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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
Science translational medicine, 02/2020, Volume: 12, Issue: 530Journal Article
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.
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