The Palette Model of Type 2 Diabetes (PDF)

Painting a new picture of personalised medicine for diabetes by Mark I. McCarthy; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford; Diabetologia (2017) 60:793–799 DOI 10.1007/s00125-017-4210-x

Abstract The current focus on delivery of personalised (or precision) medicine reflects the expectation that developments in genomics, imaging and other domains will extend our diagnostic and prognostic capabilities, and enable more effective targeting of current and future preventative and therapeutic options. The clinical benefits of this approach are already being realised in rare diseases and cancer but the impact on management of complex diseases, such as type 2 diabetes, remains limited. This may reflect reliance on inappropriate models of disease architecture, based around rare, highimpact genetic and environmental exposures that are poorly suited to our emerging understanding of type 2 diabetes. This review proposes an alternative ‘palette’ model, centred on a molecular taxonomy that focuses on positioning an individual with respect to the major pathophysiological processes that contribute to diabetes risk and progression. This model anticipates that many individuals with diabetes will have multiple parallel defects that affect several of these processes. One corollary of this model is that research efforts should, at least initially, be targeted towards identifying and characterising individuals whose adverse metabolic trajectory is dominated by perturbation in a restricted set of processes.

A few snippets –

It is worth starting to understand why this might be by noting what it is that distinguishes rare disease, pharmacogenetics and cancer (the initial foci of personalised medicine success) from a disease like type 2 diabetes.…type 2 diabetes features multiple, common, low-impact risk variants, pervasive environmental exposures and a phenotype that very clearly lies on a quantitative spectrum of metabolic disturbance. Furthermore, diseased tissue is rarely accessible.

An alternative diagnostic model for diabetes…My proposition is that we should consider a different model for diabetes, one more clearly based around a molecular or pathophysiological taxonomy of diabetes; I call this the ‘palette’ model. The analogy here is with the painter who mixes a series of primary (and other) base colours to achieve an unlimited spectrum of hues and saturations (see Fig. 1 and Table 1). In this model, the ‘base colours’ are the set of pathophysiological traits and processes (‘component pathways’) that contribute directly to the development of diabetes. It is simple to fashion a list of potential component pathways based on current knowledge; it would feature processes such as islet development, senescence and replacement (leading to variation in islet and beta cell number), islet function, islet autoimmunity, incretin activity, obesity, fat distribution and insulin resistance. This list is not meant to be exhaustive nor definitive; mapping the ontology and relationship of these processes is one of the challenges to be addressed.

As a framework for the taxonomy of diabetes, this model has greater compatibility with clinical observation and, in particular, the graded heterogeneity of the diabetic phenotype.…For most people with diabetes (such as individual ‘c’ in Fig. 1), diabetes is not the consequence of marked failure in any one process; instead it results from the aggregate impact of several contributions to risk, any one of which may be entirely unremarkable in isolation. We could imagine that individual ‘c’ has a genetic risk profile and a history of life-course exposures that means they are overweight with a somewhat adverse distribution of excess fat. In conjunction with a modest reduction in insulin secretory reserve, reflecting a below-average complement of slightly underperforming beta cells, this configuration of metabolic characteristics suffices to drive that person towards diabetes. In the palette analogy, such an individual would end up a nondescript shade of taupe (between grey and brown), reflecting the concomitant contribution from multiple pathogenetic processes.