Type II diabetes is associated with several physiological shortcomings in our organism, one of which is the inability of our tissues to respond to insulin. Also, the insulin-producing beta cells in pancreas can lose their insulin secretion capacity, which further complicates the matter, and contributes to elevated blood glucose. It is now known that a few hundred common human genetic variants may influence the capacity of beta cells to produce and secrete insulin. However, in many cases we lack a definitive proof that these genetic variants directly contribute to, and not merely associate with diabetes.  To solve this puzzle, in our research we intend to combine the latest advances in genomic editing and in human stem cell technology to uncover how common human genetic variation can jeopardize an efficient insulin production or secretion in pancreatic beta cells.

One of the hypotheses we intend to test is that a specific human genetic variation influences how the beta cell responds to melatonin. Melatonin is a sleep-related hormone that should shut down insulin secretion during fasting, i.e. when we sleep and not want our blood glucose to decrease too much. On the other hand, too much shutdown of insulin secretion by melatonin could create excessively low blood insulin levels when we need it, perhaps after an evening meal. In previous studies scientists have identified genetic variation in a gene called MTNR1B that appears to determine the levels of insulin secretion in the presence of melatonin. The response of the beta cell to melatonin, depending on what type of genetic variant in the MTNR1B gene it carries, may therefore be a potential contributing factor to diabetes.

To test the above hypothesis we need to establish cell lines that have exactly the same genomic sequence, except for the one variation in the MTNR1B gene. We intend to accomplish this using genomic editing technology called CRISPR/Cas9, which we’ll utilize on human stem cells donated by people that carry the MTNR1B gene variant often found in type 2 diabetes patients. We will attempt to switch the cells’ genetic code to one that is associated with lower risk of diabetes, and then evaluate how these stem cells develop into mature insulin-producing beta cells, and how these cells’ insulin secretion is affected by melatonin. Using this strategy we will be able to dissect the contribution of particular genetic variants to the central role of beta cells, which is providing our tissues with insulin.

Our study also carries a secondary aim – once the above-described technologies become established we will be able to study the effects of other human genetic variants on the biology of beta cells in a much more reliable way than has so far been possible. We hope that combining the latest genomic editing with stem cell technologies will result in new knowledge of type 2 diabetes genetics, and create new perspectives on personalized diabetes medicine.