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Diabetologia

, Volume 37, Supplement 2, pp S162–S168 | Cite as

The pathogenesis of NIDDM

  • C. N. Hales
Article

Summary

Improvements in the specificity and sensitivity of assays for insulin-related molecules in the circulation have proved to be necessary and informative in studies of the pathogenesis of non-insulin-dependent diabetes (NIDDM). Of particular interest has been the close relationship between increases in des 31,32 split proinsulin and susceptibility to loss of glucose tolerance and the insulin resistance syndrome. It is suggested that the analogy can be drawn between this measurement and the measurement of HbA1c. The amount of this partially processed precursor of insulin in the circulation indicates the degree of glucose stimulus applied to the beta cell combined with the inherent capacity of the insulin secretory system to respond. Further improvements of the sensitivity and specificity of the assay of proinsulin related molecules are desirable. Deterioration of the early insulin response to oral glucose is a major feature of the loss of glucose tolerance associated with the transition from normal to impaired glucose tolerance and to NIDDM. The extent to which this loss of insulin secretion reflects a major predisposing factor in the aetiology of this type of diabetes or is secondary to glucose toxicity or amyloid accumulation remains to be determined. A relationship between birth weight and impaired glucose tolerance, NIDDM and the insulin resistance syndrome has now been observed in two populations in the UK, in Mexican Americans and in Pima Indians. It is therefore reproducible and applicable to widely differing populations. Much further research is indicated to determine, amongst many questions, how much diabetes is associated with this link and what factors explain it.

Key words

Non-insulin-dependent diabetes mellitus impaired glucose tolerance immunoassay pro-insulin-related molecules birth weight 

Abbreviations

NIDDM

Non-insulin dependent diabetes mellitus

IGT

impaired glucose tolerance

MODY

maturity onset diabetes of the young

References

  1. 1.
    Temple R, Clark PMS, Hales CN (1992) Measurement of insulin secretion in type 2 diabetes: problems and pitfalls. Diab Med 9: 503–512Google Scholar
  2. 2.
    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: 22–29PubMedGoogle Scholar
  3. 3.
    Yoneda H, Ikegami H, Yamamoto Y et al. (1992) Analysis of early-phase insulin responses in nonobese subjects with mild glucose intolerance. Diabetes Care 15: 1517–1521PubMedGoogle Scholar
  4. 4.
    Davies MJ, Rayman G, Gray IP et al. (1993) Insulin deficiency and increased plasma concentration of intact and 32/33 split proinsulin in subjects with impaired glucose tolerance. Diab Med 10: 313–320Google Scholar
  5. 5.
    Rudenski AS, Hadden DR, Atkinson AB et al. (1988) Natural history of pancreatic islet B-cell function in type-2 diabetes mellitus studied over six years by homeostasis model assessment. Diab Med 5: 36–41Google Scholar
  6. 6.
    Saad MF, Pettitt DJ, Mott DM et al. (1989) Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet I: 1356–1359CrossRefGoogle Scholar
  7. 7.
    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: 337–343PubMedGoogle Scholar
  8. 8.
    Lundgren H, Bengtsson C, Blohme G et al. (1990) Fasting serum insulin concentration and early insulin response as risk determinants for developing diabetes. Diabet Med 7: 407–413PubMedGoogle Scholar
  9. 9.
    Skarfors ET, Selinus KI, Lithell HO (1991) Risk factors for developing non-insulin dependent diabetes: a 10 year follow up of men in Uppsala. BMJ 303: 755–760PubMedGoogle Scholar
  10. 10.
    Zimmet PZ, Collins VR, Dowse GK, Knight LT (1992) Hyperinsulinaemia in youth is a predictor of type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35: 534–541PubMedGoogle Scholar
  11. 11.
    Arner P, Pollare T, Lithell H (1991) Different aetiologies of type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects. Diabetologia 34: 483–487PubMedGoogle Scholar
  12. 12.
    Joffe BI, Panz VR, Wing JR et al. (1992) Pathogenesis of non-insulin-dependent diabetes mellitus in the black population of southern Africa. Lancet 340: 460–462CrossRefPubMedGoogle Scholar
  13. 13.
    Reaven GM (1988) Role of insulin resistance in human disease (1988) Diabetes 37: 1595–1607PubMedGoogle Scholar
  14. 14.
    Hales CN, Randle PJ (1963) Immunoassay of insulin with insulin-antibody precipitate. Biochem J 88: 137–146PubMedGoogle Scholar
  15. 15.
    Miles LEM, Hales CN (1968) Labelled antibodies and immunological assay systems. Nature 219: 186–189PubMedGoogle Scholar
  16. 16.
    Addison GM, Hales CN (1971) The immunoradiometric assay. In: Kirkham KE, Hunter WM (eds) Radioimmunoassay methods. Churchill Livingstone, Edinburgh, pp 481–487Google Scholar
  17. 17.
    Sobey WJ, Beer SF, Carrington CA et al. (1989) Sensitive and specific two-site immunoradiometric assays for human insulin, proinsulin, 65–66 split and 32–33 split proinsulins. Biochem J 260: 535–541PubMedGoogle Scholar
  18. 18.
    Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256: 495–497PubMedGoogle Scholar
  19. 19.
    Frank BH, Pettee JH, Zimmerman RE, Burck PH (1981) The production of human proinsulin and its transformation to human insulin and C-peptide. In: Rich DH, Cross E (eds) Peptides: synthesis-structure-function. Proceedings of the seventh American peptide symposium. Pierce Chemical Company, pp 729–738Google Scholar
  20. 20.
    Hales CN, Woodhead JS (1980) Labelled antibodies and their use in the immunoradiometric assay. In: Van Vunakis H, Lagone JJ (eds) Methods in enzymology, Vol. 70, of Immunochemical Techniques, Part A. Academic Press (London) Ltd, pp 334–355Google Scholar
  21. 21.
    Alpha B, Cox L, Crowther N et al. (1992) Sensitive amplified immunoenzymometric assays (IEMA) for human insulin and intact proinsulin. Eur J Clin Chem Clin Biochem 30: 27–32PubMedGoogle Scholar
  22. 22.
    Roth J, Gorden P, Pastan I (1968) “Big insulin”,: a new component of plasma insulin detected by immunoassay. Proc Natl Acad Sci USA 61: 138–148PubMedGoogle Scholar
  23. 23.
    Rubenstein AH, Cho S, Steiner DF (1968) Evidence for proinsulin in human urine and serum. Lancet I: 1353–1355CrossRefGoogle Scholar
  24. 24.
    Duckworth WC, Kitabchi AE, Heinemann M (1972) Direct measurement of plasma proinsulin in normal and diabetic subjects. Am J Med 53: 418–427CrossRefPubMedGoogle Scholar
  25. 25.
    Goden P, Hendricks CM, Roth J (1974) Circulating proinsulin-like component in man: increased proportion in hypoinsulinaemic states. Diabetologia 10: 469–474PubMedGoogle Scholar
  26. 26.
    Mako ME, Starr JI, Rubenstein AH (1977) Circulating proinsulin in patients with maturity onset diabetes. Am J Med 63: 865–869CrossRefPubMedGoogle Scholar
  27. 27.
    Gray IP, Siddle K, Docherty K et al. (1984) Proinsulin in human serum: problems in measurement and interpretation. Clin Endocrin 21: 43–47Google Scholar
  28. 28.
    Temple RC, Carrington CA, Luzio SD et al. (1989) Insulin deficiency in non-insulin dependent diabetes. Lancet I: 293–295CrossRefGoogle Scholar
  29. 29.
    Davies MJ, Metcalfe J, Gray IP et al. (1993) Insulin deficiency rather than hyperinsulinaemia in newly diagnosed type 2 diabetes mellitus. Diabet Med 10: 305–312PubMedGoogle Scholar
  30. 30.
    Williams DRR, Byrne C, Clark PMS et al. (1991) Impaired glucose tolerance and height. BMJ 303: 1134Google Scholar
  31. 31.
    Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW (1988) Physiologic importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes. Diabetes 37: 736–744PubMedGoogle Scholar
  32. 32.
    Brown DC, Byrne CD, Clark PMS et al. (1991) Height and glucose tolerance in adult subjects. Diabetologia 34: 531–533PubMedGoogle Scholar
  33. 33.
    Barker DJP, Winter PD, Osmond C (1989) Weight in infancy and death from ischaemic heart disease. Lancet II: 577–580CrossRefGoogle Scholar
  34. 34.
    Barker DJP, Bull AR, Osmond C, Simmonds SJ (1990) Fetal and placental size and risk of hypertension in adult life. BMJ 301: 259–262PubMedGoogle Scholar
  35. 35.
    Hales CN, Barker DJP, Clark PMS et al. (1991) Fetal and infant growth and impaired glucose tolerance at age 64 years. BMJ 303: 1019–1022PubMedGoogle Scholar
  36. 36.
    Phipps K, Barker DJP, Hales CN et al. (1993) Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36: 225–228PubMedGoogle Scholar
  37. 37.
    Barker DJP, Hales CN, Fall CHD et al. (1993) Type 2 (noninsulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36: 62–67PubMedGoogle Scholar
  38. 38.
    Athens M, Valdez R, Stern M (1993) Effect of birthweight on future development of “syndrome X” in adult life. Diabetes 42 [Suppl 1]: 61A (Abstract)Google Scholar
  39. 39.
    McCance DR, Pettit DJ, Hanson RL et al. (1993) Low birth weight and type 2 diabetes in Pima Indians. Diabetologia 36 [Suppl 1]: A4 (Abstract)Google Scholar
  40. 40.
    Pettit DJ, Bennett PH, Saad MF et al. (1991) Abnormal glucose tolerance during pregnancy in Pima Indian women. Long-term effects on offspring. Diabetes 40 [Suppl. 2]: 126–130PubMedGoogle Scholar
  41. 41.
    Hales CN, Barker DJP (1993) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35: 595–601Google Scholar
  42. 42.
    Phillips DIW, Barker DJP, Hales CN, Hirst S, Osmond C (1993) Thinness at birth and insulin resistance in adult life. Diabetologia 37: 150–154CrossRefGoogle Scholar
  43. 43.
    Hirst S, Phillips DIW, Vines SK et al. (1993) Reproducibility of the short insulin tolerance test. Diabet Med 10: 839–842PubMedGoogle Scholar
  44. 44.
    Bonora E, Moghetti P, ZanCanaro C et al. (1989) Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycaemic clamp and hyperinsulinaemic clamp studies. J Clin Endocrinol Metab 68: 374–378PubMedGoogle Scholar
  45. 45.
    Akinmokum PL, Selby K, Ramaiya K, Alberti KGMM (1992) The short insulin tolerance test for determination of insulin sensitivity: a comparison with the euglycaemic clamp. Diabet Medicine 9: 432–437Google Scholar
  46. 46.
    Hattersley AT, Clark PM, Cook JTE et al. (1993) Maturity onset diabetes of the young is a beta-cell disorder with normal proinsulin levels. Diabetologia 36 [Suppl 1]: A67 (Abstract)Google Scholar
  47. 47.
    Rhodes CJ, Lincoln B, Shoelson SE (1992) Preferential cleavage of des-31, 32-proinsulin over intact proinsulin by the insulin secretory granule type 2 endopeptidase: implications of a favoured route for prohormone processing. J Biol Chem 267: 22719–22727PubMedGoogle Scholar
  48. 48.
    Alarcon C, Lincoln B, Rhodes CJ (1993) The biosynthesis of the subtilisin-related proprotein convertase PC3, but not that of the PC2 convertase, is regulated by glucose in parallel to proinsulin biosynthesis in rat pancreatic islets. J Biol Chem 268: 4276–4280PubMedGoogle Scholar
  49. 49.
    Robinson S, Walton RJ, Clark PM et al. (1992) The relation of fetal growth to plasma glucose in young men. Diabetologia 35: 444–446PubMedGoogle Scholar
  50. 50.
    Phillips DIW, Phillips DIW, Hirst S, Clark, PMS et al. (1994) Fetal growth and insulin secretion in adult life. Diabetologia 37: 592–596CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • C. N. Hales
    • 1
  1. 1.Department of Clinical BiochemistryUniversity of Cambridge, Addenbrooke's HospitalCambridgeUK

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