On the origin of obesity and type 2 diabetes

Abstract

The incidence of type 2 diabetes (T2D) is rising rapidly worldwide and there are already more than 180 million diabetic subjects. T2D risk factors include ethnic background, age, hypertension, overweight, increased abdominal fat, and lack of physical exercise. Obesity is considered to be the most important risk factor for T2D and the main one driving the current epidemic as 90% of T2D patients are obese. Worldwide obesity has also reached epidemic proportions, with 300 million adults classified as clinically obese. T2D and obesity are multifactorial disorders in which both genetic and non-genetic (environmental and lifestyle) factors play a role. The past years has witnessed substantial advances in understanding the genetic basis of obesity and T2D. To date, 17 common obesity loci and 18 common T2D loci have been identified. However, only around 10% of the genetic risk for these traits can be explained. Therefore, many more risk loci for obesity and T2D still need to be discovered. The high prevalence of T2D in many human populations poses a further evolutionary question: Why is the disease so common, when it should disappear as those genetically susceptible to it are removed by natural selection? In the present thesis we focus on (I) evaluating alternative methods to find candidate genes for T2D and obesity, (II) studying genetic and environmental risk factors for T2D and obesity, and (III) studying the origin of the high prevalence of T2D and obesity in modern societies. Both obesity and T2D are complex genetic traits but they share some non-genetic risk factors. In the introduction, chapter 2, we describe the genes recently identified for T2D and obesity by genome-wide association studies (GWAS) and evaluate their functions in an effort to determine whether there is any support for the hypothesis that T2D and obesity share some underlying mechanism(s). In the first, methodological, part of the thesis (part I), we use an alternative strategy to find candidate genes for obesity and T2D and explore alternative methods for the investigation of GWAS data to obtain valuable information on the biology and evolutionary origin of T2D. In chapter 3 we combine six tools for disease gene identification to analyse the overlapping T2D and obesity susceptibility loci to pinpoint shared candidate genes for T2D and obesity. In this study, we evaluated alternative methods to study GWAS data. Instead of focusing on the single nucleotide polymorphisms (SNPs) with the highest statistical significance, we took advantage of prior biological information and tried to detect overrepresented pathways in the GWAS data in chapter 4. We evaluated whether pathway classification analysis can help prioritize the biological pathways most likely to be involved in the disease etiology. Part II of the thesis reports on studies investigating genetic and environmental risk factors for T2D and obesity. In chapter 5 we investigated the role of variants in NPY1R, NPY2R and NPY5R genes, involved in the hypothalamic pathway, in total and nutrient-specific energy intake. In chapter 6, we investigate whether we can replicate the recently reported associations of the susceptibility loci with different obesity related phenotypes and explored the effect of variation in the currently implicated obesity genes affects on dietary energy and macronutrient intake. In chapter 7, we assessed the association between both parity and age at first full-term pregnancy with the risk of T2D in women. The studies, described in part III, aim to investigate the evolutionary explanation of obesity and T2D. In chapter 8 we tested a theory on the evolutionary origin of obesity and T2D, the thrifty gene hypothesis, by investigating whether recently identified T2D and obesity risk alleles have been under recent positive selection. In chapter 9 we investigate whether sub- or infertility predicts later-in-life T2D risk. To investigate body weight from a historical perspective, we studied weight distribution in an 18th century criminal gang (chapter 10). Chapter 11 provides a general discussion on the origin of obesity and T2D.