clearance is consistent with the mean difference in GFR and a proportional loss of insulin extraction through peritubular capillaries.…”

Insulin kinetics and the Neonatal Intensive Care Insulin–Nutrition–Glucose (NICING) model

“…Glomerular filtration compromises about 60% of total insulin clearance by the kidney [57]. Creatinine and inulin clearance are two common molecules used to estimate glomerular filtration rate (GFR).…”

Insulin Sensitivity Measured With Euglycemic Clamp Is Independently Associated With Glomerular Filtration Rate in a Community-Based Cohort

“…Also, insulin resistance is linked to increased activity of proinflammatory cytokines and adipokines, factors that have been suggested to contribute to the progression of renal disease (19). There are also data suggesting that renal insufficiency suppresses renal clearance of insulin, leading to higher circulating levels of insulin and thus further stimulation of the deleterious effect of insulin on the kidney, i.e., leading to a vicious circle (20). We are not able to fully evaluate the potential influence of reduced renal clearance of insulin in our study, but the strong positive association between the glucose disposal rate (M) and GFR and the similar results in individuals with normal renal function indicate that the potential impact of a reduced renal clearance of insulin on the present results is not likely to be major.…”