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. 




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