Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Nat Genet. 2010 Feb;42(2):142-8. doi: 10.1038/ng.521. Epub 2010 Jan 17.

Abstract

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / genetics
  • Body Mass Index
  • Denmark
  • Diabetes Mellitus, Type 2 / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genetic Loci / genetics
  • Genetic Variation*
  • Genome-Wide Association Study
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Incretins / genetics
  • Insulin / metabolism*
  • Male
  • Meta-Analysis as Topic
  • Polymorphism, Single Nucleotide / genetics
  • Proteins / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Gastrointestinal Hormone / genetics*
  • Receptors, Gastrointestinal Hormone / metabolism

Substances

  • Incretins
  • Insulin
  • Proteins
  • RNA, Messenger
  • Receptors, Gastrointestinal Hormone
  • VPS13C protein, human
  • gastric inhibitory polypeptide receptor
  • Adenylyl Cyclases
  • Glucose

Grant support