137HUMAN ENTERO ENDOCRINE ? CELL SECRETION IN DYRK1A AND GLP-1 AGAINST TYPE -II DIABETES MELLITUSGlucagon-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 ? cells and to reduce caloric intake. Unfortunately, they fail to increase human ? cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human ? cell proliferation, but rates are modest (~2%), and their specificity to ? 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 ? cell replication (5 to 6%) accompanied by an actual increase in numbers of human ? cells. GLP1R agonist–DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to ? cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human ? cells and ? cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist–DYRK1A inhibitor combination to enhance human ? cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immuno efficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative ? cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human ? cell specificityPrabhu@gmail.comResearch1412024Diabetes, Human, Endocrine, GlucagonPrabhu T*, Guhan S, Kiruthiga S, Yazhini .B, Nivetha B, Kavya Y R, Thirunavukarasu AAssistant Professor, SNS College of Pharmacy and Health Sciences Coimbatore-35, Tamil Nadu, India