Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging
Year: 2020
Type: preprint
Abstract: 463 million people globally suffer from diabetes. The majority are deficient in insulin-producing pancreatic beta cells, although beta cells remain in most people with diabetes. Unfortunately, although many diabetes drugs exist, none is able to increase adult human beta cell numbers. Recently, small molecules that inhibit the kinase, DYRK1A, have been suggested to induce human beta cell replication in vitro and in vivo as assessed using proliferation markers, and this is enhanced by drugs that stimulate the GLP1 receptor (GLP1R) on beta cells. DYRK1A inhibitors also enhance human beta cell differentiation and function. However, it is unknown whether any drug can actually increase human beta cell mass in vivo , reflecting: 1) the intrinsic resistance of human beta cells to regeneration; and, 2) the current technical inability to accurately assess human beta cell mass in vivo . Here, we demonstrate for the first time that combining a DYRK1A inhibitor with a GLP1R agonist increases actual human beta cell numbers and overall mass in vivo by 400-700% in diabetic and non-diabetic mice over three months. We further describe a novel application of tissue-clearing and 3D imaging for quantification of human beta cell mass. These findings should be transformative for diabetes treatment.
Authors: Carolina Rosselot, Alexandra Alvarsson, Peng Wang, Yansui Li, Kara Beliard, Geming Lu, Rosemary Li, Hongtao Liu, Virginia Gillespie, Nikolaos Tzavaras, Kunal Kumar, Robert J. DeVita, Andrew F. Stewart, Sarah A. Stanley, Adolfo Garcia-Ocaña
Institution: Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G113413678, G1193134389, Collaborative Research: Elucidating the Mechanism of Magnetogenetics for Remote Activation of Cell Function, G30550971, G3358720692, G3799973674, G464855746, Central nervous system regulation of glucose metabolism, G5582335657, G5807023910, G5850682332, Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration, Novel Selective Type II kinase Inhibitors to treat Diabetes, G8059969488, G836681807, G8671509285, G9000065207, G9000160732, G9000201241, NYR-Diabetes Research Center (NYR-DRC)
OpenAlex ID: W3045127331