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

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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Ackeifi C,Wang P,Karakose E,Manning Fox JE,González BJ,Liu H,Wilson J,Swartz E,Berrouet C,Li Y,Kumar K,MacDonald PE,Sanchez R,Thorens B,DeVita R,Homann D,Egli D,Scott DK,Garcia-Ocaña A,Stewart AF

doi

10.1126/scitranslmed.aaw9996

subject

Has Abstract

pub_date

2020-02-12 00:00:00

issue

530

eissn

1946-6234

issn

1946-6242

pii

12/530/eaaw9996

journal_volume

12

pub_type

杂志文章

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