Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity.
Author
Summary, in English
We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-based measures of insulin resistance and secretion, and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs-per-allele [95%CI]:-0.03[-0.04,-0.01];p=0.004). This score was associated with lower BMI (-0.01[-0.01,-0.0;p=0.02) and gluteofemoral fat-mass : -0.03[-0.05,-0.02;p=1.4x10(-6)), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (0.02[0.01,0.03];p=0.001). While the secretion score had a stronger association with T2D in leaner individuals (pinteraction=0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI- or waist-strata(pinteraction>0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
Department/s
Publishing year
2014
Language
English
Pages
4378-4387
Publication/Series
Diabetes
Volume
63
Issue
12
Links
Document type
Journal article
Publisher
American Diabetes Association Inc.
Topic
- Endocrinology and Diabetes
Status
Published
Research group
- Genomics, Diabetes and Endocrinology
- Genetic and Molecular Epidemiology
- Internal Medicine - Epidemiology
ISBN/ISSN/Other
- ISSN: 1939-327X