Type 2 diabetes: a multifaceted disease

Abstract

Type 2 diabetes is a complex disease usually diagnosed with little regard to aetiology. In the broader sense, it is a mix of different clearly defined aetiologies, such as monogenic diabetes, that we need to be better at identifying as this has major implications for treatment and patient management. Beyond this, however, type 2 diabetes is a highly heterogeneous polygenic disease. This review outlines the recent developments that recognise this heterogeneity by deconvoluting the aetiology of type 2 diabetes into pathophysiological processes, either by measuring physiological variables (such as beta cell function or insulin resistance) or using partitioned polygenic scores, and addresses recent work that clusters type 2 diabetes into distinct subgroups. Increasing evidence suggests that considering the aetiological components of type 2 diabetes matters, in terms of progression rates, treatment response and complications. In other words, clinicians need to recognise that type 2 diabetes is multifaceted and that its characteristics are important for how patients are managed.

Keywords: Aetiology; Clustering; Complex disease; Monogenic diabetes; Palette model; Pathophysiology; Review; Type 2 diabetes.

Fig. 1

Deconvoluting the diabetes component pathways. The McCarthy palette model of diabetes represents each person as a colour, resulting from different contributions of the colours representing the various pathophysiological processes that can contribute to diabetes. It is possible to deconvolute these pathways (i.e. determine the underlying contribution made by each process) by measuring the processes directly (where possible), by measuring the underlying genetic contribution, or by measuring the intermediate metabolic phenotype (i.e. metabolites or gene expression); all three strategies could be combined in an integrative multi-omic approach. To convert values for HbA_1c in % into mmol/mol, subtract 2.15 and multiply by 10.929. Adapted from McCarthy [11] under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium. This figure is available as a downloadable slide