title: Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.
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.
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Tove
authors.initials: T
authors.lastname: Fall
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
authors.forename: Dorota
authors.initials: D
authors.lastname: Pasko
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Barker
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sharp
authors.affiliation: Public Health Division of Gipuzkoa, San Sebastian, Spain.|Instituto BIO-Donostia, Basque Government, San Sebastian, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors.forename: Larraitz
authors.initials: L
authors.lastname: Arriola
authors.affiliation: Inserm, CESP, U1018, Villejuif, France.|Univ Paris-Sud, UMRS 1018, Villejuif, France.
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.affiliation: Navarre Public Health Institute (ISPN), Pamplona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Barricarte
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.|University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.affiliation: Inserm, CESP, U1018, Villejuif, France.|Univ Paris-Sud, UMRS 1018, Villejuif, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.affiliation: University of Oxford, United Kingdom.
authors.forename: Francesca L
authors.initials: FL
authors.lastname: Crowe
authors.affiliation: Department of Epidemiology and Biostatistics, VrijeUniversiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.affiliation: Inserm, CESP, U1018, Villejuif, France.|Univ Paris-Sud, UMRS 1018, Villejuif, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Fagherazzi
authors.affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nita G
authors.initials: NG
authors.lastname: Forouhi
authors.affiliation: Lund University, Malmö, Sweden.|Umeå University, Umeå, Sweden.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Gavrila
authors.affiliation: Department of Public Health and Caring Sciences, Geriatrics, Uppsala University Sweden.
authors.forename: Vilmantas
authors.initials: V
authors.lastname: Giedraitis
authors.affiliation: Epidemiology and Prevention Unit, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Grioni
authors.affiliation: University Hospital Scania, Malmö, Sweden.|Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Leif C
authors.initials: LC
authors.lastname: Groop
authors.affiliation: German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.affiliation: University of Oxford, United Kingdom.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Key
authors.affiliation: German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Kühn
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Luca A
authors.initials: LA
authors.lastname: Lotta
authors.affiliation: Lund University, Malmö, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Nilsson
authors.affiliation: Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.|Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.affiliation: Cancer Research and Prevention Institute (ISPO), Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.affiliation: Public Health Directorate, Asturias, Spain.
authors.forename: J Ramón
authors.initials: JR
authors.lastname: Quirós
authors.affiliation: Umeå University, Umeå, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Rolandsson
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Roswall
authors.affiliation: Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, Italy.|Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.affiliation: Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Sala
authors.affiliation: Andalusian School of Public Health, Granada, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Spain.|Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada (Spain).
authors.forename: María-José
authors.initials: MJ
authors.lastname: Sánchez
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Schulze
authors.affiliation: School of Public Health, Imperial College London, UK.
authors.forename: Afshan
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Slimani
authors.affiliation: University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Sluijs
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Annemieke Mw
authors.initials: AM
authors.lastname: Spijkerman
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Tjonneland
authors.affiliation: ASP Ragusa, Italy.|Aire Onlus, Ragusa, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Daphne L
authors.initials: DL
authors.lastname: van der A
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Oxford NIHR Biomedical Research Centre, Oxford, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.affiliation: School of Public Health, Imperial College London, UK.
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D001823:Body Composition / Q000235:genetics*; D050218:Body Fat Distribution; D015992:Body Mass Index; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D050177:Overweight / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D055105:Waist Circumference / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D007328:Insulin; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase