Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes

Anand Thakarakkattil Narayanan Nair, Agata Wesolowska-Andersen, Caroline A. Brorsson, Aravind Lathika Rajendrakumar, Simona Hapca, Sushrima Gan, Adem Y. Dawed, Louise A. Donnelly, Rory McCrimmon, Alexander S. F. Doney, Colin N. A. Palmer, Viswanathan Mohan, Ranjit M. Anjana, Andrew T. Hattersley, John M. Dennis, Ewan R. Pearson (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)
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Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from 23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.

Original languageEnglish
Pages (from-to)982-988
Number of pages7
JournalNature Medicine
Publication statusPublished - 9 May 2022


  • Type 2 diabetes

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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