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

thesis
posted on 2024-09-03, 01:46 authored by He Gao

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.

List of scientific papers

I. Gao H, Salim A, Lee J, Tai ES, van Dam RM. Can body fat distribution, adiponectin levels and inflammation explain differences in insulin resistance between ethnic Chinese, Malays and Asian Indians? International journal of obesity. 2012; 36:1086-93.
https://doi.org/10.1038/ijo.2011.185

II. Gao H, Kim YM, Chen P, Igase M, Kawamoto R, Kim MK, Kohara K, Lee J, Miki T, Ong TH, Onuma H, Osawa H, Sim X, Teo YY, Tabara Y, Tai ES, van Dam RM. Genetic variation in CDH13 is associated with lower plasma adiponectin levels, but greater adiponectin sensitivity in East Asian populations. [Accepted]
https://doi.org/10.2337/db13-0129

III. Gao H, Fall T, van Dam RM, Flyvbjerg A, Zethelius B, Ingelsson E, Hägg S. Evidence of a causal relationship between adiponectin levels and insulin sensitivity: a mendelian randomization study. Diabetes. 2013; 62:1338-44.
https://doi.org/10.2337/db12-0935

IV. Gao H, Hägg S, Sjögren P, Lambert P, Ingelsson E, van Dam RM. Serum selenium in relation to measures of glucose metabolism and incidence of type 2 diabetes in an older Swedish population. [Submitted]

History

Defence date

2013-09-17

Department

  • Department of Medical Epidemiology and Biostatistics

Publisher/Institution

Karolinska Institutet

Main supervisor

van Dam, Rob

Publication year

2013

Thesis type

  • Doctoral thesis

ISBN

978-91-7549-242-1

Number of supporting papers

4

Language

  • eng

Original publication date

2013-08-30

Author name in thesis

Gao, He

Original department name

Department of Medical Epidemiology and Biostatistics

Place of publication

Stockholm

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