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

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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.


  • Robert A Scott
  • Tove Fall
  • Dorota Pasko
  • Adam Barker
  • Stephen J Sharp
  • Larraitz Arriola
  • Beverley Balkau
  • Aurelio Barricarte
  • Inês Barroso
  • Heiner Boeing
  • Françoise Clavel-Chapelon
  • Francesca L Crowe
  • Jacqueline M Dekker
  • Guy Fagherazzi
  • Ele Ferraninini
  • Nita G Forouhi
  • Diana Gavrila
  • Vilmantas Giedraitis
  • Sara Grioni
  • Rudolf Kaaks
  • Timothy J Key
  • Tilman Kühn
  • Luca Lotta
  • Kim Overvad
  • Domenico Palli
  • Salvatore Panico
  • J Ramón Quirós
  • Olov Rolandsson
  • Nina Roswall
  • Carlotta Sacerdote
  • Núria Sala
  • María-José Sánchez
  • Matthias B Schulze
  • Afshan Siddiq
  • Nadia Slimani
  • Ivonne Sluijs
  • Annemieke Mw Spijkerman
  • Anne Tjonneland
  • Rosario Tumino
  • Daphne L van der A
  • Hanieh Yaghootkar
  • Mark I McCarthy
  • Robert K Semple
  • Elio Riboli
  • Mark Walker
  • Erik Ingelsson
  • Tim M Frayling
  • David B Savage
  • Claudia Langenberg
  • Nicholas J Wareham
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)4378-4387
Issue number12
Publication statusPublished - 2014
Publication categoryResearch