Research ArticleRegenerative Medicine

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

See allHide authors and affiliations

Science Translational Medicine  12 Feb 2020:
Vol. 12, Issue 530, eaaw9996
DOI: 10.1126/scitranslmed.aaw9996

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Best buddies for β cells

Regeneration of insulin-producing pancreatic β cells is a key therapeutic strategy for diabetes. Previous efforts to stimulate β cell proliferation through combined inhibition of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) and TGFβ/SMAD signaling have had restricted clinical development due to their combined action on human cell types other than β cells. Ackeifi et al. show that glucagon-like peptide-1 receptor agonists partner with DYRK1A inhibitors to stimulate proliferation of functional β cells in cadaveric human pancreatic islets, with a relatively β cell–specific effect. Streptozocin-induced diabetic mice transplanted with human islets showed improved insulin secretion and glycemic control after in vivo combination treatment.

Abstract

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.

View Full Text

Stay Connected to Science Translational Medicine


Editor's Blog