Diabetes Mellitus: Pathogenesis and Natural History

  • Jay S. Skyler


Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia arising as a consequence of a relative or absolute deficiency of insulin secretion, resistance to insulin action, or both.1,2 Although diabetes mellitus is recognized by its characteristic hyperglycemia, the metabolic derangements are more pervasive, involving altered metabolism of carbohydrates, fats, and proteins. As a function of time and consequent to the metabolic disruption, diabetic patients may suffer the tragic ravages of long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.


Glycemic Control Diabetic Nephropathy Diabetic Retinopathy Autonomic Neuropathy Diabetic Macular Edema 


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  1. 1.
    American Diabetes Association. Report of The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Di-abetes Care 1997; 20: 1183.Google Scholar
  2. 2.
    Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Med 1998; 15: 539–553.PubMedCrossRefGoogle Scholar
  3. 3.
    Rabinovitch A, Skyler JS. Prevention of type I diabetes. Med Clin North Am 1998; 82: 739–755.PubMedCrossRefGoogle Scholar
  4. 4.
    Atkinson MA, Eisenbarth GS. Type I diabetes: New perspectives on disease pathogenesis and treatment. Lancet 2001; 358: 221–229.PubMedCrossRefGoogle Scholar
  5. 5.
    Wucherpfennig KW, Eisenbarth GS. Type I diabetes. Nature Immunol 2001; 2: 767–768.CrossRefGoogle Scholar
  6. 6.
    Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Co-hen M, Lang DA. Latent autoimmune diabetes mellitus in adults (LADA): The role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabetic Med 1994; 11: 299–303.PubMedCrossRefGoogle Scholar
  7. 7.
    Gepts W. Pathological anatomy of the pancreas in juvenile dia- betes mellitus. Diabetes 1965; 14: 619–633.PubMedGoogle Scholar
  8. 8.
    Pugliese A. Unraveling the genetics of insulin-dependent type IA diabetes: The search must go on. Diabetes Rev 1999; 7: 39–54.Google Scholar
  9. 9.
    Dahlquist GG. Viruses and other perinatal exposures as initiating events for beta-cell destruction. Ann Med 1997; 29: 413–417.PubMedCrossRefGoogle Scholar
  10. 10.
    Gerstein HC. Cow’s milk exposure and type I diabetes mellitus. A critical overview of the clinical literature. Diabetes Care 1994; 17: 13–19.CrossRefGoogle Scholar
  11. 11.
    Rabinovitch A. An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Diabetes Metab Rev 1998; 14: 129–151.PubMedCrossRefGoogle Scholar
  12. 12.
    Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414: 782–787.PubMedCrossRefGoogle Scholar
  13. 13.
    DeFronzo RA, Bonadonna RC, Ferrannini E Pathogenesis of NIDDM: A balanced overview. Diabetes Care 1992; 15: 318–368.CrossRefGoogle Scholar
  14. 14.
    Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states: Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994; 94: 1714.PubMedCrossRefGoogle Scholar
  15. 15.
    Gerich JE. The genetic basis of type II diabetes mellitus: Impaired insulin secretion versus impaired insulin sensitivity. En-docrine Rev 1998; 19: 491.CrossRefGoogle Scholar
  16. 16.
    Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epi-demic of type II diabetes in youth. Diabetes Care 1999; 22: 345.PubMedCrossRefGoogle Scholar
  17. 17.
    American Diabetes Association. Type 2 diabetes in children and adolescents (consensus statement). Diabetes Care 2000; 23: 381–389.Google Scholar
  18. 18.
    Yki-Jarvinen H. Glucose toxicity. Endocrine Rev 1992; 13: 415.Google Scholar
  19. 19.
    Kahn CR. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 1994; 43: 1066.PubMedCrossRefGoogle Scholar
  20. 20.
    Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799–806.PubMedCrossRefGoogle Scholar
  21. 21.
    Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607.PubMedCrossRefGoogle Scholar
  22. 22.
    DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–194.PubMedCrossRefGoogle Scholar
  23. 23.
    Porte D. Mechanisms for hyperglycemia in the metabolic syndrome. The key role of beta-cell dysfunction. Ann NY Acad Sci 1999; 892: 73–83.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoppener JW, Ahren B, Lips CJ. Islet amyloid and type II diabetes mellitus. N Engl J Med 2000; 343: 411–419.PubMedCrossRefGoogle Scholar
  25. 25.
    Permutt MA, Chiu K, Ferrer J, Glaser B, Inoue H, Nestorowicz A, Stanley CA, Tanizawa Y. Genetics of type II diabetes. Rec Prog Hormone Res 1998; 53: 201.Google Scholar
  26. 26.
    Busch CP, Hegele RA. Genetic determinants of type II diabetes mellitus. Clin Genet 2001; 60: 243–254.PubMedCrossRefGoogle Scholar
  27. 27.
    Bell GI, Polonsky KS. Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 2001; 414: 788–791.PubMedCrossRefGoogle Scholar
  28. 28.
    Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Endocrinol Metab Clin North Am 2000; 29: 683–705.PubMedCrossRefGoogle Scholar
  29. 29.
    Cryer PE. Hypoglycemia is the limiting factor in the management of diabetes. Diabetes Metab Res Rev 1999; 15: 42–46.PubMedCrossRefGoogle Scholar
  30. 30.
    Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997; 46: 271–286.Google Scholar
  31. 31.
    Skyler JS, Oddo C. Diabetes trends in the United States of America. Diabetes Metab Res Rev 2002 (in press).Google Scholar
  32. 32.
  33. 33.
    Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: A review. Diabetologia 2001; 44: 129–146.PubMedCrossRefGoogle Scholar
  34. 34.
    Chellan P, Nagaraj RH. Protein crosslinking by the Maillard reaction: Dicarbonyl-derived imidazolium crosslinks in aging and diabetes. Arch Biochem Biophys 1999; 368: 98–104.PubMedCrossRefGoogle Scholar
  35. 35.
    Ways DK, Sheetz MJ. The role of protein kinase C in the development of the complications of diabetes. Vitamins Hormones 2000; 60: 149–193.PubMedCrossRefGoogle Scholar
  36. 36.
    Carrington AL, Litchfield JE. The aldose reductase pathway and nonenzymatic glycation in the pathogenesis of diabetic neuropathy: A critical review for the end of the 20th century. Diabetes Rev 1999; 7: 275–299.Google Scholar
  37. 37.
    Woodrow D, Moss J, Shore I, Spiro RG. Diabetic glomerulosclerosis-immunogold ultrastructural studies on the glomerular distribution of type IV collagen and heparan sulphate proteoglycan. J Pathol 1992; 167: 49–58.PubMedCrossRefGoogle Scholar
  38. 38.
    Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type II diabetes. Diabetes Care 2001; 24: 1476–1485.PubMedCrossRefGoogle Scholar
  39. 39.
    O’Bryan GT, Hostetter TH. The renal hemodynamic basis of diabetic nephropathy. Sem Nephrol 1997; 17: 93–100.Google Scholar
  40. 40.
    Hostetter TH. Hypertrophy and hyperfunction of the diabetic kidney. J Clin Invest 2001; 107: 161–162.PubMedCrossRefGoogle Scholar
  41. 41.
    Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 683–689.Google Scholar
  42. 42.
    Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993; 329: 304–309.PubMedCrossRefGoogle Scholar
  43. 43.
    Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbAlc) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995; 44: 968–993.Google Scholar
  44. 44.
    Skyler JS. Diabetic complications: Glucose control is important. Endocrinol Metab Clin North Am 1996; 25: 243–254.PubMedCrossRefGoogle Scholar
  45. 45.
    UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type II diabetes (UKPDS 33). Lancet 1998; 352: 837–853.Google Scholar
  46. 46.
    UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type II diabetes (UKPDS 34). Lancet 1998; 352: 854–865.Google Scholar
  47. 47.
    Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoski S, Kojima Y, Furuyoshi N, Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res Clin Pract1995; 28: 103–117.Google Scholar
  48. 48.
    Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type II diabetes (UKPDS 35): Prospective observational study. Br Med J 2000; 321: 405–412.Google Scholar
  49. 49.
    Davis MD. Diabetic retinopathy. Diabetes Care 1992; 15: 1844.PubMedCrossRefGoogle Scholar
  50. 50.
    Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL, Klein R. Technical review-diabetic retinopathy. Diabetes Care 1998; 21: 143–156.PubMedGoogle Scholar
  51. 51.
    Neely KA, Quillen DA, Schachat AP, Gardner TW, Blankenship GW. Diabetic retinopathy. Med Clin North Am 1998; 82: 847–876.PubMedCrossRefGoogle Scholar
  52. 52.
    Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976; 81: 383–396.Google Scholar
  53. 53.
    Diabetic Retinopathy Study Research Group. Photocoagulation treatment of diabetic retinopathy: Clinical application of Diabetic Retinopathy Study (DRS) findings. DRS report number 8. Ophthalmology 1981; 88: 583–600.Google Scholar
  54. 54.
    Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. ETDRS report number 1. Arch Ophthalmol 1985; 103: 1796–1806.Google Scholar
  55. 55.
    Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy: Four-year results of a randomized trial (report 5). Arch Ophthalmol 1990; 108: 958–964.Google Scholar
  56. 56.
    Marks JB, Raskin P Nephropathy and hypertension in diabetes. Med Clin North Am 1998; 82: 877–907.PubMedCrossRefGoogle Scholar
  57. 57.
    U.S. Renal Data System. USRDS 2001 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2001.Google Scholar
  58. 58.
    Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in type I (insulin-dependent) diabetes mellitus. Diabetologia 1985; 28: 590–596.PubMedCrossRefGoogle Scholar
  59. 59.
    Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: Origin and development of ideas. Diabetologia 1999; 42: 263–285.CrossRefGoogle Scholar
  60. 60.
    Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes MW. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 1989; 321: 80–85.PubMedCrossRefGoogle Scholar
  61. 61.
    Microalbuminuria Captopril Study Group. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabetologia 1996; 39: 587–593.Google Scholar
  62. 62.
    Ravid M, Lang R, Rachmani R, et al. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 1996; 156: 286–289.PubMedCrossRefGoogle Scholar
  63. 63.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (for the Collaborative Study Group). The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–1462.PubMedCrossRefGoogle Scholar
  64. 64.
    Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type II diabetes. N Engl J Med 2001; 345: 870–878.PubMedCrossRefGoogle Scholar
  65. 65.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type II diabetes. N Engl J Med 2001; 345: 851–860.PubMedCrossRefGoogle Scholar
  66. 66.
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type II diabetes and nephropathy. N Engl J Med 2001; 345: 861–869.PubMedCrossRefGoogle Scholar
  67. 67.
    Pedrini MT, Levey AS, Lau J, et al. Dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: A meta-analysis. Ann Intern Med 1996; 124: 627–632.PubMedGoogle Scholar
  68. 68.
    Boulton AJ, Malik RA. Diabetic neuropathy. Med Clin North Am 1998; 82: 909–929.PubMedCrossRefGoogle Scholar
  69. 69.
    Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia 2000; 43: 957–973.PubMedCrossRefGoogle Scholar
  70. 70.
    Low PA. Diabetic autonomic neuropathy. Sem Neurol 1996; 16: 143–151.CrossRefGoogle Scholar
  71. 71.
    Ziegler D. Diabetic cardiovascular autonomic neuropathy: Prognosis, diagnosis and treatment. Diabetes Metab Rev 1994; 10: 339–383.PubMedCrossRefGoogle Scholar
  72. 72.
    Vinik A, Erbas T, Stansberry K. Gastrointestinal, genitourinary, and neurovascular disturbances in diabetes. Diabetes Rev 1999; 7: 358–378.Google Scholar
  73. 73.
    Kaplan SA, Blaivas JG. Diabetic cystopathy. J Diabetes Complicat 1988; 2: 133–139.CrossRefGoogle Scholar
  74. 74.
    Vinik AI, Richardson D. Erectile dysfunction in diabetes. Diabetes Rev 1998; 6: 16–33.Google Scholar
  75. 75.
    Jovanovic L. Sex and the diabetic woman: Desire versus dysfunction. Diabetes Rev 1998; 6: 65–72.Google Scholar
  76. 76.
    Marks JB, Raskin P. Cardiovascular risk in diabetes: A brief review. J Diabetes Complicat 2000; 14: 108–115.PubMedCrossRefGoogle Scholar
  77. 77.
    Garber AJ. Vascular disease and lipids in diabetes. Med Clin North Am 1998; 82: 931–948.PubMedCrossRefGoogle Scholar
  78. 78.
    Wilson PF. Diabetes mellitus and coronary heart disease. Endocrinol Metab Clin North Am 2001; 30: 857–881.PubMedCrossRefGoogle Scholar
  79. 79.
    Donahue RP, Skyler JS, Schneiderman N, Prineas RI. Hyperin-sulinemia and elevated blood pressure: Cause, confounder, or coincidence? Am J Epidemiol 1990; 132: 827–836.PubMedGoogle Scholar
  80. 80.
    Skyler JS, Marks JB, Schneiderman N. Hypertension in patients with diabetes. Am J Hypertens 1995; 8: 100S - 105S.PubMedCrossRefGoogle Scholar
  81. 81.
    American Diabetes Association. Clinical practice recommendations 2003. Diabetes Care 2003; 26 (suppl 1): S1 — S156.Google Scholar
  82. 82.
    American Diabetes Association. Position statement. Treatment of hypertension in adults with diabetes. Diabetes Care 2003; 26 (suppl 1): S80 - S82.Google Scholar
  83. 83.
    Arauz-Pacheco C, Parrott MA, Raskin P. The treatment of hypertension in adult patients with diabetes (technical review). Diabetes Care 2002; 25: 134–147.PubMedCrossRefGoogle Scholar
  84. 84.
    American Diabetes Association. Position statement. Management of dyslipidemia in adults with diabetes. Diabetes Care 2003; 26 (suppl 1): S83 - S86.Google Scholar
  85. 85.
    Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497.Google Scholar
  86. 86.
    American Diabetes Association. Consensus statement. Diagnosis of coronary heart disease in people with diabetes. Diabetes Care 1998; 21: 1551–1559.Google Scholar
  87. 87.
    American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care 2003; 26 (suppl 1): S87 - S88.Google Scholar

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© Springer Science+Business Media New York 2004

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  • Jay S. Skyler

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