Biochemistry of the Basement Membrane in Diabetes Mellitus

  • Michael Brownlee
  • Robert G. Spiro
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 124)


In recent years, extensive investigations have demonstrated that numerous biochemical and physiological abnormalities occur in various tissues of hyperglycemic animals and humans (Brownlee and Cahill, 1979). Where the effect of treatment has been studied, many, if not all of these abnormalities, are returned towards normal with insulin, and it seems likely that some of these may play a role in the pathogenesis of diabetic renal disease. Others are likely to be mere concomitants of the microvascular disease which reflect common metabolic abnormalities of the diabetic state, but are causally unrelated. Although it appears increasingly likely that the morphological and clinical features of diabetic nephropathy result from a complex combination of interacting variables, the relative significance of individual factors is currently unknown. Whatever the sequence of events leading from abnormal glucose homeostasis to progressive renal failure with persistent proteinuria, the final clinical manifestations reflect irreversible glomerular capillary occlusion and increased permeability of the glomerular filtration barrier. Both of these result from alterations in basement membrane.


Basement Membrane Diabetic Nephropathy Glomerular Basement Membrane Diabetic Kidney Disaccharide Unit 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Beisswenger, P. 1973. Specificity of the chemical alteration in the diabetic glomerular basement membrane. Diabetes 22:744–750.PubMedGoogle Scholar
  2. Beisswenger, P.J. 1976. Glomerular basement membrane: Biosynthesis and chemical composition in the streptozocin diabetic rat. J. Clin. Invest. 58:844–852.PubMedCrossRefGoogle Scholar
  3. Beisswenger, P.J. and Spiro, R.G. 1970. Human glomerular basement membrane: Chemical alteration in diabetes mellitus. Science 168:596–598.PubMedCrossRefGoogle Scholar
  4. Beisswenger, P.J. and Spiro, R.G. 1973. Studies on the human glomerular basement membrane: Composition, nature of the carbohydrate units and chemical changes in diabetes. Diabetes 22:180–193.PubMedGoogle Scholar
  5. Birkeland, A.J. and Christensen, T.B. 1975. Resistance of glycoproteins to proteolysis: Ribonuclease A and B compared. J. Carb. Nucl. 2:83–90.Google Scholar
  6. Brownlee, M. 1976. Alpha-2 macroglobulin and reduced basement membrane degradation in diabetes. Lancet 1:779–780.PubMedCrossRefGoogle Scholar
  7. Brownlee, M. and Cahill, G.F. 1979. Diabetic control and vascular complication, pp. 29–70. IN R. Paoletti and A.M. Gotto (Eds.) Atherosclerosis Reviews. Vol. 4. New York: Raven PressGoogle Scholar
  8. Brownlee, M. and Spiro, R.G. 1979. Glomerular basement membrane metabolism in the diabetic rat: In vivo studies. Diabetes 28:121–125.PubMedCrossRefGoogle Scholar
  9. Butcher, D., Kikkawa, R., Klein, L., and Miller, M. 1977. Size and weight of glomeruli isolated from human diabetic and non-diabetic kidneys. J. Lab. Clin. Med. 89:544–555.PubMedGoogle Scholar
  10. Chang, A.Y. 1976. Reduction of kidney beta-galactosidase in hereditary diabetic Chinese hamsters. 9th Congr. Int. Diab. Fed. ICS 400:149. (Abstr.)Google Scholar
  11. Cohen, M.P. and Khalifa, A. 1977. Effect of diabetes and insulin on rat renal glomerular protocollagen hydroxylase activities. Biochim. Biophys. Acta 496:88–94.PubMedCrossRefGoogle Scholar
  12. Cohen, M.P. and Klein, C.V. 1976. Evidence for heterogeneous origin of glomerular basement membrane. Biochem. Biophys. Res. Commun. 77:1326–1332.CrossRefGoogle Scholar
  13. Cohen, M.P. and Klein, C.V. 1979. Glomerulopathy in rats with diabetes. Accumulation of glomerular basement membrane analogous to human diabetic nephropathy. J. Exp. Med. 149:623–631.PubMedCrossRefGoogle Scholar
  14. Cohen, M.P. and Vogt, C.A. 1972. Evidence for enhanced basement membrane synthesis and lysine hydroxylation in renal glomerulus in experimental diabetes. Biochem. Biophys. Res. Corrmun. 49:1542–1546.CrossRefGoogle Scholar
  15. Cohen, M.P. and Vogt, C.A. 1975a. Collagen synthesis and secretion by isolated rat renal glomeruli. Bioohim. Biophys. Acta 393:78–87.CrossRefGoogle Scholar
  16. Cohen, M.P. and Vogt, C.A. 1975b. The effect of diabetes on renal lysine utilization. Horm. Metab. Res. 7:338–342.PubMedCrossRefGoogle Scholar
  17. DeOlivera, M.H. 1976. Membrana basal glomerular: Estudo bioquimico da membrana basal glomerular normal e suas variacoes com a idade e com a diabetes mellitus. Doctoral thesis.Google Scholar
  18. Fox, C.J. and Darby, S.C. 1977. Blood glucose control and glomerular capillary basement membrane thickening in experimental diabetes. Brit. Med. J. 2:605–607.PubMedCrossRefGoogle Scholar
  19. Freytag, J.W., Ohno, M., and Hudson, B.G. 1976. Bovine renal glomerular basement membrane: Assessment of proteolysis during isolation. Biochem. Biophys. Res. Commun. 72:796–802.PubMedCrossRefGoogle Scholar
  20. Fushimi, H. and Tarui, S. 1976. Zteta-glycosidases and diabetic microangiopathy. I. Decreases of beta-glycosidase activities in diabetic rat kidney. J. Biochem. 79:265–270.PubMedGoogle Scholar
  21. Grant, M.E., Harwood, R., and Williams, I.F. 1975. The biosynthesis of basement membrane collagen by isolated rat glomeruli. Eur. J. Biochem. 54:531–540.PubMedCrossRefGoogle Scholar
  22. Grant, M.E., Harwood, R., and Williams, I.F. 1976. Increased synthesis of glomerular basement membrane collagen in streptozotocin diabetes. J. Physiol. 257:56–57.Google Scholar
  23. Gundersen, H.J.G. and Osterby, R. 1977. Glomerular size and structure in diabetes mellitus. II. Late abnormalities. Didbetologia 13:43–48.CrossRefGoogle Scholar
  24. Hoyer, J.R. and Spiro, R.G. 1978. Studies on the rat glomerular basement membrane: Age-related changes in composition. Arch. Biochem. Biophys. 185:496–503.PubMedCrossRefGoogle Scholar
  25. Hudson, B.G. and Spiro, R.G. 1972a. Studies on the native and reduced alkylated renal glomerular basement membrane: Solubility, subunit size, and reaction with cyanogen bromide. J. Biol. Chem. 247:4229–4238.PubMedGoogle Scholar
  26. Hudson, B.G. and Spiro, R.G. 1972b. Fractionation of glycoprotein components of the reduced alkylated renal glomerular basement membrane. J. Biol. Chem. 247:4239–4247.PubMedGoogle Scholar
  27. Kefalides, N.A. 1974. Biochemical properties of human glomerular basement membrane in normal and diabetic kidneys. J. Clin. Invest. 53:403–407.PubMedCrossRefGoogle Scholar
  28. Khalifa, A. and Cohen, M.P. 1975. Glomerular protocollagen lysyl-hydroxylase activity in streptozotocin diabetes. Biochim. Biophys. Acta 386:332–339.PubMedCrossRefGoogle Scholar
  29. Klein, L., Yoshida, M., and Miller, M. 1977. Does experimental diabetes in rats produce basement membrane thickening in renal glomeruli? Diabetes 26:361.Google Scholar
  30. Lazarow, A. and Speidel, E. 1964. The chemical composition of the glomerular basement membrane and its relationship to the production of diabetic complications, p. 127. IN M.D. Siperstein, A.R. Colwell, Sr., and K. Meyer (Eds.) Small blood vessel involvement in diabetes mellitus. Washington, DC: American Institute of Biological Sciences.Google Scholar
  31. Maragoudakis, M., Kalinsky, H.J., and Wasvary, J. 1978. Effects of L-dopa, GPA 1734 and other agents on basement membrane biosynthesis. J. Pharm. Exp. Ther. 204:377–383.Google Scholar
  32. Osterby, R. 1978. Growth hormone enhances basement membrane thickening in experimental diabetes. Diabetologia 15:487–489.PubMedCrossRefGoogle Scholar
  33. Peterson, D.T., Greene, W.C., and Reaven, G.M. 1971. Effects of experimental diabetes mellitus on kidney ribosomal protein synthesis. Diabetes 20:649–654.PubMedGoogle Scholar
  34. Price, R.G. Personal communication.Google Scholar
  35. Price, R.G. and Spiro, R.G. 1977. Studies on the metabolism of the renal glomerular basement membrane: Turnover measurements in the rat with the use of radiolabeled amino acids. J. Biol. Chem. 252:8597–8602.PubMedGoogle Scholar
  36. Rasio, E. and Bendayan, M. 1978. Le metabolisme de tissu capillaire et ses anomalies au cours du diabete. Diab. Metab. 4: 57–62.Google Scholar
  37. Reid, K.B.M. 1974. A collagen-like amino acid sequence in a polypeptide chain of human Clq (a subcomponent of the first component of complement). Biochem. J. 141:189.PubMedGoogle Scholar
  38. Risteli, J., Koivisto, V.A., Akerblom, H.K., and Kivirriko, K. (1976. Intracellular enzymes of collagen biosynthesis in rat kidney in streptozotocin diabetes. Diabetes 25:1066–1070.PubMedCrossRefGoogle Scholar
  39. Sato, T. and Spiro, R.G. 1976. Studies on the subunit composition of the renal glomerular basement membrane. J. Biol. Chem. 251:4062–4070.PubMedGoogle Scholar
  40. Seyer-Hansen, K. 1977. Renal hypertrophy in experimental diabetes: Relation to severity of diabetes. Diabetologia 13:141–143.PubMedCrossRefGoogle Scholar
  41. Spiro, R.G. 1967a. Studies on the renal glomerular basement membrane: Preparation and chemical composition. J. Biol. Chem. 242:1915–1922.PubMedGoogle Scholar
  42. Spiro, R.G. 1967b. Studies on the renal glomerular basement membrane: Nature of the carbohydrate units and their attachment to the peptide portion. J. Biol. Chem. 242:1923–1932.PubMedGoogle Scholar
  43. Spiro, R.G. 1971. Glycoproteins and diabetic microangiopathy. pp. 146–156. IN A. Marble, P. White, and R.F. Bradley (Eds.) Joslin’s diabetes mellitus. Philadelphia:Google Scholar
  44. Spiro, R.G. 1973a. Glycoproteins. Adv. Protein Chem. 27:349–467.PubMedCrossRefGoogle Scholar
  45. Spiro, R.G. 1973b. Biochemistry of the renal glomerular basement membrane and its alterations in diabetes mellitus. New Eng. J. Med. 288:1337–1342.PubMedCrossRefGoogle Scholar
  46. Spiro, R.G. 1976. Search for a biochemical basis of diabetic microangiopathy. Diabetologia 12:1–14.PubMedCrossRefGoogle Scholar
  47. Spiro, R.G. and Spiro, M.J. 1971a. Effect of diabetes on the biosynthesis of the renal glomerular basement membrane: Studies on the glycosyltransferase. Diabetes 20:641–648.PubMedGoogle Scholar
  48. Spiro, R.G. and Spiro, M.J. 1971b. Studies on the biosynthesis of the hydroxylysine -linked disaccharide unit of basement membranes and collagens. I. Kidney glucosyltransferase. J. Biol. Chem. 246:4899–4909.PubMedGoogle Scholar
  49. Spiro, R.G. and Spiro, M.J. 1971c. Studies on the biosynthesis of the hydroxylysine-linked disaccharide unit of basement membranes and collagens. II. Kidney galactosyltransferase. J. Biol. Chem. 246:4910–4918.PubMedGoogle Scholar
  50. Taylor, S.A. and Price, R.G. 1977. Characterization of subunits of rat glomerular basement membrane. Biochem. Soc. Trans. 5:236–238.PubMedGoogle Scholar
  51. Villee, D.B. and Lowers, M.L. 1977. Effect of glucose and insulin on collagen secretion by human skin fibroblasts in vitro. Nature 268:156–158.CrossRefGoogle Scholar
  52. Weil, R., Nozawa, M., Koss, M., Weber, C., Reemtsma, K., and Mcintosh, R. 1976. The kidney in streptozotocin diabetic rats. Morphologic, ultrastructural, and function studies. Arch. Pathol. Lab. Med. 100:37–49.PubMedGoogle Scholar
  53. Westberg, A.G. and Michael, A.F. 1970. Human glomerular basement membrane: Preparation and composition. Biochemistry 9:3837–3846.PubMedCrossRefGoogle Scholar
  54. Westberg, A.G. and Michael, A.F. 1973. Human glomerular basement membrane: Chemical composition in diabetes mellitus. Acta Med. Soand. 194:39–47.CrossRefGoogle Scholar
  55. Yagihashi, S., Goto, Y., Kakizaki, M., and Kaseda, N. 1978. Thickening of glomerular basement membrane in spontaneously diabetic rats. Diabetologia 15:309–313.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1979

Authors and Affiliations

  • Michael Brownlee
    • 1
  • Robert G. Spiro
    • 1
  1. 1.Elliot P. Joslin Research LaboratoryHarvard Medical SchoolBostonUSA

Personalised recommendations