Nils Wierup

Hjelt grant holder 2019

Lund University



The pancreatic islets are key regulators of blood sugar and it is well established that islet dysfunction is the final culprit in type 2 diabetes (T2D). However, the exact mechanisms explaining what fails in the islets in T2D are not known. Studies aiming to understand this have been difficult to pursue due to the complex cellular composition of the islets. The islets are composed of at least 5 cell types and it has not previously been possible to study what fails in T2D in each cell type at a time. This has been made possible thanks to new technology (single-cell RNA-sequencing) that enables measurement of the expression of all genes in a single cell.

We have used single-cell RNA-sequencing on cells from patients with T2D as well as healthy subjects. This way we identified numerous genes with altered expression levels in T2D in each of the 5 islet cell types. We anticipated that these genes would represent at least to some extent the already experimentally proven disease mechanisms of T2D. But this was not the case. Guided by this fact we decided to instead assess alterations in entire genetic programs between T2D and healthy cells. To this end we created a novel analysis algorithm.

When this algorithm was employed to the data set, we found the absolute majority of the biological processes and genes known to be affected in T2D beta cells. We also identified several less well studied processes, as well as numerous genes without a known role in beta cell function. Thereafter we tested the function of a large number of such genes with previously unknown function in beta cells. We found that the absolute majority of them were regulators of insulin secretion or production. Thus our approach can accurately pinpoint both known and unknown T2D disease mechanisms.  This is a major leap forward for the understanding of the altered characteristics of beta cells in T2D, and will promote development of T2D therapeutics.