Metabolic programming in the pathogenesis of insulin resistance



This review focuses on different animal models of nutrient perturbations, inclusive of restrictive and excessive states mimicking human situations during pregnancy and lactation that cause aberrations in the offspring. These aberrations consist of diminished insulin sensitivity in the presence of defective insulin production. These phenotypic changes are due to altered peripheral tissue post-insulin receptor signaling mechanisms and pancreatic β-islet insulin synthesis and secretion defects. While these changes during in utero or postnatal life serve as essential adaptations to overcome adverse conditions, they become maladaptive subsequently and set the stage for type 2 diabetes mellitus. Pregnancy leads to gestational diabetes with trans-generational propagation of the insulin resistant phenotype. This is in response to the metabolically aberrant maternal in utero environment, and tissue specific epigenetic perturbations that permanently alter expression of critical genes transmitted to future generations. These heritable aberrations consisting of altered DNA methylation and histone modifications remodel chromatin and affect transcription of key genes. Along with an altered in utero environment, these chromatin modifications contribute to the world-wide epidemic of type 2 diabetes mellitus, with nutrient excess dominating in developed and nutrient restriction in developing countries.


Nutrient restriction Intra-uterine growth restriction Epigenetic regulation Trans-generational propagation Type 2 diabetes mellitus Developmental origins of adult disease 



Grant support is from the National Institutes of Health, HD-41230, -25024, -33997 and -46979 (to SUD).


  1. 1.
    Barker DJ. The developmental origins of adult disease. J Am Coll Nutr 2004;23:588S–95S.PubMedGoogle Scholar
  2. 2.
    Barker DJ. The origins of the developmental origins theory. J Intern Med 2007;261:412–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Martin-Gronert MS, Ozanne SE. Experimental IUGR and later diabetes. J Intern Med 2007;261:437–52.PubMedCrossRefGoogle Scholar
  4. 4.
    Van Assche FA, Holemans K, Aerts L. Long-term consequences for offspring of diabetes during pregnancy. Br Med Bull 2001;60:173–82.PubMedCrossRefGoogle Scholar
  5. 5.
    Cutfield WS, Hofman PL, Mitchell M, Morison IM. Could epigenetics play a role in the developmental origins of health and disease. Pediatr Res 2007;61:68R–75R.PubMedCrossRefGoogle Scholar
  6. 6.
    Hovi P, Andersson S, Eriksson JG, Jarvenpaa AL, Strang-Karlsson S, Makitie O et al. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007;356:2053–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Schroder HJ. Models of fetal growth restriction. Eur J Obstet Gynecol Reprod Biol 2003;110(Suppl 1):S29–39.PubMedCrossRefGoogle Scholar
  8. 8.
    Holemans K, Gerber R, Meurrens K, De Clerck F, Poston L, Van Assche FA. Maternal food restriction in the second half of pregnancy affects vascular function but not blood pressure or rat female offspring. Br J Nutr 1999;81:73–9.PubMedGoogle Scholar
  9. 9.
    Lesage J, Hahn D, Léonhardt M, Blondeau B, Bréant B, Dupouy JP. Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels. J Endocrinol 2002;174:37–43.PubMedCrossRefGoogle Scholar
  10. 10.
    Ozanne SE, Hales CN. Early programming of glucose–insulin metabolism. Trends Endocrinol Metab 2002;13:368–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab 2000;279:E83–7.PubMedGoogle Scholar
  12. 12.
    Collins S, Sadler K, Dent N, Khara T, Guerrero S, Myatt M et al. Key issues in the success of community-based management of severe malnutrition. Food Nutr Bull 2006;27:S49–82.PubMedGoogle Scholar
  13. 13.
    Ahokas RA, Reynolds SL, Anderson GD, Lipshitz J. Catecholamine mediated reduction in uteroplacental blood flow in the diet-restricted, term pregnant rat. J Nutr 1986;116:412–8.PubMedGoogle Scholar
  14. 14.
    Bussey ME, Finley S, LaBarbera A, Ogata ES. Altered growth, hypoglycemia, hypoalaninemia and ketonemia in the young rat: postnatal consequences of intrauterine growth retardation. Pediatr Res 1985;19:32–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Fatoba IO, Cha CJ, Oh W. Effect of respiratory acidosis on glucose homeostasis in experimental intrauterine growth retardation in rats. Early Hum Dev 1996;13:107–14.CrossRefGoogle Scholar
  16. 16.
    Pham TD, MacLennan NK, Chiu CT, Laksana GS, Hsu JL, Lane RH. Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in full term IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol 2003;285:R962–70.PubMedGoogle Scholar
  17. 17.
    Thamotharan M, McKnight RA, Thamotharan S, Kao DJ, Devaskar SU. Aberrant insulin-induced GLUT4 translocation predicts glucose intolerance in the offspring of a diabetic mother. Am J Physiol Endocrinol Metab 2003;284:E901–14.PubMedGoogle Scholar
  18. 18.
    Corcoran MP, Lamon-Fava S, Fielding RA. Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. Am J Clin Nutr 2007;85:662–77.PubMedGoogle Scholar
  19. 19.
    Merzouk H, Khant NA. Implications of lipids in macrosomia of diabetic pregnancy: can n-3 polyunsaturated fatty acids exert beneficial effects? Clin Sci 2003;105:519–29.PubMedCrossRefGoogle Scholar
  20. 20.
    Patel MS, Vadlamudi SP, Johanning GL. Overview of pup in a cup model: hepatic lipogenesis in rats artificially reared on a high-carbohydrate formula. J Nutr 1993;123:373–7.PubMedGoogle Scholar
  21. 21.
    Lopez-Soldado I, Munilla MA, Herrera E. Long-term consequences of undernutrition during suckling on glucose tolerance and lipoprotein profile in female and male rats. Br J Nutr 2006;96:1030–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Aerts L, Van Assche FA. Animal evidence for the transgenerational development of diabetes mellitus. Int J Biochem Cell Biol 2006;38:894–903.PubMedCrossRefGoogle Scholar
  23. 23.
    Vadlamudi S, Kalhan SC, Patel MS. Persistence of metabolic consequences in the progeny of rats fed a HC formula in their early postnatal life. Am J Physiol Endocrinol Metab 1995;269:E731–8.Google Scholar
  24. 24.
    Srinivasan M, Katewa SD, Palaniyappan A, Pandya JD, Patel MS. Maternal high-fat diet consumption results in fetal malprogamming predisposing to the onset of metabolic syndrome-like phenotype in adulthood. Am J Physiol Endocrinol Metab 2006;291:E792–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Siemelink M, Verhoef A, Dormans JA, Span PN, Piersma AH. Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring. Diabetologia 2002;45:1397–403.PubMedCrossRefGoogle Scholar
  26. 26.
    Gallou-Kabani C, Vige A, Gross MS, Boileau C, Rabes JP, Fruchart-Naiib J et al. Resistance to high-fat diet in the female progeny of obese mice fed a control diet during the periconceptual, gestation, and lactation periods. Am J Physiol Endocrinol Metab 2007;292:E1095–100.PubMedCrossRefGoogle Scholar
  27. 27.
    Fernandez E, Martin MA, Fajardo S, Bailbe D, Gangnerau MN, Portha B et al. Undernutrition does not alter the activation of beta-cell neogenesis and replication in adult rats after partial pancreatectomy. Am J Physiol Endocrinol Metab 2006;291:E913–21.PubMedCrossRefGoogle Scholar
  28. 28.
    Thompson NM, Norman AM, Donkin SS, Shankar RR, Vickers MH, Miles JL et al. Prenatal and postnatal pathways to obesity: different underlying mechanisms, different metabolic outcomes. Endocrinology 2007;148:2345–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Vickers MH, Breier BH, McCarthy D, Gluckman PD. Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. Am J Physiol Regul Integr Comp Physiol 2003;285:R271–3.PubMedGoogle Scholar
  30. 30.
    Nyirenda MJ, Welberg LA, Seckl JR. Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids—fetal effect or maternal influence? J Endocrinol 2001;170:653–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Drake AJ, Walker BR, Seckl JR. Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 2005;288:R34–8.PubMedGoogle Scholar
  32. 32.
    He J, Varma A, Weissfeld LA, Devaskar SU. Postnatal glucocorticoid exposure alters the adult phenotype. Am J Physiol Regul Integr Comp Physiol 2004;287:R198–208.PubMedGoogle Scholar
  33. 33.
    Garg M, Thamotharan M, Rogers L, Bassilian S, Lee WNP, Devaskar SU. Glucose metabolic adaptations in the intrauterine growth-restricted adult female adult offspring. Am J Physiol Endocrinol Metab 2006;290:1218–26.CrossRefGoogle Scholar
  34. 34.
    Holemans K, Verhaeghe J, Dequecker J, Van Assche FA. Insulin sensitivity in adult female rats subjected to malnutrition during the perinatal period. J Soc Gynaecol 1996;3:71–7.CrossRefGoogle Scholar
  35. 35.
    Eriksson JG, Osmond C, Kajante E, Forsen TJ, Barker DJP. Patterns of growth among children who later develop type 2 diabetes or its risk factors. Diabetologia 2006;49:2853–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Bhargava SK, Sachdev HS, Fall CH, Osmond C, Lakshmy R, Barker DJ et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 2004;26:865–75.CrossRefGoogle Scholar
  37. 37.
    Ozanne SE, Dorling MW, Wang CL, Nave BT. Impaired PI-3-kinase activation in adipocytes from early growth-restricted male rats. Am J Physiol Endocrinol Metab 2001;280:E534–9.PubMedGoogle Scholar
  38. 38.
    Ozanne SE, Wang CL, Dorling MW, Petry CJ. Dissection of the metabolic actions of insulin in adipocytes from early growth-retarded male rats. J Endocrinol 1999;162:313–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Oak SA, Tran C, Pan G, Thamotharan M, Devaskar SU. Perturbed skeletal muscle insulin signaling in the adult female intrauterine growth-restricted rat. Am J Physiol Endocrinol Metab 2006;290:E1321–30.PubMedCrossRefGoogle Scholar
  40. 40.
    Ozanne SE, Smith GD, Tikerpae J, Hales CN. Altered regulation of glucose output in the male offspring of protein-malnourished rat dams. Am J Physiol 1996;270:E559–64.PubMedGoogle Scholar
  41. 41.
    Ozanne SE, Olsen GS, Hansen LL, Tingey KJ, Nave BT, Wang CL et al. Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. J Endocrinol 2003;177:235–41.PubMedCrossRefGoogle Scholar
  42. 42.
    Fernandez-Twinn DS, Wayman A, Ekizoglou S, Martin MS, Hales CN, Ozanne SE. Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 21 mo-old female rat offspring. Am J Physiol Regul Integr Comp Physiol 2005;288:R368–73.PubMedGoogle Scholar
  43. 43.
    Ozanne SE, Jensen CB, Tingey TJ, Storgaard H, Madsbad S, Vang AA. Low birthweight is associated with specific changes in muscle insulin-signaling protein expression. Diabetologia 2005;48:547–52.PubMedCrossRefGoogle Scholar
  44. 44.
    Ozanne SE, Jensen CB, Tingey KJ, Martin-Gronert MS, Grunnet L, Brons C et al. Decreased protein levels of key insulin signaling molecules in adipose tissue from young men with a low birthweight—potential link to increased risk of diabetes? Diabetologia 2006;49:2993–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Thamotharan M, Shin BC, Suddirikku DT, Thamotharan S, Garg M, Devaskar SU. GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring. Am J Physiol Endocrinol Metab 2005;288:E935–47.PubMedCrossRefGoogle Scholar
  46. 46.
    Boloker J, Gertz SJ, Simmons RA. Gestational diabetes leads to the development of diabetes in adulthood in the rat. Diabetes 2002;51:1499–506.PubMedCrossRefGoogle Scholar
  47. 47.
    Zambrano E, Martinez-Samayoa PM, Bautista CJ, Deas M, Guileen L, Rodriquez-Gonzalez GL et al. Sex differences in transgenerational alterations of growth and metabolism in pregnancy (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation. J Physiol 2005;566:225–36.PubMedCrossRefGoogle Scholar
  48. 48.
    Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD, Hanson MA. Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res 2007;61:5R–10R.PubMedCrossRefGoogle Scholar
  49. 49.
    Malandro MS, Beveridge MJ, Kilberg MS, Novak DA. Effect of low-protein diet-induced intrauterine growth retardation on rat placental amino acid transport. Am J Physiol 1996;271:C295–303.PubMedGoogle Scholar
  50. 50.
    Chamson-Reig A, Thyssen SM, Arany E, Hill DJ. Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein in time and gender specific. J Endocrinol 2006;191:83–92.PubMedCrossRefGoogle Scholar
  51. 51.
    Eriksson JG, Yliharshila H, Forsen T, Osmond C, Barker DJ. Exercise protects against glucose intolerance in individuals with a small body size at birth. Prev Med 2004;39:164–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Simmons RA, Templeton LJ, Gertz SJ. Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 2001;50:2279–86.PubMedCrossRefGoogle Scholar
  53. 53.
    Thamotharan M, Garg M, Oak S, Rogers LM, Pan G, Sangiorgi F et al. Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring. Am J Physiol Endocrinol Metab 2007;292:E1270–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Benyshek DC, Johnston CS, Martin JF. Glucose metabolism is altered in the adequately-nourished grand-offspring (F3 generation) of rats malnourished during gestation and perinatal life. Diabetologia 2006;49:1117–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Petrik J, Srinivasan M, Aalinkeel R, Coukell S, Arany E, Patel MS, et al. A long term high carbohydrate diet causes an altered ontogeny of pancreatic islets of Langerhans in the neonatal rat. Pediatr Res 2001;49:84–92.PubMedCrossRefGoogle Scholar
  56. 56.
    Devaskar SU, Raychaudhuri S. Epigenetics—A science of heritable biological adaptation. Pediatr Res 2007;61:1R–4R.PubMedCrossRefGoogle Scholar
  57. 57.
    Chuang JC, Jones PA. Epigenetics and microRNAs. Pediatr Res 2007;61:24R–9R.PubMedCrossRefGoogle Scholar
  58. 58.
    Lillycrop KA, Slater-Jefferies J-L, Hanson MA, Godfrey KM, Jackson AA, Burdge GC. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyl transferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 2007;1–10, doi: 10.1017/S000711450769196X.
  59. 59.
    Burdge GC, Hanson MA, Slater-Jefferies JL, Lillycrop KA. Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr 2007;1–11, doi: 10.1017/S0007114507682920.
  60. 60.
    Fu Q, McKnight RA, Yu X, Callaway CW, Lane RH. Growth retardation alters the epigenetic characteristics of hepatic dual specificity phosphatase 5. FASEB J 2006;20:2127–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Simmons RA. Developmental origins of β-cell failure in type 2 diabetes: the role of epigenetic mechanisms. Pediatr Res 2007;61:64R–7R.PubMedCrossRefGoogle Scholar
  62. 62.
    Yokomori N, Tawata M, Onaya T. DNA demethylation during the differentiation of 3T3-L1 cells affects the expression of the mouse GLUT4 gene. Diabetes 1999;48:685–90.PubMedCrossRefGoogle Scholar
  63. 63.
    Stoffers DA, Desai BM, DeLeon DD, Simmons RA. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes 2003;52:734–40.PubMedCrossRefGoogle Scholar
  64. 64.
    Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A et al. Neonatal leptin treatment reverses developmental programming. Endocrinology 2005;146:4211–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Vickers MH, Ikenasio BA, Breier BH. IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. Endocrinology 2001;142:3964–73.PubMedCrossRefGoogle Scholar
  66. 66.
    Vickers MH, Ikenasio BA, Breier BH. Adult growth hormone treatment reduces hypertension and obesity induced by an adverse prenatal environment. J Endocrinol 2002;175:615–23.PubMedCrossRefGoogle Scholar
  67. 67.
    Jennings BJ, Ozanne SE, Dorling MW, Hales CN. Early growth determines longevity in male rats and may be related to telomere shortening in the kidney. FEBS Lett 1999;448:4–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Samaras TT, Elrick H, Storms LH. Birthweight, rapid growth, cancer and longevity: a review. J Natl Med Assoc 2003;95:1170–83.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Sherin U. Devaskar
    • 1
    • 2
  • Manikkavasagar Thamotharan
    • 1
  1. 1.Division of Neonatology & Developmental Biology and the Neonatal Research Center, Department of PediatricsDavid Geffen School of Medicine UCLALos AngelesUSA
  2. 2.Los AngelesUSA

Personalised recommendations