, Volume 39, Issue 10, pp 1201–1207 | Cite as

Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance

  • S. M. Haffner
  • H. Miettinen
  • S. P. Gaskill
  • M. P. Stern


The relative importance of insulin resistance and abnormal insulin secretion as risk factors for the development of impaired glucose tolerance (IGT) is controversial. Few prospective data are available on metabolic precursors of IGT. We examined the relation of fasting serum insulin level (as a marker of insulin resistance) and change in insulin/glucose ratio (ΔI30/ΔG30) over the first 30 min after glucose ingestion (as a marker of insulin secretion) as predictors of the 7-year development of IGT in 839 Mexican Americans and non-Hispanic whites with normal glucose tolerance at baseline from the San Antonio Heart Study. IGT eventually developed in 148 subjects. When modelled separately, fasting serum insulin (odds ratio (OR)=2.60,95 % confidence interval (CI)=1.58,4.28,p<0.005), but not ΔI30/ΔG30 (OR=0.80, 95 % CI=0.50,1.27,p=0.339) predicted the development of IGT. However, when both variables were included in the same logistic regression model, fasting serum insulin (OR=3.50, 95 % CI=1.97,6.21,p<0.001) and low ΔI30/ΔG30 (OR=0.48, 95 % CI=0.28,0.82,p=0.008) both predicted IGT. These results were basically unchanged after further adjustment for obesity, body fat distribution and fasting plasma glucose level. We conclude that both decreased insulin secretion (as assessed by low ΔI30/ΔG30) and increased insulin resistance (as assessed by fasting serum insulin) predict the development of IGT and are thus early precursors of non-insulin-dependent diabetes mellitus; further studies of insulin secretion should take into account the level of basal insulin resistance.


Insulin resistance insulin secretion impaired glucose tolerance 



Impaired glucose tolerance


non-insulin-dependent diabetes mellitus


confidence interval


odds ratio


acute insulin response


normal glucose tolerance


waist/hip ratio


analysis of variance


oral glucose tolerance test


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  1. 1.
    Lillioja S, Mott DM, Spraul M et al. (1993) Insulin resistance and insulin secretory dysfunction as precursors of non-insulin dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 329: 1988–1992CrossRefPubMedGoogle Scholar
  2. 2.
    Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR (1990) Slow glucose removal rate and hyperinsulinaemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113: 909–915CrossRefPubMedGoogle Scholar
  3. 3.
    Sicree RA, Zimmet PZ, King HOM, Coventry JS (1987) Plasma insulin response among Nauruans: prediction of deterioration in glucose tolerance over 6 yrs. Diabetes 36: 179–186CrossRefPubMedGoogle Scholar
  4. 4.
    Haffner SM, Stern MP, Mitchell BD, Hazuda 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: 283–288CrossRefPubMedGoogle Scholar
  5. 5.
    Bergstrom RW, Newell-Morris LL, Leonetti DL, Shuman WP, Wahl PW, Fujimoto WY (1990) Association of elevated fasting C-peptide level and increased intra-abdominal fat distribution with development of NIDDM in Japanese American men. Diabetes 39: 104–111CrossRefPubMedGoogle Scholar
  6. 6.
    Charles MA, Fontbonne A, Thibult N, Warnet JM, Rosselin GE, Eschwege E (1991) Risk factors for NIDDM in white population: Paris Prospective Study. Diabetes 40: 796–799CrossRefPubMedGoogle Scholar
  7. 7.
    Mykkänen L, Kuusisto J, Pyörälä K, Laakso M (1993) Cardiovascular disease risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects. Diabetologia 36: 553–559CrossRefPubMedGoogle Scholar
  8. 8.
    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: 1500–1506CrossRefPubMedGoogle Scholar
  9. 9.
    Lundgren H, Bengtsson C, Blohme G, Lapidus L, Waldenström J (1990) Fasting serum insulin concentration and early insulin response as risk determinants for developing diabetes. Diabet Med 7: 407–413CrossRefPubMedGoogle Scholar
  10. 10.
    Efendic S, Luft R, Wajngot A (1984) Aspects of the pathogenesis of type 2 diabetes. Endocrine Reviews 5: 395–410CrossRefPubMedGoogle Scholar
  11. 11.
    Kosaka K, Hagura R, Kuzuya T (1977) Insulin responses in equivocal and definite diabetes with special reference to subjects who had mild glucose intolerance but later developed definite diabetes. Diabetes 26: 944–952CrossRefPubMedGoogle Scholar
  12. 12.
    Kadowaki T, Miyake Y, Hagura R et al. (1984) Risk factors for worsening to diabetes in subjects with impaired glucose tolerance. Diabetologia 26: 44–49CrossRefPubMedGoogle Scholar
  13. 13.
    Haffner SM, Miettinen H, Gaskill SP, Stern MP (1995) Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of non-insulin dependent diabetes mellitus in Mexican Americans. Diabetes 44: 1386–1391CrossRefPubMedGoogle Scholar
  14. 14.
    Knowler WC, Bennett PH, Hamman RF et al. (1978) Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester, Minnesota. Am J Epid 108: 497–505Google Scholar
  15. 15.
    Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Charles MA, Bennett PH (1991) A two step model for development of non-insulin dependent diabetes. Am J Med 90: 229–235CrossRefPubMedGoogle Scholar
  16. 16.
    Lillioja S, Mott DM, Howard BV et al. (1988) Impaired glucose tolerance as a disorder of insulin action: longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 318: 1217–1225CrossRefPubMedGoogle Scholar
  17. 17.
    Stern MP, Rosenthal M, Haffner SM, Hazuda HP, Franco LJ (1984) Sex difference in the effects of sociocultural status on diabetes and cardiovascular risk factors in Mexican Americans: the San Antonio Heart Study. Am J Epid 120: 834–851CrossRefGoogle Scholar
  18. 18.
    Hamman RF, Marshall JA, Baxter J et al. (1989) Methods and prevalence of non-insulin dependent diabetes mellitus in a biethnic Colorado population: the San Luis Valley Diabetes Study. Am J Epidemiol 129: 295–311PubMedGoogle Scholar
  19. 19.
    Haffner SM, Hazuda HP, Mitchell BD, Patterson JK, Stern MP (1991) Increased incidence of type II diabetes mellitus in Mexican Americans. Diabetes Care 14: 102–108CrossRefPubMedGoogle Scholar
  20. 20.
    Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK (1986) Hyperinsulinaemia in a population at high risk for non-insulin dependent diabetes mellitus. N Engl J Med 315: 220–224CrossRefPubMedGoogle Scholar
  21. 21.
    Hazuda HP, Comeaux PJ, Stern MP, Haffner SM, Eifler CW, Rosenthal M (1986) A comparison of three indicators for identifying Mexican Americans in epidemiologic research: methodological findings from the San Antonio Heart Study. Am J Epidemiol 123: 96–112PubMedGoogle Scholar
  22. 22.
    Haffner SM, Bowsher RR, Mykkänen L et al. (1994) Proinsulin and specific insulin concentration in high and low risk populations for non-insulin dependent diabetes mellitus. Diabetes 43: 1490–1493CrossRefPubMedGoogle Scholar
  23. 23.
    World Health Organization Expert Committee on Diabetes Mellitus (1985) Second Report. World Health Organization (Tech. Rep. Ser. No. 727) Geneva, SwitzerlandGoogle Scholar
  24. 24.
    Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK, Malina R (1986) Upper body and centralized adiposity in Mexican Americans and non-Hispanic whites: relationship to body mass index and other behavioral and demographic variables. Int J Obesity 10: 493–502Google Scholar
  25. 25.
    Hollenbeck CB, Chen N, Chen YDI, Reaven GM (1984) Relationship between the plasma insulin response to oral glucose and insulin stimulated glucose utilization in normal subjects. Diabetes 33: 460–463CrossRefPubMedGoogle Scholar
  26. 26.
    Saad MF, Anderson RL, Laws A et al. for the Insulin Resistance Atherosclerosis Study (1994) A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Diabetes 43: 1114–1121CrossRefPubMedGoogle Scholar
  27. 27.
    Laakso M (1993) How good a marker is insulin level for insulin resistance? Am J Epidemiol 137: 959–965PubMedGoogle Scholar
  28. 28.
    Philips DIW, Clark PM, Hales CN, Osmond C (1993) Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and secretion. Diabet Med 11: 286–292CrossRefGoogle Scholar
  29. 29.
    Skafors ET, Selinas KI, Lithell HO (1991) Risk factors for the developing non-insulin dependent diabetes: a 10 year follow-up of men in Uppsala. BMJ 303: 755–760CrossRefGoogle Scholar
  30. 30.
    Mitrakou A, Kelley D, Mokan M et al. (1992) Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326: 22–29CrossRefPubMedGoogle Scholar
  31. 31.
    Kahn SE, Prigeon RL, McCulloch DK et al. (1993) Quantification of the relationship between insulin sensitivity and beta cell function in human subjects: evidence for a hyperbolic function. Diabetes 42: 1663–1672CrossRefPubMedGoogle Scholar
  32. 32.
    Watanabe RM, Laws A, Rewers M, Bergman RN for the IRAS investigators (1995) Impaired glucose tolerant subjects exhibit a β cell defect despite normal fasting glycemia. Diabetes 44[Suppl 1]:5A (Abstract)Google Scholar
  33. 33.
    Weir GC (1995) Which comes first in non-insulin dependent diabetes mellitus: insulin resistance or β cell failure? Both come first. JAMA 273: 1878–1879 (Editorial)CrossRefPubMedGoogle Scholar
  34. 34.
    Eriksson J, Franssilla-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: 337–343CrossRefPubMedGoogle Scholar
  35. 35.
    Gulli G, Ferrannini E, Stern MP, Haffner S, DeFronzo RA (1992) The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican American NIDDM parents. Diabetes 41: 1575–1586CrossRefPubMedGoogle Scholar
  36. 36.
    Pimenta W, Korytkowski M, Mitrakou A et al. (1995) Pancreatic β cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose tolerant individuals with a first-degree NIDDM relative. JAMA 273: 1855–1861CrossRefPubMedGoogle Scholar
  37. 37.
    O’Rahilly SP, Nugent Z, Rudenski AS et al. (1986) Beta cell dysfunction, rather than insulin insensitivity is the primary defect in familial type 2 diabetes. Lancet 2: 361–364Google Scholar
  38. 38.
    Vaag A, Henriksen JE, Madsbad S, Holm N, Beck-Nielsen H (1995) Insulin secretion, insulin action and hepatic glucose production in identical twins for non-insulin-dependent diabetes mellitus. J Clin Invest 95: 690–698CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Temple RC, Carrington CA, Luzio SD et al. (1989) Insulin deficiency in non-insulin dependent diabetes. Lancet 1: 293–295CrossRefPubMedGoogle Scholar
  40. 40.
    Reaven GM, Chen YDI, Hollenbeck CB, Sheu WHH, Ostrega D, Polonsky KS (1993) Plasma insulin, C-peptide and proinsulin concentrations in obese and non-obese individuals with varying degrees of glucose tolerance. J Clin Endocrinol Metab 76: 44–48PubMedGoogle Scholar
  41. 41.
    Yoshioka N, Kuzuya T, Matsuda A, Taniguchi M, Iwamoto Y (1988) Serum proinsulin levels at fasting and after oral glucose load in patients with type 2 (non-insulin dependent) diabetes mellitus. Diabetologia 31: 355–360CrossRefPubMedGoogle Scholar
  42. 42.
    Saad MF, Kahn SE, Nelson RG et al. (1990) Disproportionately elevated proinsulin in Pima Indians with non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 70: 1247–1253CrossRefPubMedGoogle Scholar
  43. 43.
    Porte D (1991) Banting Lecture 1990. β cells in type II diabetes mellitus. Diabetes 40: 166–180CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • S. M. Haffner
    • 1
  • H. Miettinen
    • 1
  • S. P. Gaskill
    • 1
  • M. P. Stern
    • 1
  1. 1.Division of Clinical Epidemiology, Department of MedicineUniversity of Texas Health Science Center at San AntonioSan AntonioUSA

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