Genetic predisposition and dietary factors in relation to adiponectin and insulin resistance

Abstract: Diabetes mellitus is a global health problem, owing to the high prevalence and enormous associated economic burden. Insulin resistance is a critical condition to the development of type 2 diabetes (T2D). Adip onectin, a hormone secreted by the adipose cells, has attracted much atten tion for its insulin-sensitizing and anti-diabetic effects. The overall aim of this thesis was to ha ve a better understanding of the roles of ethnicity, genetic variants and dietary fact ors in relation to adiponectin and insulin resistance by means of different analytical approaches. In Study I, using path analysis, we ex amined potential mediators including body fatness, adiponectin levels, and inflammatio n for the extent they mediate the ethnic differences in insulin resistance among Si ngaporean Chinese, Malays and Indians. General adiposity explained the difference in insulin resistance between Chinese and Malays, whereas abdominal fat distributi on, inflammation, an d unexplained factors contributed to excess insulin resistance in As ian Indians as compar ed with Chinese and Malays. In Study II, we carried out a genome-wide asso ciation study to identify genetic variants that influence adiponectin levels in East Asian populations. The top signal from CDH13 explains a substantial part of va riation in high-molecular-weight (HMW) adiponectin levels, but its effect on circul ating HMW adiponectin levels did not appear to translate into effects on insulin-resistan ce related metabolic traits, suggesting that compensatory mechanisms ex ist that lead to greater ‘adiponectin sensitivity’. In Study III, the ques tion whether changes in adiponec tin levels causally influence insulin sensitivity was addressed by a Mende lian randomization design in a cohort of Swedish men. Genetically determined adipon ectin levels influence euglycemic clamp- measured insulin sensitivity to the same degree as the observed epidemiological associations. Thus, the observed association between higher adiponectin levels and increased insulin sensitivity is likel y to represent a causal relationship. In Study IV, we examined relations between serum selenium levels and measures of glucose and insulin metabolism, as well as risk of T2D lo ngitudinally in Swedish men. There was no clear evidence of an effect of selenium status on various measures of insulin sensitivity or β -cell function. Selenium levels were also not associated with risk of T2D. These results do not support a role for selenium supplementation as a broad approach for the prevention of T2D. In conclusion, mediators of ethnic differences in insulin resistance di ffered markedly in the Singaporean populations. In East Asians, CDH13 strongly influences adiponectin levels and associates with a beneficial metabolic profile when controlling for circulating adiponectin. Inferred from ge netics, the positive relationship between adiponectin and insulin sensitivity appears to be causal. There is no evidence of an effect of selenium intake on glucose and insulin metabolism or risk of T2D in the Swedish population.