Current Diabetes Reports

, Volume 2, Issue 1, pp 77–82 | Cite as

The effect of in-utero undernutrition on the insulin resistance syndrome

  • Delphine Jaquet
  • Juliane Leger
  • Paul Czernichow
  • Claire Levy-Marchal


The metabolic and cardiovascular complications associated with in-utero undernutrition have been identified during the past 10 years. Reduced fetal growth is independently associated with an increased risk for the development of cardiovascular diseases, the insulin resistance syndrome and its components: hypertension, dyslipidemia, impaired glucose tolerance, and type 2 diabetes. All appear to result from the initial development of insulin resistance that seems to be a key component underlying this association. Several hypotheses have been proposed over the past 10 years to understand this unexpected association. Each of them points to either a detrimental fetal environment or genetic susceptibilities or interactions between these two components as playing a critical role in this context. The hypothesis that this association could be the consequence of genetic/environmental interactions remains at the moment the most attractive. Although the mechanism remains unclear, there is also some evidence that adipose tissue plays a role in the emergence of insulin resistance associated with in-utero undernutrition.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Barker DJ, Osmond C, Golding J, et al.: Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989, 298:564–567.PubMedGoogle Scholar
  2. 2.
    Hales CN, Barker DJ, Clark PM, et al.: Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991, 303:1019–1022.PubMedGoogle Scholar
  3. 3.
    McCance DR, Pettitt DJ, Hanson RL, et al.: Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ 1994, 308:942–945.PubMedGoogle Scholar
  4. 4.
    Lithell HO, McKeigue PM, Berglund L, et al.: Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years. BMJ 1996, 312:406–410.PubMedGoogle Scholar
  5. 5.
    Barker DJ, Hales CN, Fall CH, et al.: Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993, 36:62–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Léger J, Lévy-Marchal C, Bloch J, et al.: Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ 1997, 315: 341–347.PubMedGoogle Scholar
  7. 7.
    Valdez R, Athens MA, Thompson GH, et al.: Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 1994, 37:624–631.PubMedGoogle Scholar
  8. 8.
    Haffner SM, Valdez RA, Hazuda HP, et al.: Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 1992, 41: 715–722.PubMedCrossRefGoogle Scholar
  9. 9.
    Phillips DI, Barker DJ, Hales CN, et al.: Thinness at birth and insulin resistance in adult life. Diabetologia 1994, 37:150–154.PubMedCrossRefGoogle Scholar
  10. 10.
    McKeigue PM, Lithell HO, Leon DA: Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia 1998, 41: 1133–1138.PubMedCrossRefGoogle Scholar
  11. 11.
    Jaquet D, Gaboriau A, Czernichow P, et al.: Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J Clin Endocrinol Metab 2000, 85:1401–406. Showed that IUGR subjects have decreased insulin-stimulated glucose uptake, as early as 25 years of age, without major impairment of insulin secretion. A role of adipose tissue at an early stage of insulin resistance in these subjects is suggested.PubMedCrossRefGoogle Scholar
  12. 12.
    Flanagan DE, Moore VM, Godsland IF, et al.: Fetal growth and the physiological control of glucose tolerance in adults: a minimal model analysis. Am J Physiol Endocrinol Metab 2000, 208:E700-E706.Google Scholar
  13. 13.
    Law CM, Gordon GS, Shiell AW, et al.: Thinness at birth and glucose tolerance in seven-year-old children. Diabet Med 1995, 12:24–29.PubMedGoogle Scholar
  14. 14.
    Whincup PH, Cook DG, Adshead F, et al.: Childhood size is more strongly related than size at birth to glucose and insulin levels in 10-11-year-old children. Diabetologia 1997, 40:319–326.PubMedCrossRefGoogle Scholar
  15. 15.
    Bavdekar A, Yajnik CS, Fall CH, et al.: Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both? Diabetes 1999, 48:2422–2429.PubMedCrossRefGoogle Scholar
  16. 16.
    Vestbo E, Damsgaard EM, Froland A, et al.: Birth weight and cardiovascular risk factors in an epidemiological study. Diabetologia 1996, 39:1598–1602.PubMedCrossRefGoogle Scholar
  17. 17.
    Carlsson S, Persson PG, Alvarsson M, et al.: Low birth weight, family history of diabetes, and glucose intolerance in Swedish middle-aged men. Diabetes Care 1999, 22:1043–1047. Indicated that low birth weight is associated with type 2 diabetes, impaired glucose tolerance, and impaired fasting glucose in men. Men seem to be at particularly high risk of developing type 2 diabetes if they have a combination of low birth weight and a family history of diabetes.PubMedCrossRefGoogle Scholar
  18. 18.
    Robinson S, Walton RJ, Clark PM, et al.: The relation of fetal growth to plasma glucose in young men. Diabetologia 1992, 35:444–446.PubMedCrossRefGoogle Scholar
  19. 19.
    Rossetti L, Giaccari A, DeFronzo RA: Glucose toxicity. Diabetes Care 1990, 13:610–630.PubMedCrossRefGoogle Scholar
  20. 20.
    McGarry JD: Disordered metabolism in diabetes: have we underemphasized the fat component? J Cell Biochem 1994, 55:29–38.PubMedCrossRefGoogle Scholar
  21. 21.
    Kulkarni RN, Brüning JC, Winnay JN, et al.: Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999, 96:329–339.PubMedCrossRefGoogle Scholar
  22. 22.
    Garofano A, Cernichow P, Bréant B: In utero undernutrition impairs rat beta-cell development. Diabetologia 1997, 40:1231–1234.PubMedCrossRefGoogle Scholar
  23. 23.
    Garofano A, Cernichow P, Bréant B: Effect of aging on beta cell mass and function in rats malnourished during the perinatal period. Diabetologia 1999, 42:711–718.PubMedCrossRefGoogle Scholar
  24. 24.
    Reaven G: Role of insulin-resistance in human disease. Diabetes 1988, 37:1595–1607.PubMedCrossRefGoogle Scholar
  25. 25.
    Leon DA, Koupilova I, Lithell HO, et al.: Failure to realize growth potential in utero and adult obesity in relation to blood pressure in 50 year old Swedish men. BMJ 1996, 312:401–406.PubMedGoogle Scholar
  26. 26.
    Barker DJP, Martyn CN, Osmond C, et al.: Growth in utero and serum cholesterol concentrations in adult life. BMJ 1993, 207:1524–1527.CrossRefGoogle Scholar
  27. 27.
    Dunaif A, Graf M, Mandeli J, et al.: Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance and/or hyperinsulinism. J Clin Endocrinol Metab 1987, 65:499–507.PubMedCrossRefGoogle Scholar
  28. 28.
    Ibañez L, Potau N, Zampolli M, et al.: Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1996, 81: 1237–1243.PubMedCrossRefGoogle Scholar
  29. 29.
    Ibañnez L, Potau N, Francois I, et al.: Premature pubarche, hyperinsulinism and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab 1998, 83:3558–3562.CrossRefGoogle Scholar
  30. 30.
    Jaquet D, Léger J, Chevenne D, et al.: Intra-uterine growth retardation predisposes to insulin-resistance but not to hyperandrogenism in young women. J Clin Endocrinol Metab 1999, 84:3945–3949.PubMedCrossRefGoogle Scholar
  31. 31.
    Reaven GM: The fourth musketeer—from Alexandre Dumas to Claude Bernard. Diabetologia 1995, 38:3–13.PubMedCrossRefGoogle Scholar
  32. 32.
    Petersen S, Gotfredsen A, Knudsen FU: Lean body mass in small for gestational age and appropriate for gestational age infants. J Pediatr 1988, 113:886–889.PubMedCrossRefGoogle Scholar
  33. 33.
    Enzi G, Zanardo V, Caretta F, et al.: Intrauterine growth and adipose tissue development. Am J Clin Nutr 1981, 34:1785–1790.PubMedGoogle Scholar
  34. 34.
    Albertsson-Wikland K, Wennergren G, Wennergren M, et al.: Longitudinal follow-up of growth in children born small for gestational age. Acta Paediatr 1993, 82:438–443.PubMedGoogle Scholar
  35. 35.
    Jaquet D, Léger J, Lévy-Marchal, et al.: Ontogeny of leptin in human fetuses and newborns. Effect of intra-uterine growth retardation. J Clin Endocrinol Metab 1998, 83:1243–1246.PubMedCrossRefGoogle Scholar
  36. 36.
    Jaquet D, Léger J, Tabone MD, et al.: High serum leptin concentrations during catch-up growth of children born with intra-uterine growth retardation. J Clin Endocrinol Metab 1999, 84:1949–1953.PubMedCrossRefGoogle Scholar
  37. 37.
    Ravelli GP, Stein ZA, Susser MW: Obesity in young men after famine exposure in utero and early infancy. New Engl J Med 1976, 296:349–353.CrossRefGoogle Scholar
  38. 38.
    Ong KK, Ahmed ML, Emmett PM, et al.: Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 2000, 320:967–971.PubMedCrossRefGoogle Scholar
  39. 39.
    Malina RM, Katzmarzyk PT, Beunen G: Birth weight and its relationship to size attained and relative fat distribution at 7 to 12 years of age. Obes Res 1996, 4:385–390.PubMedGoogle Scholar
  40. 40.
    Léger J, Limoni C, Collin D, et al.: Prediction factors in the determination of final height in subjects born small for gestational age. Pediatr Res 1998, 43:808–812.PubMedCrossRefGoogle Scholar
  41. 41.
    Jaquet D, Gaboriau A, Czernichow P, et al.: Relatively low serum leptin levels in adults born with intra-uterine growth retardation. Int J Obes Relat Metab Disord 2001, 25:491–495. Showed that adults born with IUGR developed an excess of adipose tissue associated with relatively low serum leptin levels, suggestive of an altered adipocyte function. These observations point to the potential implication of abnormal adipose tissue development in the longterm metabolic consequences associated with in-utero nutrition.PubMedCrossRefGoogle Scholar
  42. 42.
    Haffner SM, Miettinen H, Mykkanen H, et al.: Leptin concentrations and insulin sensitivity in normoglycemic men. Int J Obes Relat Metab Disord 1997, 21: 393–399.PubMedCrossRefGoogle Scholar
  43. 43.
    Shinomura I, Hammer R, Ikemoto S, et al.: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401:73–76.CrossRefGoogle Scholar
  44. 44.
    Neel JV: Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”. Am J Hum Genet 1962, 14:353–362.PubMedGoogle Scholar
  45. 45.
    Lucas A: Programming by early nutrition in man. In The Childhood Environment and Adult Disease. CIBA Foundation Symposium 156. Chichester: Wiley; 1991:38–55.Google Scholar
  46. 46.
    Lindsay RS, Dabelea D, Roumain J, et al.: Type 2 diabetes and low birth weight: the role of paternal inheritance in the association of low birth weight and diabetes. Diabetes 2000, 49:445–449. Concluded that the risk of diabetes associated with low birth weight is strongly related to the development of paternal diabetes, suggesting a genetic link between lower birth weight and later diabetes.PubMedCrossRefGoogle Scholar
  47. 47.
    Hattersley AT, Tooke JE: The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999, 353:1789–1792. Proposes that genetically determined insulin resistance results in impaired insulin-mediated growth in the fetus as well as insulin resistance in adult life.PubMedCrossRefGoogle Scholar
  48. 48.
    Poulsen P, Vaag A, Beck-Nielsen H: Does zygosity influence the metabolic profile of twins? A population based cross sectional study. BMJ 1999, 319:151–154.PubMedGoogle Scholar
  49. 49.
    Poulsen P, Vaag AA, Kyvik KO, et al.: Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs. Diabetologia 1997, 40:439–446.PubMedCrossRefGoogle Scholar
  50. 50.
    Cambien F, Léger J, Mallet C, et al.: Angiotensin I-converting enzyme gene polymorphism modulates the consequences of in utero growth retardation on plasma insulin in young adults. Diabetes 1998, 47:470–475.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2002

Authors and Affiliations

  • Delphine Jaquet
    • 1
  • Juliane Leger
  • Paul Czernichow
  • Claire Levy-Marchal
  1. 1.INSERM Unité 457Hôpital Robert DebréParisFrance

Personalised recommendations