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

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 beta cells and to reduce caloric intake. Unfortunately, they fail to increase human beta cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human beta cell proliferation, but rates are modest (similar to 2%), and their specificity to beta 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 beta cell replication (5 to 6%) accompanied by an actual increase in numbers of human beta cells. GLP1R agonist-DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to beta cell de-differentiation. These beneficial effects on proliferation were seen in both normal human beta cells and beta cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist-DYRK1A inhibitor combination to enhance human beta 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 beta cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human beta cell specificity.