A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication
Peng Wang,Juan-Carlos Alvarez-Perez,Dan P. Felsenfeld,Hongtao Liu,Sharmila Sivendran,Aaron Bender,Anil Kumar,Roberto Sanchez,Donald K. Scott,Adolfo Garcia-Ocaña,Andrew F. Stewart +10 more
Reads0
Chats0
TLDR
Using three different mouse and human islet in vivo–based models, harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control, suggesting that harmine analogs may have unique therapeutic promise for human diabetes therapy.Abstract:
Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo-based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.read more
Citations
More filters
Journal ArticleDOI
Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis
TL;DR: In type 1 and type 2 diabetes impairment of beta cell function is an early feature of disease pathogenesis while a substantial decrease in beta cell mass occurs more closely to clinical manifestation, which suggests that the development of novel strategies for protection and recovery ofBeta cell function could be most promising for successful diabetes treatment and prevention.
Journal ArticleDOI
Natural Products for the Treatment of Type 2 Diabetes Mellitus
TL;DR: This review compiles the principal articles on medicinal plants used for treating diabetes and its comorbidities, as well as mechanisms of natural products as antidiabetic agents, and considers compounds of high interest as potential antidiabetics.
Journal ArticleDOI
Single-cell transcriptomics of the human endocrine pancreas
Yue J. Wang,Jonathan Schug,Kyoung-Jae Won,Chengyang Liu,Ali Naji,Dana Avrahami,Maria L. Golson,Klaus H. Kaestner +7 more
TL;DR: It is shown that α- and β-cells from children exhibit less well-defined gene signatures than those in adults, and a robust computational biology framework for cell type annotation is developed, which provides a stepping stone for future explorations of cellular heterogeneity in pancreatic endocrine cells.
Journal ArticleDOI
Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.
Weijun Shen,Brandon Taylor,Qihui Jin,Van Nguyen-Tran,Shelly Meeusen,You-Qing Zhang,Anwesh Kamireddy,Austin De Swafford,Andrew F. Powers,John P Walker,John Lamb,Badry Bursalaya,Michael DiDonato,George Harb,Minhua Qiu,Christophe M. Filippi,Lisa Deaton,Carolina N. Turk,Wilma L. Suarez-Pinzon,Yahu Liu,Xueshi Hao,Tingting Mo,Shanshan Yan,Jing-Jing Li,Ann E. Herman,Bernhard J. Hering,Tao Wu,H. Martin Seidel,Peter McNamara,Richard Glynne,Bryan Laffitte +30 more
TL;DR: The feasibility of treating diabetes with an oral therapy to restore β-cell mass is supported, a tractable pathway for future drug discovery efforts is highlighted, and Dyrk1a is highlighted as the key molecular target.
Journal ArticleDOI
SerpinB1 Promotes Pancreatic β Cell Proliferation
Abdelfattah El Ouaamari,Ercument Dirice,Nicholas Gedeon,Jiang Hu,Jian-Ying Zhou,Jun Shirakawa,Lifei Hou,Jessica Goodman,Christos Karampelias,Guifeng Qiang,Jeremie Boucher,Jeremie Boucher,Rachael Martinez,Marina A. Gritsenko,Dario F. De Jesus,Sevim Kahraman,Shweta Bhatt,Richard D. Smith,Hans-Dietmar Beer,Prapaporn Jungtrakoon,Yanping Gong,Allison B. Goldfine,Chong Wee Liew,Alessandro Doria,Olov Andersson,Wei-Jun Qian,Eileen Remold-O'Donnell,Rohit N. Kulkarni +27 more
TL;DR: Proteomics shows that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish, and implicate ser pinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.
References
More filters
Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Journal ArticleDOI
A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.
TL;DR: A screening window coefficient, called "Z- factor," is defined, which is reflective of both the assay signal dynamic range and the data variation associated with the signal measurements, and therefore is suitable for assay quality assessment.
Journal ArticleDOI
Identification of c-MYC as a Target of the APC Pathway
Tong-Chuan He,Andrew B. Sparks,Carlo Rago,Heiko Hermeking,Leigh Zawel,Luis T. da Costa,Patrice J. Morin,Bert Vogelstein,Kenneth W. Kinzler +8 more
TL;DR: The c-MYC oncogene is identified as a target gene in this signaling pathway and shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c- MYC promoter.
Journal ArticleDOI
β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes
Alexandra E. Butler,Juliette Janson,Susan Bonner-Weir,Robert A. Ritzel,Robert A. Rizza,Peter C. Butler +5 more
TL;DR: Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation andβ-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 Diabetes.
Journal ArticleDOI
Suppression of Myc-Induced Apoptosis in β Cells Exposes Multiple Oncogenic Properties of Myc and Triggers Carcinogenic Progression
TL;DR: The data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.