Handling of insulin by the isolated perfused rat kidney

Abstract

The organ clearance of insulin calculated from the rate of disappearance of immunoreactive insulin from the perfusate averages 0.76 ml.min-1.g kidneys wt-1, a value greater than the simultaneously measured glomerular filtration rate. Clearance does not fall when hormone concentration is as high as 7 X 10(-8) M (10,000 microunits/ml). Fifteen percent of the cleared insulin is excreted in the urine; the remainder is chemically modified and appears in the perfusate both as low molecular weight fragments and as high molecular weight species. In the process of clearing the hormone, kidney tissue accumulates both intact insulin and 125I-labeled insulin degradation products. the organ clearance of insulin is not curtailed when the glomerular filtration rate is sufficiently reduced (by lowering perfusate pressure) to cause urine flow to cease. Studies using hyperglycemic perfusates and kidneys taken from starving or streptozotocin-diabetic animals provided no evidence that the kidney plays a role in the regulation of plasma glucose by modulating the rate of insulin degradation.

Insulin Binding and Degradation by Luminal and Basolateral Tubular Membranes from Rabbit Kidney

“…Degradation of insulin by both membranes proceeded without evidence of saturation, consistent with in vivo and in vitro observations by others that insulin degradation by the renal parenchyma fails to reach saturation even at pharmacologic insulin concentrations (1,10,12,14). Although brush border membranes were more active in this respect, substantial insulindegrading activity was also demonstrated in the contraluminal membrane fraction (Figs.…”

“…The apparent dissociation constants for the "low" and "high affinity" sites were 35 and 2.4 nM, respectively. Using only data from experiments with labeled insulin, i.e., with the lowest concentrations of (1, 10-12), studies with isolated perfused kidneys (13,14), and experiments in which insulin was injected into the renal portal circulation of the chicken (15) (Fig. 1).…”

“…Binding of insulin to receptors at this site, besides initiating the cellular action of the hormone, could be linked in some way to its degradation, the latter performing a regulatory function by terminating the hormone signal on the tubular cell. Measurements of renal organ clearance of insulin in humans (1,10), dogs (11), and rats (12) (in vivo), studies with the isolated perfused kidney (13,14), and injection of the hormone in the portal circulation of the chicken (15) all strongly suggest that insulin degradation by the kidney involves in addition to glomerular filtration and luminal uptake, also catabolism of the hormone by peritubular mechanisms. Further support for this view was provided by recent observations that tubule fragments bound specifically and degraded insulin avidly in vitro, despite the fact that their collapsed lumina were exposed only to a very limited extent to the hormone (14,16,17).…”

“…Measurements of renal organ clearance of insulin in humans (1,10), dogs (11), and rats (12) (in vivo), studies with the isolated perfused kidney (13,14), and injection of the hormone in the portal circulation of the chicken (15) all strongly suggest that insulin degradation by the kidney involves in addition to glomerular filtration and luminal uptake, also catabolism of the hormone by peritubular mechanisms. Further support for this view was provided by recent observations that tubule fragments bound specifically and degraded insulin avidly in vitro, despite the fact that their collapsed lumina were exposed only to a very limited extent to the hormone (14,16,17). In contrast, studies based on electron microscopic autoradiography and tubule microperfusion were interpreted to indicate only negligible participation of the contraluminal uptake route in the renal metabolism of insulin (18).…”

Glucose and Insulin Metabolism in Uremia

“…Less than 1% of filtered insulin appears in the urine [4][5][6]. The renal clear ance of insulin in man significantly exceeds the glomerular filtration rate [7], indicating significant uptake and degrada tion of insulin in the peritubular epithelial and endothelial cell membranes [8][9][10], In man little change in the metabolic clearance of insulin occurs until the glomerular filtration rate (GFR) has decreased to 40 ml/min. Peritubular insulin uptake increases as renal function declines to maintain renal insulin clearance until the GFR has fallen to less than 15-20 ml/min [4,7], At this point, the metabolic clearance rate of insulin falls precipitously [4,7,11], This decline in insulin degradation is responsible for the progressive fall in insulin requirement of diabetic subjects who develop chronic renal failure [12][13][14], A similar phenomenon may also account for the hypoglycemia observed in nondiabetic patients with advanced renal insufficiency [15].…”