Title: The developmental basis of the metabolic syndrome and diabetes

 

Key words: obesity, CVD, cardiovascular disease, type 2 diabetes, type II, metabolic syndrome, hypertension, insulin resistance, dyslipidaemia, diabetes, genetics, intrauterine, growth factors, monozygotic, dizygotic, twin studies, foetal birth weight, placental failure, maternal undernutrition, famine, low protein intake, low birthweight, hypertensive, low protein diets, glucocorticoid, social, lifestyle issues, elevated BMI, body mass index, overnutrition, malnutrition, protein malnutrition, pregestational, gestational,

 

Date: Sept 2006

 

Category: Specific conditions

 

Nutrimed Module:

 

Type: Article

 

Author: Morgan, G

 

The developmental basis of the metabolic syndrome and diabetes

Increasing levels of obesity over recent years have been associated with rising levels of cardiovascular disease and type 2 diabetes in the developed and developing worlds. The metabolic syndrome, the combination of hypertension, insulin resistance and dyslipidaemia, has been postulated as a prodromal state for established cardiovascular disease and diabetes. Its possible developmental origin is discussed in this review.

 

The developmental theory of the metabolic syndrome and type 2 diabetes has been well documented (Barker 2004, Gluckman 2004). Numerous epidemiological and cross-sectional studies have confirmed an association between low birth weight and these conditions. The contribution of genetic and intrauterine growth factors has been analysed in many studies. Monozygotic and dizygotic twin studies have concluded that intrauterine growth factors have a greater bearing on foetal birth weight than genetic factors per se (B0 2000, Johannson 2001). Intrauterine growth retardation may be due to placental failure or maternal undernutrition. Experiments with rats have shown that low protein intake during pregnancy leads to low birth weight offspring who subsequently go on to become hypertensive (Langley 1994, Kwong 2000).

 

Data from the Dutch famine showed a similar pattern of foetal underdevelopment, more marked with undernutrition during the middle and late trimesters of gestation (Ravelli 1998). Greater degrees of insulin resistance and impaired glucose tolerance were observed in children born under such conditions (Ravelli 1998). Thin babies born to underweight mothers carried the worst prognosis. Low protein diets in humans have been associated with reduced pancreatic insulin production (James 2002), and have led some workers to attribute the late development of the metabolic syndrome and type 2 diabetes in low birth weight babies to dysfunctional insulin production in early life – the ‘foetal insulin hypothesis’ (Hattersley 1999). Others have postulated dysregulation of the hypothalamic-pituitary- adrenal axis resulting from dysfunction of insulin and glucocorticoid production during intrauterine and early postnatal life as being responsible for these later metabolic changes (Phillips 2001, James 2002, Ward 2004).

 

Though low birth weight has been stated to be independent of prematurity and confounding factors as a predictor of later diabetes and the metabolic syndrome (Byrne 2000, Barker 2004), the difficulty of carrying out properly controlled longitudinal studies makes it difficult to establish such causal relationships. A recent extensive review of 55 studies (Huxley 2002) looking at the effect of low birth weight on later hypertension found that, in the larger studies, the reduction in systolic blood pressure of 2-4 mm Hg/Kg with increasing birth weight was reduced to around 0.4 mm Hg/Kg when bias and confounding factors was taken into account. This modest association would appear to be overshadowed by the much closer association between adult obesity, the metabolic syndrome and type 2 diabetes, suggesting that social and lifestyle issues have a greater impact on the evolution of these disorders than genetic or intrauterine factors. This is born out by the frequent observation that the metabolic syndrome is a frequent accompaniment to low birth weight and a relatively rapid weight increase occurring after the age of 7 years (Eriksson 2000, Barker 2002, Zhao 2002).

 

Associations have also been made between mothers with an elevated BMI, gestational diabetes mellitus, and the development of obesity and the metabolic syndrome in the offspring (Forsen 2000, James 2002), reinforcing the argument that poorer socio-economic status can lead to the evolution of the metabolic syndrome in both low and high birth weight babies (Williams 1999, Eriksson 2003, Burke 2004). This would tend to reflect the pattern observed in many underdeveloped countries, characterized by relative undernutrition up to the age of 3 years followed by overnutrition and an increased growth spurt from the age of 7 years (Branca 2002, Prentice 2005).

 

In summary, the evidence from animal experiments and the Dutch famine indicate that malnutrition, particularly protein malnutrition, has a deleterious effect on placental and intrauterine foetal development. In humans, the effect on birth weight and the later development of the metabolic syndrome and type 2 diabetes appears small. Against this, socio-economic factors, known to be closely linked to both obesity and the metabolic syndrome, appear to be more determinant, both in the mother, and in their children beyond the age of 7 years. Failure to address these dietary issues during the pregestational, gestational and childhood periods, it is hypothesized, have led to an unnecessary biasing of the results of studies, with the conclusion that low birth weight and the metabolic syndrome are developmentally preprogrammed and not susceptible to dietary interventions. This raises important questions for public health care both in the developed and underdeveloped world that need to be addressed. 

 

 

References

1. Barker DJ (2004) The developmental origins of well-being. Philosoph Transact Royal Soc London – Series B: Biological Sciences 359:  1359-66

2. Gluckman PD, Hanson MA (2004) The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 15: 183-7

3. Bo S, Cavallo-Perin P, Scaglione L, Ciccone G, Pagano G (2000) Low birthweight and metabolic abnormalities in twins with increased susceptibility to Type 2 diabetes mellitus. Diabetic Medicine 17: 365-70

4. Johannson M, Rasmussen E (2001) Birthweight and body mass index inyoung adulthood: the Swedish young male twins study. Twin Research 4: 400-5

5. Langley SC, Jackson AA (1994) Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets.Clinical Science 86: 217-22

6. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP (2000) Maternal undernutrition during the preimplantation period of rat  development causes blastocyst abnormalities and programming of postnatal hypertension.

7. Ravelli AC, et al. (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351: 173-7

8. James WP (2002) Will feeding mothers prevent the Asian metabolic syndrome epidemic? Asia Pacific J Clin Nutr 11: S516-23 9. Hattersley AT, Toole JE (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353: 1789-92

10. Phillips DI (2001) Fetal growth and programming of the hypothalamic-pituitary-adrenal axis. Clin Experiment Pharmacol Physiol 28:  967-70

11. Ward AM, et al. (2004) Size at birth and cardiovascular responses to psychological stressors: evidence for prenatal programming in women. J Hypertension 22: 2295-301

12. Byrne CD, Phillips DI (2000) Fetal origins of adult disease: epidemiology and mechanisms. J Clin Pathol 53: 822-8

13. Huxley R, Neil A, Collins R (2002) unraveling the fetal origins hypothesis: is there really an inverse association between birth-weight and subsequent blood pressure? Lancet 360: 659-65

14. Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker D (2000) Fetal and childhood growth and hypertension in adult life. Hypertension 36: 790-4

15. Barker DJ, Forsen T, Eriksson JG, Osmond C (2002) Growth and living conditions in childhood and hypertension in adult life: a longitudinal study. J Hypertension 20: 1951-6

16. Zhao M, et al. (2002) Birthweight, childhood growth and hypertension in adulthood. Int J Epidemiol 31: 1043-51

17. Forsen T, et al. (2000) The fetal and childhood growth of persons who develop type 2 diabetes. Ann Int Med 133: 176-82

18. Williams MA, Emanuel I, Kimpo C, Leisenring WM, Hale CB (1999) A population-based cohort study of the relation between maternal birthweight and risk of gestational diabetes mellitus in four racial/ethnic groups. Paed Perinatal Epidemiol 13: 452-65

19. Eriksson JG, Forsen TJ, Osmond C, Barker DJ (2003) Pathways of infant and childhood growth that lead to type 2 diabetes. Diabetes Care 26: 3006-10

20. Burke V, et al. (2004) Indicators of fetal growth do not independently predict blood pressure in 8-year-old Australians: a prospective cohort study. Hypertension 43: 208-13

21. Branca F, Ferrari M (2002) Impact of micronutrient deficiencies on growth: the stunting syndrome. Ann Nutr Metab 46: 8-17

22. Prentice AM, Moore SE (2005) Early programming of adult disease in resource poor countries. Arch Dis Childhood 90: 429-32