Genetic variation in the glucose-dependent insulinotropic polypeptide receptor modifies the association between carbohydrate and fat intake and risk of type 2 diabetes in the Malmo Diet and Cancer cohort

J Clin Endocrinol Metab. 2012 May;97(5):E810-8. doi: 10.1210/jc.2011-2444. Epub 2012 Mar 7.


Context: A common genetic variant (rs10423928, A-allele) in the glucose-dependent insulinotropic polypeptide receptor gene (GIPR) is associated with decreased insulin secretion. Glucose-dependent insulinotropic polypeptide is secreted after food consumption and gipr knockout mice fed a high-fat diet are protected against obesity and disturbances in glucose homeostasis.

Objective: Our objective was to examine the interactions between rs10423928 and macronutrients and fiber intakes on body mass index and type 2 diabetes risk.

Design, setting, and participants: Among nondiabetic subjects in the Swedish population-based Malmö Diet and Cancer cohort (n = 24,840; 45-74 yr), 1541 diabetes cases were identified during 12 yr of follow-up. Dietary intakes were assessed using a diet history method.

Main outcome measure: Incident type 2 diabetes was identified through registers.

Results: There was no indication that dietary intakes significantly modify the association between GIPR genotype and body mass index (P interaction >0.08). We observed significant interactions between GIPR genotype and quintiles of carbohydrate (P = 0.0005) and fat intake (P = 0.0006) on incident type 2 diabetes. The TT-genotype carriers within the highest compared with the lowest carbohydrate quintile were at 23% (95% confidence interval = 5-39%) decreased type 2 diabetes risk. In contrast, AA-genotype carriers in the highest compared with the lowest fat quintile were at 69% (95% confidence interval = 29-86%) decreased risk.

Conclusions: Our prospective, observational study indicates that the type 2 diabetes risk by dietary intake of carbohydrate and fat may be dependent on GIPR genotype. In line with results in gipr knockout mice, AA-genotype carriers consuming high-fat low-carbohydrate diets had reduced type 2 diabetes risk, whereas high-carbohydrate low-fat diets benefitted the two thirds of population homozygous for the T-allele.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Body Composition / genetics
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / epidemiology*
  • Diabetes Mellitus, Type 2 / genetics*
  • Diet*
  • Dietary Carbohydrates*
  • Dietary Fats*
  • Female
  • Follow-Up Studies
  • Gene-Environment Interaction
  • Genetic Variation*
  • Genotype
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Obesity / genetics
  • Prospective Studies
  • Receptors, Gastrointestinal Hormone / genetics*


  • Dietary Carbohydrates
  • Dietary Fats
  • Receptors, Gastrointestinal Hormone
  • gastric inhibitory polypeptide receptor