Effect of Renal Disease on Renal Uptake and Excretion of Insulin in Man

Rabkin, Ralph; Simon, Norman; Steiner, Sheldon H.; Colwell, John A.

doi:10.1056/nejm197001222820402

Cited by 197 publications

(110 citation statements)

References 27 publications

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“…The mean renal arteriovenous difference of insulin was 40%, which is in good agreement with values of 29% (39) and 39% (40) reported in man and of 41% in the dog (41). The renal extraction of insulin in the rat was proportional to its arterial concentration in the range between 1 and 15 ng/ml, the latter value exceeding physiological levels in the fed state.…”

Section: Resultssupporting

confidence: 88%

Metabolism of Proinsulin, Insulin, and C-Peptide in the Rat

Katz¹,

Rubenstein²

1973

J. Clin. Invest.

256

121

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A B S T R A C T The renal extraction and excretion of bovine proinsulin, insulin, and C-peptide and the contribution of the kidney to their total metabolic clearance rate (MCR) were studied in the rat. Metabolic clearance rates were measured by the constant infusion technique and plasma and urine concentrations of each polypeptide were determined by radioimmunoassay.The MCR of insulin (16.4±0.4 ml/min) was significantly greater than that of either proinsulin (6.7 ±0.3 ml/min) or C-peptide (4.6±0.2 ml/min). Metabolic clearance rates were independent of plasma levels over a range of steady-state plasma concentrations varying from 1 to 15 ng/ml.In contrast to the differences in their metabolic clearance rates, the renal disposition of the three polypeptides was similar, being characterized by high extraction and very low urinary clearance. The renal arteriovenous difference of proinsulin, insulin, and C-peptide averaged 36, 40, and 44%, respectively, and was linearly related to their arterial concentration between 2 and 25 ng/ml. When glomerular filtration was markedly reduced or stopped by ureteral obstruction, the renal extraction of proinsulin, insulin, and C-peptide was invariably greater than the simultaneously measured extraction of inulin, indicating that these polypeptides are removed from the renal circulation by both glomerular filtration and direct uptake from peritubular capillary blood. The fractional urinary clearance of each polypeptide never exceeded 0.6%, indicating that more than 99% of the amount filtered was sequestered in the kidney.The renal removal of proinsulin and C-peptide from the circulation accounts for 55 and 69% of their metabolic clearance rates, while the renal contribution to the peripheral metabolism of insulin was smaller, averThis work was published in abstract form in 1972 J. Clin. Invest. 51: 49a.Received for publication 18 September 1972 and in revised form 13 December 1972. aging 33%. This difference is due to the fact that insulin, but not the other two polypeptides, is metabolized to a significant extent by the liver. These results define the renal handling of proinsulin, insulin, and Cpeptide in the rat and indicate that in this species the kidney represents a major site for insulin metabolism and is the main organ responsible for the degradation of proinsulin and C-peptide. INTRODUCTIONDifferential secretion rates of insulin, proinsulin, and C-peptide by pancreatic beta cells have generally been considered to be the major determinant of their plasma concentrations (1-3). However, in vivo and in vitro studies have indicated that the peripheral distribution, metabolism, and degradation of insulin and proinsulin differ, suggesting that these factors may play an important role in determining their blood levels. Thus, the half disappearance time of proinsulin in dogs (4), swine (5), rats (6), and baboons (5) is two-to threefold longer than that of insulin. Experiments with the isolated perfused liver (7,8) have shown a high clearance of insulin compared with the removal...

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Section: Resultssupporting

confidence: 88%

Metabolism of Proinsulin, Insulin, and C-Peptide in the Rat

Katz¹,

Rubenstein²

1973

J. Clin. Invest.

256

121

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“…18 In that study and others using renal vein catheterization, net renal insulin clearance has been estimated to be approximately 200 ml/min in healthy subjects, with two thirds attributable to glomerular filtration and tubular reabsorption and one third attributable to tubular uptake through peritubular capillaries. [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.…”

Section: Discussionmentioning

confidence: 99%

Impaired Glucose and Insulin Homeostasis in Moderate-Severe CKD

Zelnick

Afkarian

Ayers

et al. 2016

JASN

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Kidney disease leads to clinically relevant disturbances in glucose and insulin homeostasis, but the pathophysiology in moderate-severe CKD remains incompletely defined. In a cross-sectional study of 59 participants with nondiabetic CKD (mean eGFR =37.6 ml/min per 1.73 m 2 ) and 39 healthy control subjects, we quantified insulin sensitivity, clearance, and secretion and glucose tolerance using hyperinsulinemiceuglycemic clamp and intravenous and oral glucose tolerance tests. Participants with CKD had lower insulin sensitivity than participants without CKD (mean[SD] 3.9[2.0] versus 5.0 [2.0] mg/min per mU/ml; P,0.01). Insulin clearance correlated with insulin sensitivity (r=0.72; P,0.001) and was also lower in participants with CKD than controls (876 [226] versus 998 [212] ml/min; P,0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations of CKD with insulin sensitivity (adjusted difference, 20.7; 95% confidence interval, 21.4 to 0.0 mg/min per mU/ml) and insulin clearance (adjusted difference, 285; 95% confidence interval, 2160 to 210 ml/min). Among participants with CKD, eGFR did not significantly correlate with insulin sensitivity or clearance. Insulin secretion and glucose tolerance did not differ significantly between groups, but 65% of participants with CKD had impaired glucose tolerance. In conclusion, moderate-severe CKD associated with reductions in insulin sensitivity and clearance that are explained, in part, by differences in lifestyle and body composition. We did not observe a CKD-specific deficit in insulin secretion, but the combination of insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance.

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“…The disruption of insulin signaling associated with CKD was described in 1955, 32 and the effects of kidney disease on renal uptake and excretion of insulin were reported in 1970. 33 Insulin resistance in CKD was evidenced by DeFronzo et al 17 using the "gold standard" euglycemic hyperinsulinemic clamp technique. In CKD, the decline of renal function is associated with the development of insulin resistance, and insulin resistance is recognized as an independent risk factor for cardiovascular morbidity and mortality in patients with CKD.…”

Section: Discussionmentioning

confidence: 99%

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

Koppe

Pillon

Vella

et al. 2013

Journal of the American Society of Nephrology

227

175

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The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.

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Effect of Renal Disease on Renal Uptake and Excretion of Insulin in Man

Cited by 197 publications

References 27 publications

Metabolism of Proinsulin, Insulin, and C-Peptide in the Rat

Metabolism of Proinsulin, Insulin, and C-Peptide in the Rat

Impaired Glucose and Insulin Homeostasis in Moderate-Severe CKD

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

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