Diabetologia

, Volume 35, Issue 4, pp 389–397 | Cite as

Pathogenesis of Type 2 (non-insulin dependent) diabetes mellitus: a balanced overview

  • R. A. DeFronzo
For Debate

References

  1. 1.
    DeFronzo RA (1988) Lilly Lecture. The triumvirate: beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–687Google Scholar
  2. 2.
    DeFronzo RA, Ferrannini E (1987) Regulation of hepatic glucose metabolism in humans. Diab Metab Rev 3: 415–459Google Scholar
  3. 3.
    DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry. Diabetes 30: 1000–1007Google Scholar
  4. 4.
    DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J (1985) Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent diabetes mellitus. J Clin Invest 76: 149–155Google Scholar
  5. 5.
    Faber OK, Damsgaard EM (1984) Insulin secretion in type II diabetes. Acta Endocrinol 262 [Suppl]: 47–50Google Scholar
  6. 6.
    Faber OK, Markussen J, Naithani VK et al. (1978) Kinetics of human connecting peptide in normal and diabetic subjects. J Clin Invest 62: 197–203Google Scholar
  7. 7.
    DeFronzo RA, Ferrannini E, Simonson DC (1989) Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38: 387–395Google Scholar
  8. 8.
    Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH (1989) Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet I: 1356–1359Google Scholar
  9. 9.
    Lillioja S, Mott DM, Howard BV (1988) Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 318: 1217–1225Google Scholar
  10. 10.
    Warram JH, Martin BC, Gleason RE, Soeldner JS (1987) Slow glucose removal rate but not insulin secretion predicts development of NIDDM in offspring of two NIDDM parents. Diabetes 36 [Suppl 1]: 14A (Abstract)Google Scholar
  11. 11.
    Yudkin JS, Alberti KGMM, McClarity DG, Swai ABM (1990) Impaired glucose tolerance-Is it a risk factor for diabetes or a diagnostic ragbag? BMJ 301: 397–401Google Scholar
  12. 12.
    Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH (1988) The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 319: 1500–1505Google Scholar
  13. 13.
    Felber JP, Jallut D, Golay A, Munger R, Frascarolo P, Jequier E (1989) Obesity to diabetes. A longitudinal study of glucose metabolism in man. Diabetes 20 [Suppl 1] 221A (Abstract)Google Scholar
  14. 14.
    Hansen BC, Bodkin NH (1986) Heterogenity of insulin responses: phases leading to Type 2 (non-insulin-dependent) diabetes mellitus in the rhesus monkey. Diabetologia 29: 713–719Google Scholar
  15. 15.
    Bodkin NL, Metzger BL, Hansen BC (1989) Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys. Am J Physiol 256: E676-E681Google Scholar
  16. 16.
    Sicree RA, Zimmet P, King HO, Coventry JO (1987) Plasma insulin response among Nauruans. Prediction of deterioration in glucose tolerance over 6 years. Diabetes 36: 179–186Google Scholar
  17. 17.
    Haffner SM, Stern MP, Mitchell BD, Hazula HP, Patterson JK (1990) Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution. Diabetes 39: 283–288Google Scholar
  18. 18.
    Haffner SM, Stern MP, Hazula HP, Mitchell BD, Patterson JK (1988) Increased insulin concentrations in non-diabetic offspring of diabetic parents. N Engl J Med 319: 1297–1301Google Scholar
  19. 19.
    Balkau B, King H, Zimmet P, Raper LR (1985) Factors associated with the development of diabetes in the Micronesian population of Nauru. Am J Epidemiol 122: 594–605Google Scholar
  20. 20.
    Boyko EJ, Keane EM, Marshall JA, Hamman RF (1991) Higher insulin and C-peptide concentrations in Hispanic population at high risk for NIDDM. San Luis Valley Diabetes Study. Diabetes 40: 509–515Google Scholar
  21. 21.
    Eriksson J, Franssila-Kallunki A, Ekstrand A et al. (1989) Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 321: 337–343Google Scholar
  22. 22.
    Ho LT, Chang ZY, Wang JT et al. (1990) Insulin insensitivity in off-spring of parents with type 2 diabetes mellitus. Diab Med 7: 31–34Google Scholar
  23. 23.
    Westermark P, Wilander E (1978) The influence of amyloid deposits on the islet volume in maturity-onset diabetes mellitus. Diabetologia 15: 417–421Google Scholar
  24. 24.
    Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger R (1982) Quantitation of endocrine cell content in the pancreas of non-diabetic and diabetic humans. Diabetes 31: 694–700Google Scholar
  25. 25.
    Steiner DF, Tager HS, Chan SJ, Nanjo T, Sanke T, Rubenstein AH (1990) Lessons learned from molecular biology of insulin-gene mutations. Diab Care 13: 600–607Google Scholar
  26. 26.
    Rossetti L, Giaccari A, DeFronzo RA (1990) Glucose toxicity. Diab Care: 13: 610–630Google Scholar
  27. 27.
    Leahy JL (1990) Natural history of beta cell dysfunction in non-insulin-dependent diabetes mellitus. Diab Care 13: 992–1010Google Scholar
  28. 28.
    Reaven GM, Hollenbeck CB, Chen YDI (1989) Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 32: 52–55Google Scholar
  29. 29.
    Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA (1990) Obesity and insulin resistance in man. A dose response study. Metabolism 39: 452–459Google Scholar
  30. 30.
    Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D (1984) Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non-diabetic and non-insulin-dependent subjects. J Clin Invest 74: 1238–1246Google Scholar
  31. 31.
    Reaven GM, Miller R (1968) Study of the relationship between glucose and insulin responses to an oral glucose load in man. Diabetes 17: 560–569Google Scholar
  32. 32.
    Zimmet P, Whitehouse S, Alford F, Chisholm D (1978) The relationship of insulin response to a glucose stimulus over a wide range of glucose tolerance. Diabetologia 15: 23–27Google Scholar
  33. 33.
    Groop LC, Bonadonna RC, Del Prato S (1989) Glucose and free fatty acid metabolism in non-insulin dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84: 205–213Google Scholar
  34. 34.
    Firth R, Bell P, Rizza R (1987) Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism 36: 1091–1095Google Scholar
  35. 35.
    Campbell PJ, Mandarino LJ, Gerich JE (1988) Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus. Metabolism 37: 15–21Google Scholar
  36. 36.
    DeFronzo RA, Ferrannini E, Koivisto V (1983) New concepts in the pathogenesis and treatment of non-insulin-dependent diabetes mellitus. Am J Med 75 (1A): 52–81Google Scholar
  37. 37.
    DeFronzo RA, Deibert D, Hendler R, Felig P (1982) Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes. J Clin Invest 63: 939–946Google Scholar
  38. 38.
    DeFronzo RA, Simonson D, Ferrannini E (1982) Hepatic and peripheral insulin resistance: a common feature in non-insulin-dependent and insulin dependent diabetes. Diabetologia 23: 313–319Google Scholar
  39. 39.
    Simonson D, Ferrannini E, Bevilacqua S et al. (1984) Mechanism of improvement in glucose metabolism following chronic glyburide therapy. Diabetes 33: 838–845Google Scholar
  40. 40.
    Golay A, DeFronzo RA, Ferrannini E et al. (1988) Oxidative and non-oxidative glucose metabolism in non-obese Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 31: 585–591Google Scholar
  41. 41.
    Golay A, Felber JP, Jequier E, DeFronzo RA, Ferrannini E (1988) Metabolic basis of obesity and noninsulin-dependent diabetes mellitus. Diab Metab Rev 4: 727–747Google Scholar
  42. 42.
    Henry RR, Wallace P, Olefsky JM (1986) Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin dependent diabetes mellitus. Diabetes 35: 990–998Google Scholar
  43. 43.
    Best JD, Judzewitsch RG, Pfeiffer MA, Beard JC, Halter JB, Porte D (1982) The effect of chronic sulfonyl urea therapy on hepatic glucose production in non-insulin-dependent diabetes mellitus. Diabetes 31: 333–338Google Scholar
  44. 44.
    Firth RG, Bell PM, Marsh HM, Hansen I, Rizza RA (1986) Postprandial hyperglycemia in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 77: 1525–1532Google Scholar
  45. 45.
    Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG (1985) The effect of insulin treatment on insulin action in type II diabetes mellitus. Diabetes 34: 222–234Google Scholar
  46. 46.
    DeFronzo RA, Ferrannini E, Hendler R, Feiig P, Wahren J (1983) Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia. Diabetes 32: 35–45Google Scholar
  47. 47.
    Butterfield WJH, Whichelow MJ (1965) Peripheral glucose metabolism in control subjects and diabetic patients during glucose, glucose-insulin, and insulin sensitivity tests. Diabetologia 1: 43–53Google Scholar
  48. 48.
    Revers R, Fink R, Griffin J, Olefsky J, Kolterman O (1984) Influence of hyperglycemia in insulin's in vivo effects in type II diabetes. J Clin Invest 73: 664–672Google Scholar
  49. 49.
    Kalant N, Leibovici D, Fukushima J, Ozaki S (1982) Insulin responsiveness of superficial forearm tissues in Type 2 (non-insulin-dependent) diabetes. Diabetologia 22: 239–244Google Scholar
  50. 50.
    Campbell P, Mandarino L, Gerich J (1988) Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose intake in non-insulin-dependent diabetes mellitus. Metabolism 37: 15–22Google Scholar
  51. 51.
    Jackson RA, Perry G, Rogers J, Advoni U, Pilkington TRE (1973) Relationship between the basal glucose concentration, glucose tolerance, and forearm glucose uptake in maturity onset diabetes. Diabetes 22: 751–761Google Scholar
  52. 52.
    Mitrakou A, Kelley D, Veneman T et al. (1990) Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39: 1381–1390Google Scholar
  53. 53.
    Butterfield WJH, Whichelow MJ (1965) Peripheral glucose metabolism in control subjects and diabetic patients during glucose, glucose-insulin and insulin sensitivity tests. Diabetologia 1: 43–53Google Scholar
  54. 54.
    Zierler KL, Rabinowitz D (1963) Roles of insulin and growth hormone, based on studies of forearm metabolism in man. Medicine 42: 385–402Google Scholar
  55. 55.
    Capaldo B, Napoli R, Dimarino L, Picardi A, Riccardi G, Sacca L (1988) Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type 2 diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance. J Clin Endocrinol Metab 67: 893–898Google Scholar
  56. 56.
    Marin P, Rebuffe-Scrive, Smith U, Bjorntorp P (1987) Glucose uptake in human adipose tissue. Metabolism 36: 1154–1160Google Scholar
  57. 57.
    Ferrannini E, Reichard GA, Bjorkman O et al. (1985) The disposal of an oral glucose load in normal subjects. A quantitative study. Diabetes 34: 580–588Google Scholar
  58. 58.
    Grill V (1990) A comparison of brain glucose metabolism in diabetes as measured by positron emission tomography or by arteriovenous techniques. Ann Med 22: 171–175Google Scholar
  59. 59.
    Kelley D, Mitrakou A, Marsh H et al.: Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. J Clin Invest 81: 1563–1571Google Scholar
  60. 60.
    Jackson RA, Roshania RD, Hawa MI, Sim BM, DiSilvio L (1986) Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab 63: 541–549Google Scholar
  61. 61.
    Katz LD, Glickman MG, Rapoport S, Ferrannini E, DeFronzo RA (1983) Splanchnic and peripheral disposal of oral glucose in man. Diabetes 32: 675–679Google Scholar
  62. 62.
    Ferrannini E, Simonson DC, Katz LD et al. (1988) The disposal of an oral glucose load in patients with non-insulin dependent diabetes. Metabolism 37: 79–55Google Scholar
  63. 63.
    McMahon V, Marsh HM, Rizza RA (1989) Effects of basal insulin supplementation on disposition of mixed meal in obese patients with NIDDM. Diabetes 38: 291–303Google Scholar
  64. 64.
    Firth RG, Bell PM, Rizza RA (1986) Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 314: 1280–1286Google Scholar
  65. 65.
    Gerich JE (1991) Is muscle the major site of insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus? Diabetologia 34: 607–610Google Scholar
  66. 66.
    Chen Y-DI, Jeng CY, Hollenbeck CB, Wu MS, Reaven GM (1988) Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes. J Clin Invest 82: 21–25Google Scholar
  67. 67.
    Gulli G, Haffner S, Ferrannini E, DeFronzo RA (1990) What is inherited in NIDDM? Diabetes 39 [Suppl 1]: 116A (Abstract)Google Scholar
  68. 68.
    Gerich JE, Mitrakou A, Kelly D et al. (1990) Contribution of impaired muscle glucose clearance to reduced postabsorptive systemic glucose clearance in NIDDM. Diabetes 39: 211–215Google Scholar
  69. 69.
    Zierler KL, Rabinowitz D (1964) Effect of very small concentrations of insulin on forearm metabolism. Persistence of its action on potassium and free fatty acids without its side effect on glucose. J Clin Invest 43: 950–962Google Scholar
  70. 70.
    Natali A, Santoro D, Palombo C, Cerri M, Ghione S, Ferrannini E (1991) Impaired insulin action on skeletal muscle metabolism in essential hypertension. Hypertension 17: 170–178Google Scholar
  71. 71.
    Marshall S, Olefsky J (1980) Effect of insulin incubation on insulin binding, glucose transport, and insulin degradation by isolated adipocytes. Evidence of hormone-induced desensitization at the receptor and post-receptor level. J Clin Invest 66: 763–772Google Scholar
  72. 72.
    Amatruda JM, Newmeyer HW, Chang CL (1982) Insulin-induced alterations in insulin binding and insulin action in primary cultures of rat hepatocytes. Diabetes 31: 145–148Google Scholar
  73. 73.
    Felber JP, Ferrannini E, Golay A (1987) Role of lipid oxidation in the pathogenesis of the insulin resistance of obesity and type II diabetes. Diabetes 36: 1341–1350Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • R. A. DeFronzo
    • 1
  1. 1.Division of DiabetesThe University of Texas Health Science Center and Audie L. Murphy Veterans Administration HospitalSan AntonioUSA

Personalised recommendations