Summary
A large number of experimental studies in animals and retrospective or non-randomised prospective studies in humans provide support for the concept that the microvascular complications of diabetes mellitus are dependent on hyperglycaemia. This review focuses on four potential bio-chemical pathways linking hyperglycaemia to changes within the kidney which can plausibly be linked to the functional and structural changes characterising diabetic nephropathy. These four pathways are the polyol pathway, non-enzymatic glycation, glucose autoxidation and de novo synthesis of diacylglycerol leading to protein kinase C and phospholipase A2 activation. Rather than being independent, there are several potential interactions between these four pathways which may explain confusing and overlapping effects observed in studies examining inhibitors of individual pathways. As many of the steps which follow on glucose metabolism are subject to modification by dietary and pharmacological means, the further delineation of the pathogenetic sequence leading to tissue damage in diabetes should allow a logical and effective approach to the prevention or treatment of the complications of diabetes.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Pirart J (1978) Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diab Care 1: 168–188
Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR (1985) The changing natural history of nephropathy in type 1 diabetes. Am J Med 78: 785–794
Deckert T, Poulsen JE (1981) Diabetic nephropathy: fault or destiny? Diabetologia 21: 178–183
Kern TS, Engerman RL (1990) Arrest of glomerulopathy in diabetic dogs by improved glycaemic control. Diabetologia 33: 522–525
The DCCT Research Group (1987) Diabetes control and complications trial (DCCT): results of feasibility study. Diab Care 10: 1–19
Gabbay KH, Merola LO, Field RA (1966) Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 151: 209–210
Travis SF, Morrison AD, Clements RS Jr, Winegrad AI, Oski FA (1971) Metabolic alterations in the human erythrocyte produced by increase in glucose concentration: the role of the polyol pathway. J Clin Invest 50: 2104–2112
Gabbay KH (1973) The sorbitol pathway and the complications of diabetes. N Engl J Med 288: 831–836
Beyer-Mears A, Cruz E, Edelist T, Varagiannis E (1986) Diminished proteinuria in diabetes mellitus by sorbinil, an aldose reductase inhibitor. Pharmacology 32: 52–60
McCaleb ML, Sredy J, Millen J, Ackerman DM, Dvornik D (1988) Prevention of urinary albumin excretion in 6 month streptozotocin diabetic rats with the aldose reductase inhibitor tolrestat. J Diab Comp 2: 16–18
Tilton RG, Chang K, Pugliese G et al. (1989) Prevention of hemodynamic and vascular albumin filtration changes in diabetic rats by aldose reductase inhibitors. Diabetes 37: 1258–1270
Chang WP, Dimitriadis E, Allen T, Dunlop ME, Cooper M, Larkins RG (1991) The effect of aldose reductase inhibitors on glomerular prostaglandin production and urinary albumin excretion in experimental diabetes mellitus. Diabetologia 34: 225–231
Goldfarb S, Ziyadeh FN, Kern EFO, Simmons DA (1991) Effects of polyol-pathway inhibition and dietary myo-inositol on glomerular hemodynamic function in experimental diabetes mellitus in rats. Diabetes 40: 465–471
Pedersen MM, Christiansen JS, Mogensen CE (1991) Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by 6 mo of aldose reductase inhibition. Diabetes 40: 527–531
Frank RN, Keirn RJ, Kennedy A, Frank KW (1983) Galactose-induced retinal capillary basement membrane thickening: prevention by sorbinil. Invest Ophthalmol Vis Sci 24: 1519–1524
Robison WG Jr, Kador PF, Kinoshita JH (1983) Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor. Science 221: 1177–1179
Kador PF, Akagi Y, Terubayashi H, Wyman M, Kinoshita JH (1988) Prevention of pericyte ghost formation in retinal capillaries of galactose-fed dogs by aldose reductase inhibitors. Arch Ophthalmol 106: 1099–1102
Bank N, Coco M, Aynedjian HS (1989) Galactose feeding causes glomerular hyperperfusion: prevention by aldose reductase inhibition. Am J Physiol 256: F994-F999
Das A, Frank RN, Zhang NL (1990) Sorbinil does not prevent galactose-induced glomerular capillary basement membrane thickening in the rat. Diabetologia 33: 515–521
Kinoshita JH (1974) Mechanism initiating cataract formation. Invest Ophthalmol 13: 713–724
Heaf DJ, Galton DJ (1975) Sorbitol and other polyols in lens, adipose tissues and urine in diabetes mellitus. Clin Chim Acta 63: 41–47
Willars GB, Lambourne JE, Tomlinson DR (1987) Does galactose feeding provide a valid model of consequences of exaggerated polyol-pathway flux in peripheral nerve in experimental diabetes? Diabetes 36: 1425–1431
Greene DA, Lattimer SA, Sima AAF (1987) Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 316: 599–606
Greene DA, Lattimer SA, Sima AAF (1988) Are disturbances of sorbitol, phosphoinositide, and Na+-K+-ATPase regulation involved in pathogenesis of diabetic nephropathy? Diabetes 37: 688–693
Berridge MJ (1984) Inositol trisphosphate and diacylglycerol as second messengers. Biochem J 220: 345–360
Nishizuka Y (1984) The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308: 693–697
Greene DA, Lattimer SA (1986) Protein kinase C agonists acutely normalize decreased ouabain-inhibitable respiration in diabetic rabbit nerve. Implications for (Na,K)-ATPase regulation and diabetic complications. Diabetes 35: 242–245
Craven PA, De Rubertis FR (1989) Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mediation by glucose. J Clin Invest 83: 1667–1675
Larkins RG, Dunlop ME (1991) Prostaglandins, polyols and mesangial cell function in experimental diabetes. In: Rifkin H, Colwell JA, Taylor SI (eds) Diabetes 1991. Excerpta Medica, Amsterdam, pp 180–183
Dunlop ME, Larkins RG (1990) Insulin-dependent contractility of glomerular mesangial cells in response to angiotensin II, platelet activating factor and endothelin is attenuated by prostaglandin E2. Biochem J 272: 561–568
Craven PA, De Rubertis FR (1989) Sorbinil suppresses glomerular prostaglandin production in the streptozotocin diabetic rat. Metabolism 38: 649–654
Kuehl FA Jr, Egan RW (1990) Prostaglandins, arachidonic acid, and inflammation. Science 210: 978–983
Suarez G, Rajarani R, Bhurjan KC, Oronsky L, Goidi JA (1988) Administration of aldose reductase inhibitor induces a decrease of collagen fluorescence in diabetic rats. J Clin Invest 82: 624–627
Gabbay KH, Kinoshita JH (1972) Mechanisms of development and prevention of cataracts. Isr J Med Sci 8: 1557–1561
Odetti PR, Borgoglio A, De Pascale A, Rolandi R, Adezati L (1990) Prevention of diabetes-increased aging effect on rat collagen-linked fluorescence by aminoguanidine and rutin. Diabetes 39: 796–801
Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318: 1315–1321
Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot O, Kohn RR (1986) Relation between complications of type 1 diabetes mellitus and collagen-linked fluorescence. N Engl J Med 314: 403–408
Vlassara H, Brownlee M, Cerami A (1985) High-affinity receptor-mediated uptake and degradation of glucose-modified proteins: a potential mechanism for the removal of senescent macro-molecules. Proc Natl Acad Sci USA 82: 5588–5592
Mullarkey CJ, Edelstein D, Brownlee M (1990) Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 173: 932–939
Hunt JV, Smith CCT, Wolff SP (1990) Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose. Diabetes 39: 1420–1424
Wolff SP, Dean RT (1987) Glucose autoxidation and protein modification: the potential role of autoxidative glycosylation in diabetes. Biochem J 245: 243–250
Diamond JR (1991) Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis. Kidney Int 39 [Suppl 31]: S25-S34
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320: 915–923
Moorhead JF (1991) Lipids and progressive kidney disease. Nephron 57: 453–459
Mulec H, Johnson SA, Björck S (1990) Relationship between serum cholesterol and diabetic nephropathy. Lancet 1: 1537–1538
Berne C (1975) The metabolism of lipids in mouse pancreatic islets. The biosynthesis of triacylglycerols and phospholipids. Biochem 1152: 667–673
Dunlop ME, Larkins RG (1985) Pancreatic islets synthesize phospholipids de novo from glucose via acyl-dihydroxyacetone phosphate. Biochem Biophys Res Commun 132: 467–473
Lee T-S, Saltsman KA, Ohashi H, King GL (1989) Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci USA 86: 5141–5145
Lee T-S, MacGregor LC, Fluharty SJ, King GL (1989) Differential regulation of protein kinase C and (Na,K)-adenosine tris-phosphatase activities by elevated glucose levels in retinal capillary endothelial cells. J Clin Invest 83: 90–94
Okamura K, Akijama N, Hashimoto H, Ogawa K, Satake T (1988) Alteration of 1,2-diacylglycerol content in myocardium from diabetic rats. Diabetes 37: 1168–1171
Wolf BA, Williamson JR, Eason RA, Chang K, Sherman WR, Turk J (1991) Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels. J Clin Invest 87: 31–38
Williamson JR, Ostrow E, Eades D, Chang K, Allison W, Kilo C, Sherman WR (1990) Glucose-induced vascular functional changes in nondiabetic rats: prevention by an aldose reductase inhibitor. J Clin Invest 85: 1167–1172
Craven PA, Patterson MC, De Rubertis FR (1987) Role for protein kinase C in A23187 induced glomerular arachidonate release and PGE2 production. Biochem Biophys Res Commun 149: 658–664
Craven PA, Patterson MC, De Rubertis FR (1988) Role for protein kinase C in the modulation of glomerular PGE2 production by angiotensin II. Biochem Biophys Res Commun 152: 1481–1489
Craven PA, Davidson CM, De Rubertis FR (1990) Increase in diacylglycerol mass in isolated glomeruli by glucose from de novo synthesis of glycerolipids. Diabetes 39: 667–674
Kariya K, Kawahara Y, Tsuda T, Fukuzaki H, Takai Y (1987) Possible involvement of protein kinase C in platelet-derived growth factor-stimulated DNA synthesis in vascular smooth muscle cells. Atherosclerosis 63: 251–255
Hachiya HL, Takayama S, White MF, King GL (1987) Regulation of insulin receptor internalization in vascular endothelial cells by insulin and phorbol ester. J Biol Chem 262: 6417–6424
Caramelo C, Okada K, Tsai P, Schrier RW (1989) Phorbol esters and protein kinase C in vascular smooth muscle contraction. Am J Physiol 253: H1365-H1371
Limas CJ, Limas C (1985) Phorbol ester- and diacylglycerol-mediated desensitization of cardiac β-adrenergic receptors. Circ Res 57: 443–449
Kreisberg JI, Patel PY (1983) The effects of insulin, glucose and diabetes on prostaglandin production by rat kidney glomeruli and cultured glomerular mesangial cells. Prostaglandins Leukotrienes Med 11: 431–442
Schambelan M, Blake S, Sraer J, Bens M, Nivez MP, Wahbe F (1985) Increased prostaglandin production by glomeruli isolated from rats with streptozotocin-induced diabetes mellitus. J Clin Invest 75: 404–412
Moel DI, Safirstein RL, McEvoy RC, Hsueh W (1987) Effect of aspirin on experimental diabetic nephropathy. J Lab Clin Med 110: 300–307
Sarubbi D, McGiff JC, Quilley J (1989) Renal vascular responses and eicosanoid release in diabetic rats. Am J Physiol 257: F762-F768
Craven PA, Patterson MC, De Rubertis FR (1988) Role of enhanced arachidonate availability through the phospholipase A2 pathway in the mediation of increased prostaglandin synthesis by glomeruli from diabetic rats. Diabetes 37: 429–435
Hirata F, Matsuda K, Notsu Y, Hattori T, del Carmine R (1984) Phosphorylation of a tyrosine residue of lipomodulin in mitogen-stimulated murine thymocytes. Proc Natl Acad Sci USA 81: 4717–4721
Kasiske BL, O'Donnell MP, Keane WF (1985) Glucose-induced increases in renal hemodynamic function. Possible modulation by renal prostaglandins. Diabetes 34: 360–364
Estmatjes E, Fernandez MR, Halperin I et al. (1985) Renal hemodynamic abnormalities in patients with short term insulin-dependent diabetes mellitus: role of renal prostaglandins. J Clin Endocrinol Metab 60: 1231–1236
Jensen PK, Steven K, Blaehr H, Christiansen JS, Parving H-H (1986) Effects of indomethacin on glomerular hemodynamics in experimental diabetes. Kidney Int 29: 490–495
Craven PA, Caines MA, De Rubertis FR (1987) Sequential alterations in glomerular prostaglandin and thromboxane synthesis in diabetic rats: relationship to the hyperfiltration on early diabetes. Metabolism 36: 95–103
Barnett R, Scharschmidt L, Ko Y-H, Schlondorff D (1987) Comparison of glomerular and mesangial prostaglandin synthesis and glomerular contraction in two rat models of diabetes mellitus. Diabetes 36: 1468–1475
Ledbetter S, Copeland EJ, Noonan D, Vogeli G, Hassell JR (1990) Altered steady-state mRNA levels of basement membrane proteins in diabetic mouse kidneys and thromboxane synthase inhibition. Diabetes 39: 196–203
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Larkins, R.G., Dunlop, M.E. The link between hyperglycaemia and diabetic nephropathy. Diabetologia 35, 499–504 (1992). https://doi.org/10.1007/BF00400475
Issue Date:
DOI: https://doi.org/10.1007/BF00400475