Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

A. Williamson, G. Hatem, D.M. Aly, E. Ahlqvist, R.B. Prasad, L. Groop, J.B. Meigs, C. Langenberg, et al., Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Research output: Contribution to journalArticlepeer-review

Abstract

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Original languageEnglish
Pages (from-to)973-983
Number of pages11
JournalNature Genetics
Volume55
Issue number6
DOIs
Publication statusPublished - 2023

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Free keywords

  • Blood Glucose
  • Diabetes Mellitus, Type 2
  • Genome-Wide Association Study
  • Glucose
  • Humans
  • Insulin
  • Insulin Resistance
  • glucose
  • glucose transporter 4
  • insulin
  • adipocyte
  • ancestry group
  • Article
  • body mass
  • cell culture
  • controlled study
  • gene expression
  • gene identification
  • genetic variability
  • genome-wide association study
  • glucose transport
  • human
  • insulin level
  • insulin resistance
  • meta analysis (topic)
  • non insulin dependent diabetes mellitus
  • transcription regulation
  • genetics
  • glucose blood level
  • metabolism

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