A newly discovered mechanism behind reduced insulin production in type 2 diabetes is now being presented. In an article in Nature Communications, researchers describe how insulin-producing cells regress in their development, become immature, and do not work properly.

"If you can affect things at the cellular level and restore the body's own rapid regulation, you can more accurately adjust blood sugar compared to what is possible with insulin injections," says corresponding author.

It has long been known that the insulin-producing cells fail in type 2 diabetes. The body does not get enough insulin and blood sugar rises. One theory argues that the insulin-producing cells become fewer in number, while another argues that their function is impaired.

The new explanation, which combines the debated theories, states that the insulin-producing cells regress in their development and become immature. This reduces the number of functional cells.

With the help of 124 tissue samples, of which 41 were from people with type 2 diabetes, the researchers were able to determine which genetic changes in the cells affected the course of the disease the most. Senior author  describes the analysis by comparing it to the world of air travel.

"All airports are connected in a large network, but a disruption at a hub like Frankfurt Airport is much more serious than a disruption in Gothenburg. We searched out the hubs, i.e. the key genes, and the major links. Of almost 3,000 genes that were changed in diabetes, 168 could be described as Frankfurt genes. It was these we focused on," author says.

As the analysis continued, it showed that the gene SOX5, which was previously unknown in a diabetes context, affects the disease.

"If you experimentally suppress and deactivate SOX5, the function of the 168 genes deteriorate and the cells decrease in maturity. If you then increase the levels of SOX5, the 168 genes also increase and insulin delivery can be normalized," explains senior author.

"It's very exciting to see. It was almost like a volume control, where you could increase or decrease the maturity level of the insulin-producing cells.”

Authors show that Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2 þ -influx and b-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key b-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D.

Current research shows that SOX5 decreases if you eat unhealthy foods or exercise too little.

"It is important to remember that everyone is different. Some manage a long time despite unhealthy lifestyle habits. For others, the tipping point is much earlier. But, regardless of genetic conditions, you can do something about your disease," says the senior author.

http://sahlgrenska.gu.se/english/research/news-events/news-article//newly-discovered-disease-mechanism-for-type-2-diabetes.cid1472500

https://www.nature.com/articles/ncomms15652