Functional decoding of genetic factors underlying diabetes by use of stem cells

Type 2 Diabetes (T2D) is a multifactorial disease, involving common genetic variants. Most risk alleles compromise β-cell function and insulin secretion. However, the actual genes and mechanisms causing disease are yet to be resolved. Here, two major obstacles to reach this understanding have been removed.

First, we can make insulin-secreting β-like cells from patients carrying T2D risk alleles; second, we can “correct” pathogenic risk alleles, using single base genome editing. These advances allow us to establish causal risk alleles in T2D and the mechanisms whereby disease evolves.

To this end, fibroblasts from patients will be reprogrammed to induced pluripotent stem cells (iPSC), subjected to single base genome editing, and differentiated into β-like cells. Functional and genomic analyses will elucidate how β-cell dysfunction evolves and can be reversed by genome editing.

The approach will be applied to mitochondrial diabetes, a rare form of monogenic diabetes, as well as to individuals carrying common risk alleles for T2D, e.g., the rs950994 risk variant of TFB1M, a gene encoding a mitochondrial methyltransferase.

Using polygenic risk scores, we will identify individuals with β-cells that are genetically burdened. β-like cells made from risk individuals will be functionally characterized and subjected to multiplexed genome editing. All iPSC we create will be deposited in our biobank – LUNiPS – made available to the research community.