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

Gao, He (författare)
 
 
ISBN 9789175492421
Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics, 2013
Engelska.
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
Abstract Ämnesord
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  • 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). Adiponectin, a hormone secreted by the adipose cells, has attracted much attention for its insulin-sensitizing and anti-diabetic effects. The overall aim of this thesis was to have a better understanding of the roles of ethnicity, genetic variants and dietary factors in relation to adiponectin and insulin resistance by means of different analytical approaches. In Study I, using path analysis, we examined potential mediators including body fatness, adiponectin levels, and inflammation for the extent they mediate the ethnic differences in insulin resistance among Singaporean Chinese, Malays and Indians. General adiposity explained the difference in insulin resistance between Chinese and Malays, whereas abdominal fat distribution, inflammation, and unexplained factors contributed to excess insulin resistance in Asian Indians as compared with Chinese and Malays. In Study II, we carried out a genome-wide association study to identify genetic variants that influence adiponectin levels in East Asian populations. The top signal from CDH13 explains a substantial part of variation in high-molecular-weight (HMW) adiponectin levels, but its effect on circulating HMW adiponectin levels did not appear to translate into effects on insulin-resistance related metabolic traits, suggesting that compensatory mechanisms exist that lead to greater ‘adiponectin sensitivity’. In Study III, the question whether changes in adiponectin levels causally influence insulin sensitivity was addressed by a Mendelian randomization design in a cohort of Swedish men. Genetically determined adiponectin 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 likely 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 longitudinally 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 differed 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 genetics, 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.

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Gao, He
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Karolinska Institutet

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