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Table of Contents
EDITORIAL
Year : 2012  |  Volume : 16  |  Issue : 4  |  Page : 493-495

Developmental origins of adult metabolic disease: The Indian scenario, driving toward a unified hypothesis


1 Rolf Luft Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India
2 Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India

Date of Web Publication5-Jul-2012

Correspondence Address:
Nihal Thomas
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore - 632004. India

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-8210.97990

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How to cite this article:
Vasan SK, Thomas N. Developmental origins of adult metabolic disease: The Indian scenario, driving toward a unified hypothesis. Indian J Endocr Metab 2012;16:493-5

How to cite this URL:
Vasan SK, Thomas N. Developmental origins of adult metabolic disease: The Indian scenario, driving toward a unified hypothesis. Indian J Endocr Metab [serial online] 2012 [cited 2019 Feb 20];16:493-5. Available from: http://www.ijem.in/text.asp?2012/16/4/493/97990

In 1961, Neel et al. proposed that an individual's adaptation to the environment is dependent on genes selected over a long period of time ("thrifty-genotype"), i.e., those genes that once favored survival in the presence of adverse environmental conditions, evolved into a status of being detrimental in circumstances of sustained energy surplus. [1] This theory was subsequently challenged by Hales and Barker, who proposed that suboptimal fetal nutrition at critical points of time in intrauterine development may cause permanent alterations in fetal structure, function, and metabolism due to skewed programming ("thrifty phenotype"/"fetal origins"). [2] These theories are not mutually exclusive, but may complement one another, since the consequences of both theories are similar: adults are well adapted to an environment that is nutritionally limited, but are more likely to become unhealthy in a nutritionally rich environment. The fetal insulin hypothesis (FIH) proposed by Hattersley and Tooke states that genetic variants associated with insulin resistance may lead to impaired insulin-mediated growth prenatally, leading to low birth weight and adverse metabolic outcomes in adulthood. [3] Epidemiological studies have provided sufficient evidence in favor of the fetal origins of adult disease, and in almost all studies, "low birth weight" is used as a surrogate marker of fetal nutritional status.


   Do These Theories Apply to Indians? Top


It becomes increasingly interesting to explore the possibility as to whether these theories could provide sufficient explanation for the increasing prevalence of chronic noncommunicable diseases (NCDs) in India, for three exclusive reasons. Firstly, Indian babies weigh the least in the world. An average Indian baby weighs about 800 g less, and is leaner, compared to a European new born. [4] Secondly, maternal malnutrition is a perennial problem, despite several efforts to improve maternal health, particularly in rural India. Thirdly, the Indian "thin-fat" phenotype is typically characterized by lower lean body mass and a higher quantum of subcutaneous fat, and is associated with an increased risk for cardio-metabolic disease at any given body mass index (BMI), compared to Caucasians. [5]


   Genes and Birth Weight Top


The most obvious phenotypic expression of the "thrifty genotype" is its association with adult onset obesity, glucose intolerance and essential hypertension. According to the "thrifty genotype" the emerging epidemic of type 2 diabetes and obesity are phenotypic consequences of genetic variants that have undergone positive selection during periods of famine/food inadequacy. Earliest evidence of this was from the Dutch famine study where an increased risk of obesity was observed in low birth weight babies born to mothers exposed to the famine. [6] Subsequent studies have supported the concept of an evolutionary enrichment of thrifty genes, independent of the role of programming by maternal nutrition. Several genes have already been identified as candidates for the thrifty genotype, and include variants associated with insulin signaling and leptin-related pathways, as well as intermediary fat metabolism, but the evidence for these in humans are scanty.

If the thrifty genotype hypothesis cannot be refuted, theoretically the genes that helped survival of a low birth weight baby exposed to an unfavorable in utero environment should be associated adult-onset disease. Recent genome-wide association studies have explored the genetic variants that modulate birth weight and have identified variants in the ADCY5 and CCNL1 locus to be robustly associated with low birth weight in Europeans. [7] The GWAS also showed that the association with ponderal index was particularly strong for the near CCNL1 variants (0.094 SD [95%CI: 0.074--0.113] per risk allele), suggesting a greater association of these variants with fat mass than with skeletal growth at birth, while no association was found with adult BMI or other obesity related traits in adulthood. We were unable to replicate this genetic association with birth weight and adult obesity traits in a longitudinal cohort of South Indians followed from birth until 30 years of age. [8] Although lower statistical power could be one possible reason for non-replication of genetic association, we strongly argue that this could also be attributed to strong environmental influences that predominate over genetic effects. Interestingly, the birth weight-lowering variants in both Europeans (ADCY5, CDKALI) and Indians (ADCY5) have displayed significant associations with impaired glucose-insulin homeostasis in adulthood, reinforcing the genetic link between in utero growth, birth weight, and adult type 2 diabetes mellitus (T2DM). Evidence from genetic association studies, evaluating cardiovascular disease (CVD) risk and birth weight is another example. Contrary to the Spanish AVENA study, where variants in the APOE, APOC3, and PPAR-γ off-springs that are characterized loci were shown to influence weight at birth and elevated lipids during adulthood, [9] the New Delhi birth cohort, failed to demonstrate any interaction between the PPAR-γ and APOA5 variants and birth weight or longitudinal anthropometry, although they were associated with altered lipids in adulthood. [10] Reasons for replication failure should be acknowledged. Both the above studies among Indians raise an important question: Why do genetic variants fail to influence both ends of the spectrum - the birth weight and adult metabolic phenotype especially in Indians, unlike the Western population? We may speculate that there could be other genetic variants that possibly influence birth weight in Indians, and that upstream or downstream exons and mutations may be responsible for this "negating" effect. It is also possible that alterations in the metabolic capacity in adulthood may be due to epigenetic effects in fetal life and early infancy having life-long impact on DNA expression. The current genetic epidemiological research has provided some evidence in favor of the "thrifty genotype" hypothesis, but a highly heterogeneous nature of genetic susceptibility to complex diseases makes it difficult to speculate the true effect of the thrifty genes. However, it is quite evident that the metabolically thrifty genes (that cause insulin resistance and obesity in adulthood) adapted to powerful selective pressure and once provided survival advantage in the early periods have now become detrimental when exposed to an obesogenic environment.


   The 'Thrifty Phenotype' in Indians Top


Fetal undernutrition as a consequence of poor maternal nutrition results in permanent endocrine and metabolic adaptations that increase cardio-metabolic disease risk in adulthood. Animal models of maternal food restriction give birth to off-springs that are characterized by β-cell dysfunction and insulin resistance.[11] Epidemiological studies by Barker et al. have shown an inverse relationship between birth weight and adult CVD and T2DM in a UK population. [12] Amongst Indians birth weight is shown to be associated with adult T2DM phenotype (characterized by abnormal fat distribution, hyperinsulinemia, and insulin resistance). The Pune Maternal nutrition study, [13] the Mysore study [14] and results from the Vellore birth cohort, [15] have provided a wealth of information favoring this association. Studies have also shown an association between maternal nutrition, body composition at pregnancy, and later disease in offspring independent of birth weight. Joglekar et al.[16] was able to replicate similar inverse association between birth weight and cardio-metabolic risk factors such as unfavorable body fat distribution, insulin resistance, impaired glucose tolerance, and elevated blood pressure in young rural Indians similar to Europeans. These findings were further strengthened by Thomas et al. who showed using hyperinsulinemic euglycaemic "clamps," assessment of bone composition with Dual energy absorptiometry and energy expenditure with indirect caloriemetry that this effect was tempered when the environmental influences are less (i.e., is in fact more rural) [17] In this situation, it was found that low birth weight was associated with an elevated diastolic blood pressure, increased body fat content and low bone mineral content at the age of 20 years but was not associated with a decline in insulin sensitivity. A similar association with adult disease risk was also observed in urban Indians. [18] These studies provide robust clues to the existence of the "thrifty phenotype" in Indians. But, what is additionally interesting is if this provides sufficient explanation to the current diabetes/obesity epidemic in India. If the "thrifty phenotype" proves to be the case, the prevalence of NCDs should be higher in rural populations where low birth weight and maternal malnutrition appears to be a common phenomenon, and urban India should face relatively lower prevalence rates. However this appears not to be so. Quite explicably, the ICMR-INDIAB study reports that the prevalence of diabetes is higher in urban compared to rural India at any age interval. [19] Yajnik et al. provides a valid argument that besides in utero and maternal undernutrition, postnatal environmental cues play a significant role in the fetal origins of adult disease, and interactions between all of these factors could be more detrimental than the effect of either alone. This appears logical, since individuals born in urban communities are postnatally exposed to an obesogenic environment wherein accessibility to food is straightforward and physical activity is limited. It is now clear that the maternal phenotype influence fetal weight at birth, and in an environment where food availability is in excess, a predisposition to variability in the metabolic load exists which accounts for adverse health outcomes in adulthood.

Our understanding of the fetal origins theory among Indians has improved substantially. We conclude that both the thrifty genotype and phenotype do exist among Indians, and appear to play overlapping roles in the development of complex adult disease. The postnatal environmental is also an important factor that influences adult disease. The underlying mechanisms of this complex interaction still remain elusive. It is tempting to speculate that relatively stable epigenetic changes might explain some of these effects. However, to date, such changes, which may very well be tissue specific, have not been identified, and so remains a challenge. The current initiative that is considered toward building a consortium of the existing birth cohorts from India is promising, and optimistically may offer more opportunities to validate the fetal origins hypothesis in Indians and particularly with respect to potential gene--environment interactions and epigenetic mechanisms.

 
   References Top

1.Neel JV. Diabetes mellitus: A "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet 1962;14:353-62.  Back to cited text no. 1
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2.Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5-20.  Back to cited text no. 2
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3.Hattersley AT, Tooke JE. The fetal insulin hypothesis: An alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999;22:353:1789-92.  Back to cited text no. 3
    
4.Leary S, Fall C, Osmond C, Lovel H, Campbell D, Eriksson J, et al. Geographical variation in neonatal phenotype. Acta Obstet Gynecol Scand 2006;85:1080-9.  Back to cited text no. 4
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5.Misra A, Khurana L. Obesity-related non-communicable diseases: South Asians vs White Caucasians. Int J Obes (Lond) 2011;35:167- 87.  Back to cited text no. 5
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6.Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, et al. Coronary heart disease after prenatal exposure to the Dutch famine, 1944-1945. Heart 2000;84:595-8.  Back to cited text no. 6
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7.Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 2010;42:430-5.  Back to cited text no. 7
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8.Vasan SK, Neville MJ, Antonisamy B, Samuel P, Fall CH, Geethanjali FS, et al. Absence of birth-weight lowering effect of ADCY5 and near CCNL, but association of impaired glucose-insulin homeostasis with ADCY5 in Asian Indians. PLoS One 2011;6:e21331.  Back to cited text no. 8
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9.Ruiz JR, Labayen I, Ortega FB, Moreno LA, Gonzalez-Lamuno D, Marti A, et al. Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPARgamma2 gene polymorphisms. The AVENA Study. BMC Med Genet 2008;10:9:98.  Back to cited text no. 9
    
10.Ramakrishnan L, Sachdev HS, Sharma M, Abraham R, Prakash S, Gupta D, et al. Relationship of APOA5, PPARγ, and HL gene variants with serial changes in childhood body mass index and coronary artery disease risk factors in young adulthood. Lipids Health Dis 2011;10:68.  Back to cited text no. 10
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11.Martin-Gronert MS, Ozanne SE. Experimental IUGR and later diabetes. J Intern Med 2007;261:437-52.  Back to cited text no. 11
    
12.Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;10:1:1077-81.  Back to cited text no. 12
    
13.Yajnik CS, Fall CH, Coyaji KJ, Hirve SS, Rao S, Barker DJ, et al. Neonatal anthropometry: The thin-fat Indian baby. The Pune Maternal Nutrition Study. Int J Obes Relat Metab Disord 2003;27:173-80.  Back to cited text no. 13
    
14.Fall CH, Stein CE, Kumaran K, Cox V, Osmond C, Barker DJ, et al. Size at birth, maternal weight, and type 2 diabetes in South India. Diabet Med 1998;15:220-7.  Back to cited text no. 14
    
15.Antonisamy B, Raghupathy P, Christopher S, Richard J, Rao PS, Barker DJ, et al. Cohort Profile: The 1969-73 Vellore birth cohort study in South India. Int J Epidemiol 2009;38:663-9.  Back to cited text no. 15
    
16.Joglekar AA, Rolls S, Hirve S, Shelgikar KM, Joglekar CV, Yajnik CS. Glucose tolerance in elderly (>40 yrs) in rural India. Diabetologia 1997;Suppl 1:Abstract 190.   Back to cited text no. 16
    
17.Thomas N, Grunnet LG, Poulsen P, Christopher S, Spurgeon R, Inbakumari M, et al. Born with low birth weight in rural Southern India: What are the metabolic consequences 20 years later? Eur J Endocrinol 2012;166:647-55.  Back to cited text no. 17
    
18.Raghupathy P, Antonisamy B, Geethanjali FS, Saperia J, Leary SD, Priya G, et al. Glucose tolerance, insulin resistance and insulin secretion in young south Indian adults: Relationships to parental size, neonatal size and childhood body mass index. Diabetes Res Clin Pract 2010;87:283-92.  Back to cited text no. 18
    
19.Anjana RM, Pradeepa R, Deepa M, Datta M, Sudha V, Unnikrishnan R, et al. Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: Phase I results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study. Diabetologia 2011;54:3022-7.  Back to cited text no. 19
    




 

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