Diabetes.: co-auth.: B. Thorens

Diabetes. 2021 Aug 10;db201281. doi: 10.2337/db20-1281. Online ahead of print.

Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes: an IMIRHAPSODY Study

Roderick C Slieker 1 2Louise A Donnelly 3Hugo Fitipaldi 4Gerard A Bouland 1Giuseppe N Giordano 4Mikael Åkerlund 4Mathias J Gerl 5Emma Ahlqvist 4Ashfaq Ali 6Iulian Dragan 7Petra Elders 8Andreas Festa 9 10Michael K Hansen 11Amber A van der Heijden 8Dina Mansour Aly 4Min Kim 6 12Dmitry Kuznetsov 7Florence Mehl 7Christian Klose 5Kai Simons 5Imre Pavo 9Timothy J Pullen 13 14Tommi Suvitaival 6Asger Wretlind 6Peter Rossing 6 15Valeriya Lyssenko 16 17Cristina Legido Quigley 6 11Leif Groop 4 18Bernard Thorens 19Paul W Franks 4 20Mark Ibberson 7Guy A Rutter 13 21Joline Wj Beulens 2 22Leen M ‘t Hart 23 2 24Ewan R Pearson 25Affiliations expand


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.