Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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 -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.

Original publication

DOI

10.1038/s41588-023-01408-9

Type

Journal article

Journal

Nature genetics

Publication Date

06/2023

Volume

55

Pages

973 - 983

Addresses

MRC Epidemiology Unit Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.

Keywords

Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Insulin, Glucose, Blood Glucose, Genome-Wide Association Study