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Study Protocol

BACKGROUND AND RATIONALE

GENERAL INTRODUCTION

Type 2 diabetes mellitus and obesity are exploding problems in Singapore coincident with rapid nutritional and socioeconomic transition. Significant ethnic and individual differences in predisposition exist. We aim to examine the causal pathways and developmental contribution to this differential by evaluating the hypothesis that genomic, ethnic, developmental, lifestyle and environmental factors contribute to the variation in phenotype observed in adults with obesity and metabolic syndrome.

Although there are many large studies that examined the effect of ethnicity on the expression of obesity and the metabolic syndrome phenotype, most of these studies usually lack in-depth physiological and epigenomic/genomic studies due to their large sample sizes. We therefore aim to explore such detailed aspects of physiological and epigenomic/genomic profiles on smaller but statistically powered samples, focusing on evaluating body composition, nutritional and metabolic phenotype in relationship to epigenetic/genetic markers and developmental history. This will assist in weighting the importance of developmental and genetic pathways in contributing to individual risk.

The use of clinically well-defined populations allows our specific hypothesis to be tested. We will evaluate body composition, skeletal muscle, nutritional, and metabolic phenotype in situations of over-nutrition (overweight/obesity). The phenotypes will be related to birth weight, ethnicity, and the presence of specific genetic variants associated with obesity. Epigenomic profiles will be compared between groups having a defined range of body mass index with different birth weight and ethnicity to determine the role of epigenetic changes and developmental plasticity in the pathogenesis of any differences observed.

RATIONALE AND JUSTIFICATION FOR THE STUDY

RATIONALE FOR THE STUDY PURPOSE

Background

Developmental processes and genomic factors are important contributors to individual variation in the propensity to develop metabolic disease in an obesogenic environment. While lifestyle factors and the environment contribute strongly to the epidemic of obesity and diabetes, it is now clear that the intricate interactions between the genes, environment and lifestyle ultimately determine the phenotypic expression within any given individual. Epigenetic pathways play an important role in this nexus between genes, environment, and development. These generate further individual variability over that caused by genomic variation alone. Thus an individual’s phenotype and capacity to live healthily in a given nutritional environment is influenced by his/her developmental/epigenomic and genomic profiles. When the limits of this metabolic adaptive capacity are exceeded, insulin resistance and associated problems emerge.10,11 A major way in which environmental influences, acting during windows in development to induce long-lasting functional change is through epigenetic processes5-7 acting on both parentally imprinted8 but particularly on non-imprinted genes.9 

There are particularly cogent arguments that such factors are important in populations in rapid socioeconomic and nutritional transition such as in Singapore, which has a very high incidence of metabolic syndrome and type 2 diabetes. The rising incidence of type 2 diabetes, obesity, and its associated disorders is a global challenge and of real concern in Singapore. Here the prevalence of type 2 diabetes has increased fourfold from 1.9% in 1975 to 8.2% in 2004, making it one of the highest in the developed world. More alarmingly, there is rising incidence of juvenile obesity (12.7% in 2006 compared to 10.2% in 1999) and type 2 diabetes in the adolescence. It is well-documented that there are ethnic variations in the manifestation of the disease. In general, metabolic compromise is seen in South Asians at relatively lower levels of obvious obesity. For example, in terms of visceral adiposity, several epidemiological studies have shown that Asian Indians developed diabetes at lesser degree of obesity when compared to Caucasians. Furthermore, the age of onset for diabetes was much earlier and there was more frequent chronic diabetes complications detected at diagnosis of diabetes. It thus appears that the Asian population might be more enriched genetically for type 2 diabetes.

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