Diabetes in a Textbook

  • Milind Watve


Before we start thinking about the evolutionary origins of diabetes and related disorders, I need to briefly sketch what is currently known and well accepted about diabetes. This chapter tries to compile a textbook picture of diabetes [1–3] only to serve as a background. Readers who have studied physiology or medicine may skip this chapter straightaway since it does not contain any new argument. It may be necessary and useful for readers who need a fair amount of background information about diabetes before appreciating the paradoxes and puzzles associated with it.


Insulin Resistance Insulin Secretion Glucose Production Aldose Reductase Chronic Hyperglycemia 
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.
    Kronenberg H, Williams RH (2008) Williams textbook of endocrinology. Saunders/Elsevier, Philadelphia, PAGoogle Scholar
  2. 2.
    Pickup JC, Williams G (2003) Textbook of diabetes. Blackwell Science, OxfordGoogle Scholar
  3. 3.
    Guyton AC, Hall JE (2006) Textbook of medical physiology. Saunders, Philadelphia, PAGoogle Scholar
  4. 4.
    Leçons de physiologie opératoire: Bernard, Claude, 1813–1878: Free Download & Streaming: Internet Archive.
  5. 5.
    Monzillo LU, Hamdy O (2003) Evaluation of insulin sensitivity in clinical practice and in research settings. Nutr Rev 61:397–412PubMedCrossRefGoogle Scholar
  6. 6.
    Zimmet P, Alberti KGMM, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787PubMedCrossRefGoogle Scholar
  7. 7.
    Goran MI, Ball GDC, Cruz ML (2003) Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. J Clin Endocrinol Metab 88:1417–1427PubMedCrossRefGoogle Scholar
  8. 8.
    Diamond J (2003) The double puzzle of diabetes. Nature 423:599–602PubMedCrossRefGoogle Scholar
  9. 9.
    Cowie CC et al (2006) Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population. Diabetes Care 29:1263–1268PubMedCrossRefGoogle Scholar
  10. 10.
    Mokdad AH et al (2001) The continuing epidemics of obesity and diabetes in the United States. J Am Med Assoc 286:1195–1200CrossRefGoogle Scholar
  11. 11.
    Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS (1997) Comparison of diabetes diagnostic categories in the U.S. population according to 1997 American Diabetes Association and 1980–1985 World Health Organization diagnostic criteria. Diabetes Care 20:1859–1862PubMedCrossRefGoogle Scholar
  12. 12.
    Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR (1990) Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113:909–915PubMedGoogle Scholar
  13. 13.
    Haffner SM et al (1990) Diminished insulin sensitivity and increased insulin response in nonobese, nondiabetic Mexican Americans. Metab Clin Exp 39:842–847PubMedCrossRefGoogle Scholar
  14. 14.
    Groop L (2000) Genetics of the metabolic syndrome. Br J Nutr 83(Suppl 1):S39–S48PubMedGoogle Scholar
  15. 15.
    Lehtovirta M et al (2000) Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins. Diabetologia 43:285–293PubMedCrossRefGoogle Scholar
  16. 16.
    Mayer EJ et al (1996) Genetic and environmental influences on insulin levels and the insulin resistance syndrome: an analysis of women twins. Am J Epidemiol 143:323–332PubMedCrossRefGoogle Scholar
  17. 17.
    Hong Y, Pedersen NL, Brismar K, de Faire U (1997) Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am J Hum Genet 60:143–152PubMedGoogle Scholar
  18. 18.
    Fujioka S, Matsuzawa Y, Tokunaga K, Tarui S (1987) Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metab Clin Exp 36:54–59PubMedCrossRefGoogle Scholar
  19. 19.
    Brambilla P et al (1994) Peripheral and abdominal adiposity in childhood obesity. Int J Obes Relat Metab Disord 18:795–800PubMedGoogle Scholar
  20. 20.
    Berman DM et al (2001) Racial disparities in metabolism, central obesity, and sex hormone-binding globulin in postmenopausal women. J Clin Endocrinol Metab 86:97–103PubMedCrossRefGoogle Scholar
  21. 21.
    Hu FB et al (2001) Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med 345:790–797PubMedCrossRefGoogle Scholar
  22. 22.
    Tuomilehto J et al (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350PubMedCrossRefGoogle Scholar
  23. 23.
    Must A et al (1999) The disease burden associated with overweight and obesity. J Am Med Assoc 282:1523–1529CrossRefGoogle Scholar
  24. 24.
    Després JP, Tremblay A, Pérusse L, Leblanc C, Bouchard C (1988) Abdominal adipose tissue and serum HDL-cholesterol: association independent from obesity and serum triglyceride concentration. Int J Obes 12:1–13PubMedGoogle Scholar
  25. 25.
    Larsson B et al (1984) Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br Med J (Clin Res Ed) 288:1401–1404CrossRefGoogle Scholar
  26. 26.
    Landin K, Krotkiewski M, Smith U (1989) Importance of obesity for the metabolic abnormalities associated with an abdominal fat distribution. Metab Clin Exp 38:572–576PubMedCrossRefGoogle Scholar
  27. 27.
    Bronnegard M, Arner P, Hellstorm L, Akner G, Gustafsson J-Å (1990) Glucocorticoid receptor messenger ribonucleic acid in different regions of human adipose tissue. Endocrinology 127:1689–1696PubMedCrossRefGoogle Scholar
  28. 28.
    Nicklas BJ, Rogus EM, Colman EG, Goldberg AP (1996) Visceral adiposity, increased adipocyte lipolysis, and metabolic dysfunction in obese postmenopausal women. Am J Physiol 270:E72–E78PubMedGoogle Scholar
  29. 29.
    Mittelman SD et al (2000) Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced β-cell response. Diabetes 49:2116–2125PubMedCrossRefGoogle Scholar
  30. 30.
    Paolisso G et al (1995) A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 38:1213–1217PubMedCrossRefGoogle Scholar
  31. 31.
    Charles MA et al (1997) The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study. Diabetologia 40:1101–1106PubMedCrossRefGoogle Scholar
  32. 32.
    Pan DA et al (1997) Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46:983–988PubMedCrossRefGoogle Scholar
  33. 33.
    Carlson LA, Ekelund LG, Fröberg SO (1971) Concentration of triglycerides, phospholipids and glycogen in skeletal muscle and of free fatty acids and β-hydroxybutyric acid in blood in man in response to exercise. Eur J Clin Invest 1:248–254PubMedGoogle Scholar
  34. 34.
    Laws A, Reaven GM (1990) Effect of physical activity on age-related glucose intolerance. Clin Geriatr Med 6:849–863PubMedGoogle Scholar
  35. 35.
    Gollnick PD, Saltin B (1982) Significance of skeletal muscle oxidative enzyme enhancement with endurance training. Clin Physiol 2:1–12PubMedCrossRefGoogle Scholar
  36. 36.
    Turcotte LP, Richter EA, Kiens B (1992) Increased plasma FFA uptake and oxidation during prolonged exercise in trained vs. untrained humans. Am J Physiol 262:E791–E799PubMedGoogle Scholar
  37. 37.
    Romijn JA, Klein S, Coyle EF, Sidossis LS, Wolfe RR (1993) Strenuous endurance training increases lipolysis and triglyceride-fatty acid cycling at rest. J Appl Physiol 75:108–113PubMedGoogle Scholar
  38. 38.
    Kelley DE, Simoneau JA (1994) Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest 94:2349–2356PubMedCrossRefGoogle Scholar
  39. 39.
    Kelley DE, Mandarino LJ (1990) Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest 86:1999–2007PubMedCrossRefGoogle Scholar
  40. 40.
    Ruderman NB, Saha AK, Vavvas D, Witters LA (1999) Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 276:E1–E18PubMedGoogle Scholar
  41. 41.
    Dean D et al (2000) Exercise diminishes the activity of acetyl-CoA carboxylase in human muscle. Diabetes 49:1295–1300PubMedCrossRefGoogle Scholar
  42. 42.
    Hancock CR et al (2008) High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA 105:7815–7820PubMedCrossRefGoogle Scholar
  43. 43.
    Knauf C et al (2008) Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure. Endocrinology 149:4768–4777PubMedCrossRefGoogle Scholar
  44. 44.
    Knauf C et al (2005) Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest 115:3554–3563PubMedCrossRefGoogle Scholar
  45. 45.
    Perrin C, Knauf C, Burcelin R (2004) Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, controls muscle glycogen synthesis. Endocrinology 145:4025–4033PubMedCrossRefGoogle Scholar
  46. 46.
    Darleen S (2008) CNS GLP-1 regulation of peripheral glucose homeostasis. Physiol Behav 94:670–674CrossRefGoogle Scholar
  47. 47.
    Båvenholm PN, Pigon J, Östenson C-G, Efendic S (2001) Insulin sensitivity of suppression of endogenous glucose production is the single most important determinant of glucose tolerance. Diabetes 50:1449–1454PubMedCrossRefGoogle Scholar
  48. 48.
    Mitrakou A et al (1992) Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22–29PubMedCrossRefGoogle Scholar
  49. 49.
    Rebrin K, Steil GM, Mittelman SD, Bergman RN (1996) Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J Clin Invest 98:741–749PubMedCrossRefGoogle Scholar
  50. 50.
    Mittelman SD, Fu YY, Rebrin K, Steil G, Bergman RN (1997) Indirect effect of insulin to suppress endogenous glucose production is dominant, even with hyperglucagonemia. J Clin Invest 100: 3121–3130PubMedCrossRefGoogle Scholar
  51. 51.
    McCall RH, Wiesenthal SR, Shi ZQ, Polonsky K, Giacca A (1998) Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs. Am J Physiol 274:E346–E356PubMedGoogle Scholar
  52. 52.
    Hother-Nielsen O, Beck-Nielsen H (1991) Insulin resistance, but normal basal rates of glucose production in patients with newly diagnosed mild diabetes mellitus. Acta Endocrinol 124:637–645PubMedGoogle Scholar
  53. 53.
    Groop LC, Bonadonna RC, Shank M, Petrides AS, DeFronzo RA (1991) Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. J Clin Invest 87:83–89PubMedCrossRefGoogle Scholar
  54. 54.
    Hother-Nielsen O, Beck-Nielsen H (1990) On the determination of basal glucose production rate in patients with type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3 H-glucose infusion. Diabetologia 33:603–610PubMedCrossRefGoogle Scholar
  55. 55.
    Pick A et al (1998) Role of apoptosis in failure of β-cell mass compensation for insulin resistance and β-cell defects in the male Zucker diabetic fatty rat. Diabetes 47:358–364PubMedCrossRefGoogle Scholar
  56. 56.
    Cockburn BN et al (1997) Changes in pancreatic islet glucokinase and hexokinase activities with increasing age, obesity, and the onset of diabetes. Diabetes 46:1434–1439PubMedCrossRefGoogle Scholar
  57. 57.
    Kahn SE et al (1993) Quantification of the relationship between insulin sensitivity and β-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42:1663–1672PubMedCrossRefGoogle Scholar
  58. 58.
    Toffolo G, Bergman RN, Finegood DT, Bowden CR, Cobelli C (1980) Quantitative estimation of β cell sensitivity to glucose in the intact organism: a minimal model of insulin kinetics in the dog. Diabetes 29:979–990PubMedCrossRefGoogle Scholar
  59. 59.
    Weir GC, Bonner-Weir S (2004) Five stages of evolving Β-cell dysfunction during progression to diabetes. Diabetes 53:S16–S21PubMedCrossRefGoogle Scholar
  60. 60.
    Sako Y, Grill VE (1990) Coupling of β-cell desensitization by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats. Diabetes 39:1580–1583PubMedCrossRefGoogle Scholar
  61. 61.
    Leahy JL, Bumbalo LM, Chen C (1994) Diazoxide causes recovery of β-cell glucose responsiveness in 90% pancreatectomized diabetic rats. Diabetes 43:173–179PubMedCrossRefGoogle Scholar
  62. 62.
    Poitout V, Robertson RP (2002) Minireview: secondary β-cell failure in type 2 diabetes – a convergence of glucotoxicity and lipotoxicity. Endocrinology 143:339–342PubMedCrossRefGoogle Scholar
  63. 63.
    Robertson RP, Harmon JS, Tanaka Y, Trang PO, Poitout V (2004) Glucose toxicity of the β-cell cellular and molecular mechanisms. In: LeRoith D, Taylor SI, Olefsky J (eds) Diabetes mellitus: a fundamental and clinical text. Lippincott Williams and Wilkins, Philadelphia, PAGoogle Scholar
  64. 64.
    Gleason CE, Gonzalez M, Harmon JS, Robertson RP (2000) Determinants of glucose toxicity and its reversibility in the pancreatic islet β-cell line, HIT-T15. Am J Physiol Endocrinol Metab 279:E997–E1002PubMedGoogle Scholar
  65. 65.
    Moran A et al (1997) Differentiation of glucose toxicity from β cell exhaustion during the evolution of defective insulin gene expression in the pancreatic islet cell line, HIT-T15. J Clin Invest 99:534–539PubMedCrossRefGoogle Scholar
  66. 66.
    Donath MY, Gross DJ, Cerasi E, Kaiser N (1999) Hyperglycemia-induced β-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 48:738–744PubMedCrossRefGoogle Scholar
  67. 67.
    McGarry JD, Dobbins RL (1999) Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42:128–138PubMedCrossRefGoogle Scholar
  68. 68.
    Shimabukuro M et al (1998) Lipoapoptosis in β-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 273:32487–32490PubMedCrossRefGoogle Scholar
  69. 69.
    Robertson RP (2004) Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet Β cells in diabetes. J Biol Chem 279: 42351–42354PubMedCrossRefGoogle Scholar
  70. 70.
    Modak MA, Parab PB, Ghaskadbi SS (2009) Pancreatic islets are very poor in rectifying oxidative DNA damage. Pancreas 38:23–29PubMedCrossRefGoogle Scholar
  71. 71.
    Verchere CB et al (1996) Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic Β cell expression of human islet amyloid polypeptide. Proc Natl Acad Sci USA 93:3492–3496PubMedCrossRefGoogle Scholar
  72. 72.
    Höppener JW et al (1999) Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model. Diabetologia 42:427–434PubMedCrossRefGoogle Scholar
  73. 73.
    Soeller WC et al (1998) Islet amyloid-associated diabetes in obese Avy/A mice expressing human islet amyloid polypeptide. Diabetes 47:743–750PubMedCrossRefGoogle Scholar
  74. 74.
    Røder ME, Porte D Jr, Schwartz RS, Kahn SE (1998) Disproportionately elevated proinsulin levels reflect the degree of impaired Β cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 83:604–608PubMedCrossRefGoogle Scholar
  75. 75.
    Porte D Jr, Kahn SE (1989) Hyperproinsulinemia and amyloid in NIDDM. Clues to etiology of islet β-cell dysfunction? Diabetes 38:1333–1336PubMedCrossRefGoogle Scholar
  76. 76.
    Hoehn KL et al (2009) Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci USA 106:17787–17792PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Milind Watve
    • 1
  1. 1.Indian Institute of Science Education and Research Pune (IISER-P)PuneIndia

Personalised recommendations