, Volume 27, Issue 3, pp 351–357 | Cite as

The renal metabolism of insulin

  • R. Rabkin
  • M. P. Ryan
  • W. C. Duckworth
Review Article


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.


Glomerular Filtration Renal Clearance Tubular Cell Sequential Action Oligopeptides 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Rubenstein AH, Mako ME, Horowitz DL (1976) Insulin and the kidney. Nephron 15: 306–326Google Scholar
  2. 2.
    Duckworth WC, Kitabchi AE (1981) Insulin metabolism and degradation. Endocr Rev 2: 210–233Google Scholar
  3. 3.
    Rabkin R, Kitaji J (1983) Renal metabolism of peptide hormones. Miner Electrolyte Metab 9: 212–236Google Scholar
  4. 4.
    Rabkin R (1983) Role of the kidney in hormone metabolism. In: Massry SG, Glassock RJ, (eds) Text book of nephrology. Williams & Wilkins, New York, pp 2–8Google Scholar
  5. 5.
    Rabkin R, Simon NM, Steiner S, Colwell JA (1970) Effect of renal disease on renal uptake and excretion of insulin in man. N Engl J Med 282: 182–187Google Scholar
  6. 6.
    Katz AI, Rubenstein AH (1973) Metabolism of proinsulin, insulin and C-peptide in the rat. J Clin Invest 52: 1113–1121Google Scholar
  7. 7.
    Ferrannini E, Wahren J, Faber OK, Felig P, Binder C, DeFronzo RA (1983) Splanchnic and renal metabolism of insulin in human subjects: a dose-response study. Am J Physiol 244: E517-E527Google Scholar
  8. 8.
    Rubenstein AH, Clark JL, Melani F, Steiner D (1969) Secretion of proinsulin, C-peptide by pancreatic beta cells and its circulation in blood. Nature (Lond) 224: 697–699Google Scholar
  9. 9.
    Polonsky K, Jaspan J, Pugh W, Cohen D, Schneider M, Schwartz T, Moossa AR, Tager H, Rubenstein AH (1983) Metabolism of C-peptide in the dog. In vivo demonstration of the absence of hepatic extraction. J Clin Invest 72: 1114–1123Google Scholar
  10. 10.
    Block M, Mako M, Steiner D, Rubenstein A (1972) Circulating proinsulin, C-peptide by pancreatic beta cells and its circulation in blood. Nature (Lond) 224: 697–699, 1969Google Scholar
  11. 11.
    Block M, Mako M, Steiner D, Rubenstein A (1972) Circulating C-peptide immunoreactivity studies in normals and diabetic patients. Diabetes 21: 1013–1024Google Scholar
  12. 12.
    Brenner BM, Hostetter TM, Humes HD (1978) Glomerular permselectivity: barrier function based on discrimination of molecular size and charge. Am J Physiol 234: F455-F460Google Scholar
  13. 13.
    Pekar AH, Frank BM (1972) Conformation of proinsulin. A comparison of insulin and proinsulin self association at neutral pH. Biochemistry 11: 4013–4016Google Scholar
  14. 14.
    Berson SA, Yalow RS (1970) Plasma insulin. In: Ellenberg M, Rifkin H (eds) Diabetes mellitus: theory and practice. McGraw-Hill, New York, pp 303–367Google Scholar
  15. 15.
    Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D (1979) Renal filtration, transport and metabolism of low molecular weight proteins: a review. Kidney Int 16: 251–270Google Scholar
  16. 16.
    Kurokawa K, Silverblatt FJ, Klein KL, Wang MS, Lerner RL (1979) Binding of 125I-insulin to the isolated glomeruli of rat kidney. J Clin Invest 64: 1357–1364Google Scholar
  17. 17.
    Meezan E, Freychet P (1982) Binding and degradation of 125I-insulin by rat glomeruli and tubules isolated from rats. Diabetologia 22: 276–284Google Scholar
  18. 18.
    Bordeau JE, Chen ER-Y, Carone FA (1973) Insulin uptake in the renal proximal tubule. Am J Physiol 225: 1392–1404Google Scholar
  19. 19.
    Just M, Haberman E (1973) Interactions of a protease inhibitor and other peptides with isolated brush border membranes from rat renal cortex. Naunyn-Schmiedeberg's Arch Pharmacol 280: 161–176Google Scholar
  20. 20.
    Rabkin R, Petersen J, Mamelok R (1982) Binding and degradation of insulin by isolated renal brush border membranes. Diabetes 31: 618–623Google Scholar
  21. 21.
    Taylor Z, Emmanouel DS, Katz AI (1982) Insulin binding and degradation by luminal and basolateral renal tubular membranes. J Clin Invest 69: 1136–1146Google Scholar
  22. 22.
    Rabkin R, Kitabchi AE (1978) Factors influencing the handling of insulin by the isolated rat kidney. J Clin Invest 61: 169–175Google Scholar
  23. 23.
    Rabkin R, Gottheiner TI, Tsao TS (1981) Metabolic characteristics of renal insulin uptake. Diabetes 30: 929–934Google Scholar
  24. 24.
    Silverstein SC, Steinman RM, Cohn ZA (1977) Endocytosis. Ann Rev Biochem 46: 669–722Google Scholar
  25. 25.
    Rabkin R, Share L, Payne PA, Young J, Crofton J (1979) The handling of immunoreactive vasopressin by the isolated perfused rat kidney. J Clin Invest 63: 6–13Google Scholar
  26. 26.
    Rabkin R, Gottheiner TI, Fang VS (1981) Removal and excretion of immunoreactive rat growth hormone by the isolated kidney. Am J Physiol 240: F282-F287Google Scholar
  27. 27.
    Martin K, Hruska K, Greenwalt A, Klahr S, Slatopolsky E (1976) Selective uptake of intact parathyroid hormone by the liver. Differences between hepatic and renal uptake. J Clin Invest 58: 781–788Google Scholar
  28. 28.
    Rabkin R, Gottheiner TI, Tsao TS (1982) Amino acids enhance renal tubular absorption of the low molecular weight proteins insulin and growth hormone. Am J Physiol 242: F745-F749Google Scholar
  29. 29.
    Petersen J, Kitaji J, Duckworth WC, Rabkin R (1982) Fate of 125I-insulin removed from the peritubular circulation of isolated perfused rat kidney. Am J Physiol 243: F126-F132Google Scholar
  30. 30.
    Duckworth WC (1976) Insulin and glucagon degradation by the kidney. I. Subcellular distribution under different assay conditions. Biochim Biophys Acta 437: 518–530Google Scholar
  31. 31.
    Duckworth WC (1976) Insulin and glucagon degradation by the kidney. II. Characterization of the mechanisms at neutral pH. Biochim Biophys Acta 437: 531–542Google Scholar
  32. 32.
    Hjelle JT, Oparil S, Peterson DR (1984) Subcellular sites of insulin hydrolysis in renal proximal tubules. Am J Physiol: 246 (Renal Fluid Electrolyte Physiol 15) F409-F416)Google Scholar
  33. 33.
    Carone FA, Peterson DR (1980) Hydrolysis and transport of small peptides by the proximal tubules. Am J Physiol 238: F151-F158Google Scholar
  34. 34.
    Peterson DR, Carone FA, Oparil S, Christensen EI (1982) Differences between renal tubular processing of glucagon and insulin. Am J Physiol 242: F112-F118Google Scholar
  35. 35.
    Misbin RI, Ryan MP, Duckworth WC (1984) Methods of assaying insulin degradation. In: Pohl S, Larner J (eds) Methods in diabetes research. John Wiley, New York, (in press)Google Scholar
  36. 36.
    Chamberlain JJ, Stimmler L (1967) The renal handling of insulin. J Clin Invest 46: 911–919Google Scholar
  37. 37.
    Kurokawa K, Lerner RL (1980) Binding and degradation of insulin by isolated renal cortical tubules. Endocrinology 106: 655–662Google Scholar
  38. 38.
    Nakamura R, Emmanouel DS, Katz SI (1983) Insulin binding sites in various segments of the rabbit nephron. J Clin Invest 72: 388–392Google Scholar
  39. 39.
    Blanchard RF, Davis PJ, Blas SD (1978) Physical characteristics of insulin receptors on renal cell membranes. Diabetes 27: 88–95Google Scholar
  40. 40.
    Duckworth WC (1978) Insulin and glucagon binding and degradation by kidney cell membranes. Endocrinology 102: 1766–1774Google Scholar
  41. 41.
    Maude DL, Handelsman DG, Muthiyaliah B, Gordon EE (1981) Handling of insulin by the isolated perfused rat kidney. Am J Physiol 240 (Renal Fluid Electrolyte Physiol 9): F288-F294Google Scholar
  42. 42.
    DeFronzo RA (1981) The effect of insulin on renal sodium metabolism. A review with clinical implications. Diabetologia 21: 165–171Google Scholar
  43. 43.
    DeFronzo RA, Goldberg M, Agus ZS (1976) The effects of glucose and insulin on renal electrolyte transport. J Clin Invest 58: 83–90Google Scholar
  44. 44.
    Taylor Z, Emmanouel DS, Katz AI (1982) Insulin stimulates Na-K-ATPase activity of basolateral renal tubular membranes. Kidney Int 21: (Suppl 1) 266 (Abstract)Google Scholar
  45. 45.
    Rivera C, Reyes-Santos H, Martinez-Maldonado M (1978) Response of dog renal Na+, K+-ATPase to insulin in vitro. Renal Physiol 1: 74–83Google Scholar
  46. 46.
    Mahler RJ, Szabo O (1968) Metabolic effects of insulin in rat kidney after inhibiting degradation of the hormone. Endocrinology 83: 1166–1172Google Scholar
  47. 47.
    Nakamura R, Emmanouel DS, Katz AI (1983) Insulin degradation by various segments of rabbit nephron. Clin Res 31: 781AGoogle Scholar
  48. 48.
    Roth RA (1981) Bacitracin: an inhibitor of the insulin degrading activity of glutathione-insulin-transhydrogenase. Biochem Biophys Res Commun 98: 431–437Google Scholar
  49. 49.
    Misbin RI, Almira EC, Duckworth WC, Mehl TD (1983) Inhibition of insulin degradation by insulin-like growth factors. Endocrinology 113: 1525–1527Google Scholar
  50. 50.
    Burghen GA, Duckworth WC, Kitabchi AE, Solomon SS, Poffenbarger PL (1976) Inhibition of insulin degradation by nonsuppressible insulin like activity. J Clin Invest 57: 1089–1092Google Scholar
  51. 51.
    Kahn CR, Megyesi K, Roth J (1978) Nonsuppressible insulin-like activity of human serum. A potent inhibitor of insulin degradation. J Clin Invest 57: 526–529Google Scholar
  52. 52.
    Misbin RI, Almira EC, Froesch ER, Merimee TJ, Zopf J (1983) Resistance to subcutaneous and intramuscular insulin associated with deficiency of insulin-like growth factor. 2. Metabolism 32: 537–542Google Scholar
  53. 53.
    D'Ercole JA, Decedue CJ, Furlanetto RW, Underwood LE, Van Wyck JJ (1977) Evidence that somatomedin C is degraded by the kidney and inhibits insulin degradation. Endocrinology 101: 577–585Google Scholar
  54. 54.
    Hare JF (1978) A novel proteinase associated with mitochondrial membranes. Biochem Biophys Res Commun 83: 1206–1215Google Scholar
  55. 55.
    George SG, Kenney AJ (1973) Studies on the enzymology of purified preparations of brush border from rabbit kidney. Biochem J 134: 43–57Google Scholar
  56. 56.
    Duckworth WC, Stentz FB, Heinemann M, Kitabchi AE (1979) Initial site of insulin cleavage by insulin protease. Proc Natl Acad Sci USA 76: 635–639Google Scholar
  57. 57.
    Chandler M, Varandani PT (1972) Insulin degradation. II. The widespread distribution of glutathione-insulin transhydrogenase in the tissues of the rat. Biochim Biophys Acta 286: 136–143Google Scholar
  58. 58.
    Thomas JH, Jenkins CDG, Davey PG, Papachristodoulou DK (1973) The binding and degradation of 125I-labelled insulin by rat kidney brush-border membranes. Int J Biochem 134: 43–57Google Scholar
  59. 59.
    Willingham MC, Pastan I (1983) Formation of receptosomes from plasma membrane coated pits during endocytosis: analysis by serial sections with improved membrane labeling and preservation techniques. Proc Natl Acad Sci USA 80: 5617–5621Google Scholar
  60. 60.
    Thomas JH, Varandani PT (1979) Insulin degradation. XXV. Glutathione-insulin transhydrogenase activity of rat liver and kidney during the development of streptozotocin-diabetes. Biochim Biophys Acta 567: 88–95Google Scholar
  61. 61.
    Taylor CA, Varandani PT (1981) Insulin degradation. XXVII. Immunocytochemical localization of glutathione-insulin transhydrogenase in the pancreas, kidney and liver of normal and strepto-zotocin-diabetic rats and of lean and obese (ob/ob) mice. Diabetologia 21: 464–469Google Scholar
  62. 62.
    Goldstein BJ, Livingston JN (1981) Insulin degradation by insulin target cells. Metabolism 30: 825–835Google Scholar
  63. 63.
    Papachristodoulou DK, Bass PS, Davey P, Thomas JH (1982) Insulin binding and degradation by kidney cell membranes of streptozotocin diabetic rats. Horm Metab Res 14: 345–350Google Scholar
  64. 64.
    Yokono K, Imahura Y, Shii K, Sakai H, Baba S (1982) Insulin binding and degradation in liver of fed and fasted rats: effect of antiserum to insulin-degrading enzyme on insulin binding and degradation. Endocrinol Japon 29: 299–306Google Scholar
  65. 65.
    Yokono K, Roth RA, Baba S (1982) Identification of insulin-degrading enzyme on the surface of cultured human lymphocytes, rat hepatoma cells, and primary cultures of rat hepatocytes. Endocrinology 111: 1102–1108Google Scholar
  66. 66.
    Jaspan JB, Mako ME, Kuzuya H, Blix PM, Horowitz DL, Rubenstein AH (1977) Abnormalities in circulating beta cell peptides in chronic renal failure: comparison of C-peptide, proinsulin and insulin. J Clin Endocrinol Metab 45: 441–446Google Scholar
  67. 67.
    Mondon CE, Dolkas CB, Reaven GM (1978) Effect of acute uremia on insulin removal by the isolated perfused rat liver and muscle. Metabolism 27: 133–142Google Scholar
  68. 68.
    Rabkin R, Unterhalter SA, Duckworth WC (1979) Effect of prolonged uremia on insulin metabolism by isolated liver and muscle. Kidney Int 16: 433–439Google Scholar
  69. 69.
    Fuss M, Bergans A, Brauman H, Toussaint C, Vereerstraeten P, Franckson M, Corvilain J (1974) 125I-insulin metabolism in chronic renal failure treated by renal transplantation. Kidney Int 5: 372–377Google Scholar
  70. 70.
    Navalesi R, Pilo A, Lenzi S, Donato L (1975) Insulin metabolism in chronic uraemia and in the anephric state: effect of the dialytic treatment. J Clin Endocrinol Metab 40: 70–83Google Scholar
  71. 71.
    Hampers CL, Lowrie EG, Soeldner JS, Merrill JP (1970) The effect of uremia upon glucose metabolism. Arch Intern Med 126: 870–874Google Scholar
  72. 72.
    Maloff BL, McCaleb ML, Lockwood DH (1983) Cellular basis of insulin resistance in chronic uremia. Am J Physiol 245: E178-E184Google Scholar
  73. 73.
    Kauffman JM, Caro JF (1983) Insulin resistance in uremia. Characterization of insulin action, binding, and processing in isolated hepatocytes from chronic uremie rats. J Clin Invest 71: 698–708Google Scholar
  74. 74.
    Goldberg AP, Hagberb JM, Delmez JA, Haynes ME, Harter HR (1980) Metabolic effects of exercise training in hemodialysis patients. Kidney Int 18: 754–761Google Scholar
  75. 75.
    Klahr S, Delmez J, Harter H (1982) Endocrine and metabolic consequences of chronic renal failure. Cardiovasc Rev Rep 30: 613–626Google Scholar
  76. 76.
    Emmanouel DS, Lindheimer MD, Katz AI (1981) Metabolic and endocrine abnormalities in chronic renal failure. In: Brenner BM, Stein JH (eds) Chronic renal failure; Churchill Livingstone Edinburgh pp 46–83Google Scholar
  77. 77.
    Emmanouel DS, Lindheimer MD, Katz AI (1980) Pathogenesis of endocrine abnormalities in uremia. Endocrine Rev 1: 28–44Google Scholar
  78. 78.
    Malone JI, Root AW (1976) Renal wastage of insulin in children with diabetes mellitus. Diabetes 25: 989–993Google Scholar
  79. 79.
    Palmano JP, Elliot RB (1976) Studies in the renal handling of insulin in juvenile diabetics. Diabetologia 12: 15–21Google Scholar
  80. 80.
    Sacks H, Rabkin R, Kitabchi AE (1981) Reversible hyperinsulinuria in diabetic ketoacidosis in man. Am J Physiol 241: E396-E405Google Scholar
  81. 81.
    Livesey JH, Scott RS, Donald RA (1979) Urinary growth hormone in diabetic ketoacidosis. Horm Metab Res 11: 142–146Google Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • R. Rabkin
    • 1
    • 2
  • M. P. Ryan
    • 3
  • W. C. Duckworth
    • 3
  1. 1.Department of MedicineVeterans Administration Medical CenterPalo Alto
  2. 2.Stanford University Medical SchoolStanford
  3. 3.Department of MedicineVeterans Administration Medical Center and Indiana University School of MedicineIndianapolisUSA

Personalised recommendations