Format

Send to

Choose Destination
Diabetes. 2014 Dec;63(12):4378-4387. doi: 10.2337/db14-0319. Epub 2014 Jun 19.

Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.

Author information

1
MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
2
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
3
Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
4
Public Health Division of Gipuzkoa, San Sebastian, Spain.
5
Instituto BIO-Donostia, Basque Government, San Sebastian, Spain.
6
CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
7
Inserm, CESP, U1018, Villejuif, France.
8
Univ Paris-Sud, UMRS 1018, Villejuif, France.
9
Navarre Public Health Institute (ISPN), Pamplona, Spain.
10
The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
11
University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
12
German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
13
University of Oxford, United Kingdom.
14
Department of Epidemiology and Biostatistics, VrijeUniversiteit Medical Center, Amsterdam, The Netherlands.
15
Department of Internal Medicine, University of Pisa, Pisa, Italy.
16
Lund University, Malmö, Sweden.
17
Umeå University, Umeå, Sweden.
18
Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain.
19
Department of Public Health and Caring Sciences, Geriatrics, Uppsala University Sweden.
20
Epidemiology and Prevention Unit, Milan, Italy.
21
University Hospital Scania, Malmö, Sweden.
22
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
23
German Cancer Research Centre (DKFZ), Heidelberg, Germany.
24
Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
25
Aalborg University Hospital, Aalborg, Denmark.
26
Cancer Research and Prevention Institute (ISPO), Florence, Italy.
27
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
28
Public Health Directorate, Asturias, Spain.
29
Danish Cancer Society Research Center, Copenhagen, Denmark.
30
Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, Italy.
31
Human Genetics Foundation (HuGeF), Torino, Italy.
32
Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
33
Andalusian School of Public Health, Granada, Spain.
34
Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada (Spain).
35
School of Public Health, Imperial College London, UK.
36
International Agency for Research on Cancer, Lyon, France.
37
University Medical Center Utrecht, Utrecht, the Netherlands.
38
National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
39
ASP Ragusa, Italy.
40
Aire Onlus, Ragusa, Italy.
41
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, UK.
42
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
43
Oxford NIHR Biomedical Research Centre, Oxford, UK.
44
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
#
Contributed equally

Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-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 = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (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.

PMID:
24947364
PMCID:
PMC4241116
DOI:
10.2337/db14-0319
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Loading ...
Support Center