Harmine Selectively Drives Human Beta Cell Differentiation and Function Via Protein Kinase A Pathways
Year: 2025
Type: preprint
Abstract: Harmine and other small molecule inhibitors of the kinase DYRK1A induce human beta cells to replicate and regenerate in vitro and in vivo , and are effective at reversing diabetes in animal models. In addition to its beta cell proliferative and regenerative effects, harmine also induces expression of transcription factors and other genes involved in beta cell differentiation and function, exemplified by PDX1, MAFA, NKX6.1, GLP1R, PCSK1 and many others. Harmine also rapidly enhances glucose-stimulated insulin secretion in vitro and in vivo , reversing diabetes within days in diabetic mice transplanted with a marginal mass of human islets. We had assumed that this pro-differentiation or pro-function effect was a common feature of all DYRK1A inhibitors, and was mediated by DYRK1A inhibition. Thus, DYRK1A is a primary target (we refer to it as Target 1) for harmine. Here, to our surprise, we report that the pro-differentiation effect is not a generalized action for all small molecule DYRK1A inhibitors and does not result from DYRK1A interference or genetic silencing. Instead, the prodifferentiation effect is restricted to a small select subset of DYRK1A inhibitors (harmine, 2-2c and 5-IT). Remarkably, the pro-differentiation effect results from the unique ability of these drugs to activate protein kinase A (PKA), a dual mechanism that distinguishes this class from other DYRK1A inhibitors. The beneficial effects of harmine on PKA appear to be indirect, driven by an as yet unidentified, Target 2 in the PKA pathway. These findings make it clear that all DYRK1A inhibitors are not interchangeable, and that those that drive both proliferation and differentiation/function will likely be preferable in human clinical therapeutic settings. They also provide a novel target or roadmap for enhancing human beta cell differentiation in Type 1 and Type 2 diabetes. Graphical Abstract
Authors: Peng Wang, Kunal Kumar, Luca Lambertini, Hongtao Liu, Olivia Wood, Shuxuan Chen, Aidan Pillard, Donald K. Scott, Joao A. Paulo, Steven P. Gygi, Susmita Khamrui, Stefan Mueller, Adolfo Garcia-Ocana, Esra Karakose, Michael B. Lazarus, Robert DeVita, Andrew F. Stewart
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Human Cancer Suppressor Functions of Protein Phosphatase 2A, Epigenetic Control of Human Beta Cell Proliferation, DYRK Inhibitors for Human Beta Cell Expansion, Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration, Novel Selective Type II kinase Inhibitors to treat Diabetes, Advancing Multiplexed Isobaric Tag-based Strategies for Proteome Profiling, DREAM Complex Maintenance of Human Beta Cell Quiescence, Nrf2 and the expansion and preservation of beta cell mass, NYR-Diabetes Research Center (NYR-DRC), Chemical and Structural Approaches to Study Energy Homeostasis Pathways in Cancer and Metabolic disorders, Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations
OpenAlex ID: W4417128985