| Autor: |
Ackeifi, Courtney, Wang, Peng, Karakose, Esra, Manning Fox, Jocelyn E., González, Bryan J., Liu, Hongtao, Wilson, Jessica, Swartz, Ethan, Berrouet, Cecilia, Li, Yansui, Kumar, Kunal, MacDonald, Patrick E., Sanchez, Roberto, Thorens, Bernard, DeVita, Robert, Homann, Dirk, Egli, Dieter, Scott, Donald K., Garcia-Ocaña, Adolfo, Stewart, Andrew F. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 2/12/2020, Vol. 12 Issue 530, p1-12, 12p |
| Abstrakt: |
Best buddies for β cells: Regeneration of insulin-producing pancreatic β cells is a key therapeutic strategy for diabetes. Previous efforts to stimulate β cell proliferation through combined inhibition of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) and TGFβ/SMAD signaling have had restricted clinical development due to their combined action on human cell types other than β cells. Ackeifi et al. show that glucagon-like peptide-1 receptor agonists partner with DYRK1A inhibitors to stimulate proliferation of functional β cells in cadaveric human pancreatic islets, with a relatively β cell–specific effect. Streptozocin-induced diabetic mice transplanted with human islets showed improved insulin secretion and glycemic control after in vivo combination treatment. Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist–DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist–DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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