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Distinct molecular signatures of clinical clusters in people with Type 2 diabetes: an IMIRHAPSODY study.

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Title: Distinct molecular signatures of clinical clusters in people with Type 2 diabetes: an IMIRHAPSODY study.
Authors: Slieker, RC
Donnelly, LA
Fitipaldi, H
Bouland, GA
Giordano, GN
Åkerlund, M
Gerl, MJ
Ahlqvist, E
Ali, A
Dragan, I
Elders, P
Festa, A
Hansen, MK
Van der Heijden, AA
Aly, DM
Kim, M
Kuznetsov, D
Mehl, F
Klose, C
Simons, K
Pavo, I
Pullen, TJ
Suvitaival, T
Wretlind, A
Rossing, P
Lyssenko, V
Quigley, CL
Groop, L
Thorens, B
Franks, PW
Ibberson, M
Rutter, GA
Beulens, JW
't Hart, LM
Pearson, ER
Item Type: Journal Article
Abstract: Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
Issue Date: 10-Aug-2021
Date of Acceptance: 1-Aug-2021
URI: http://hdl.handle.net/10044/1/91436
DOI: 10.2337/db20-1281
ISSN: 0012-1797
Publisher: American Diabetes Association
Start Page: 2683
End Page: 2693
Journal / Book Title: Diabetes
Volume: 70
Issue: 11
Copyright Statement: © 2021 by the American Diabetes Association https://www.diabetesjournals.org/content/license Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.
Sponsor/Funder: MRC Programme Grant
Wellcome Trust
Funder's Grant Number: MR/R022259/1
212625/Z/18/Z
Keywords: Endocrinology & Metabolism
11 Medical and Health Sciences
Publication Status: Published
Conference Place: United States
Online Publication Date: 2021-08-10
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine