| Autor: |
Rosselot, Carolina, Li, Yansui, Wang, Peng, Alvarsson, Alexandra, Beliard, Kara, Lu, Geming, Kang, Randy, Li, Rosemary, Liu, Hongtao, Gillespie, Virginia, Tzavaras, Nikolaos, Kumar, Kunal, DeVita, Robert J., Stewart, Andrew F., Stanley, Sarah A., Garcia-Ocaña, Adolfo |
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| Zdroj: |
Science Translational Medicine; 7/10/2024, Vol. 16 Issue 755, p1-15, 15p |
| Abstrakt: |
Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing β cells are reduced in number in most people with diabetes, but most individuals still have some residual β cells. However, none of the many diabetes drugs in common use increases human β cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human β cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on β cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human β cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human β cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human β cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human β cell mass occurred through mechanisms that included enhanced human β cell proliferation, function, and survival. The increase in human β cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor–GLP1RA combination for diabetes treatment. Editor's summary: Diabetes results from insufficient β cell function and, to differing degrees, insufficient β cell mass. There are, however, no currently approved treatments to increase β cell numbers. Combined DYRK1A kinase inhibition and GLP1 receptor (GLP1R) agonism has previously been shown to induce replication of β cells in human pancreatic islets ex vivo. Here, Rosselot et al. show that combined treatment with a DYRK1A inhibitor and GLP1R agonist in vivo promoted substantial increases in human β cell mass transplanted into immunodeficient mice. Three months of combination treatment restored glucose homeostasis in a streptozotocin-induced model of diabetes, with effects lasting for at least a month after treatment withdrawal. Initial analysis suggested that these effects occurred through altered β cell proliferation, function, and survival. Although promising, further work will be needed to confirm the mechanisms of action and whether the therapeutic benefits and safety of the approach would translate to humans. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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