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GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration
Science Translational Medicine ( IF 17.161 ) Pub Date : 2020-02-12 , DOI: 10.1126/scitranslmed.aaw9996
Courtney Ackeifi, Peng Wang, Esra Karakose, Jocelyn E. Manning Fox, Bryan J. González, Hongtao Liu, Jessica Wilson, Ethan Swartz, Cecilia Berrouet, Yansui Li, Kunal Kumar, Patrick E. MacDonald, Roberto Sanchez, Bernard Thorens, Robert DeVita, Dirk Homann, Dieter Egli, Donald K. Scott, Adolfo Garcia-Ocaña, Andrew F. Stewart

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.
更新日期:2020-02-12

 

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