GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration

• Published in: Science translational medicine 2020-02, Vol.12 (530), p.1
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adult; Agonists; Animals; Beta cells; Blood glucose; Cell proliferation; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2; Dipeptidyl-peptidase IV; Dyrk Kinases; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Humans; Immunodeficiency; Insulin; Insulin secretion; Insulin-Secreting Cells; Mice; Peptidase; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Regeneration; Streptozocin; Synergism; Tyrosine
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aaw9996

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.