Signaling Pathway Found to Regulate Regeneration of Insulin producing β Cells
Two recent studies identified a signaling pathway that regulates β cell regeneration and could be targeted for new therapies. β cells, which produce insulin, are destroyed by the immune system in people with type 1 diabetes and may not function normally in people with type 2 diabetes. Identifying ways to replace the β cells and restore insulin-producing capacity could benefit people with type 1 or type 2 diabetes, and is a major goal of research. One approach to replace β cells is through regeneration, such as by coaxing existing β cells, which reside in the pancreas, to proliferate and generate new β cells. In particular, small molecules that could promote β cell regeneration could be therapeutically useful, particularly if they had limited off-target effects and could be taken orally. Toward the goal of identifying such small molecules, two different research groups participating in the Beta Cell Biology Consortium conducted screens to identify small molecules that enhanced β cell regeneration.
In one study, researchers screened over 7,000 small molecule compounds in a zebrafish model in which β cells were partially destroyed through genetic manipulation. They identified five compounds that doubled the number of β cells in the animals. Interestingly, four of the five compounds targeted the same cellular pathway—the adenosine signaling pathway. Further experiments focused on the most potent compound, called NECA. NECA was found to promote β cell proliferation specifically, without significantly affecting proliferation of other pancreatic cell types (e.g., glucagon-producing cells) or cells in other tissues (e.g., liver, gut). To determine whether NECA had a similar effect in mammals, the researchers studied an adult mouse model of diabetes in which β cells were depleted. After 15 days, β cell mass was 8-fold larger in the NECA treated mice compared to control mice, suggesting that NECA promotes β cell regeneration in the mouse model as well.
In a separate study, researchers developed a high-throughput small molecule screening system using rat islets, and used that experimental platform to screen about 850 compounds for their ability to increase β cell proliferation. Two compounds increased β cell proliferation 2 to 3 fold above control levels; the compounds also increased β cell proliferation in mouse and pig islets. Both of the compounds are inhibitors of adenosine kinase, an enzyme in the adenosine signaling pathway. They tested one of the compounds in mice, and it increased β cell proliferation but did not affect proliferation of other cell types tested, suggesting that inhibiting adenosine kinase may selectively promote β cell proliferation.
Both studies point to the adenosine signaling pathway as a key regulator of β cell regeneration. The preliminary results with the compounds tested in these studies are promising because they may promote β cell proliferation selectively, which would be critically important in any therapy used in people. The research suggests that therapies targeting this pathway could potentially be used to promote β cell regeneration to treat diabetes.