Precision treatment of type 2 diabetes based on the beta-cell phenotype

What defines the dysfunction of the insulin-secreting beta-cells in type-2 diabetes (T2D)? This question is central to the understanding of the causes, treatment and prevention of T2D.

We will explore this by novel methodology (functional sequencing) that directly correlates the beta cells’ capacity to release insulin (measured optically) to the single-cell transcriptome. This strategy affords unprecedented opportunity to map the heterogeneity of the beta-cells in health and T2D.

In pilot studies we have identified two subsets of beta-cells, characterised by low and high secretory competence and with distinct gene expression patterns.

Intriguingly, and contrary to our prediction, beta-cells from donors with T2D transcriptionally are more akin to the high than the low responders.

This highlights the urgency to consider the wide spectrum of single-cell phenotypes in T2D therapy and depart from the current ‘one-size-fit-all’ approach.

We will explore the research question by in-depth functional sequencing, advanced cell physiology, animal models and population genetics.

The overriding goal is to define the key mechanisms and genes in T2D and propose new precision treatments that - for the first time - take into account the heterogeneity of the beta-cells.

The complementary methodologies will facilitate ground-breaking translation of basic science findings into clinical utility (via repurposing of pharmacological agents) in a way that is unique also by international standards.