ArticleNature metabolism2021
In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR.
Article in Nature metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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Who cites it
25 citing papers in PubMed, 39 citations in OpenAlex.
- Harmine selectively enhances human beta cell identity markers and function via protein kinase A pathways.Diabetologia · 2026Article
- Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice.Nature communications · 2026Article
- Transient ER stress cell-autonomously promotes beta cell cycling in mice.Diabetologia · 2026Article
- Genetic recording of pancreatic beta cell proliferation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A DYRK inhibitor ameliorates glucose homeostasis and increases incretin-producing cells in diabetic mice.Journal of molecular endocrinology · 2026Article
- Enhanced Selenium Supplement Extends Lifespan and Delays Multi-Organs Aging by Regulating the Sik1 Pathway Through Maintaining Calcium Homeostasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation.The Journal of clinical investigation · 2025Article
- Drug-induced regeneration of pancreatic beta cells: An approach to cellular therapeutic targets.Cell regeneration (London, England) · 2025Review
- The Role of the Salt-inducible Kinases in the Endocrine Glands.Endocrinology · 2025Review
- Mechanistic insights and approaches for beta cell regeneration.Nature chemical biology · 2025Review
- Islet single-cell transcriptomic profiling during obesity-induced beta cell expansion in female mice.iScience · 2025Article
- Harnessing beta-cell replication: advancing molecular insights to regenerative therapies in diabetes.Frontiers in endocrinology · 2025Review
- Inhibition of SIK1 Alleviates the Pathologies of Psoriasis by Disrupting IL-17 Signaling.Mediators of inflammation · 2025Article
- Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment.Current issues in molecular biology · 2024Review
- Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.Nature metabolism · 2024Article
- High-Throughput Methods for the Discovery of Small Molecule Modulators of Pancreatic Beta-Cell Function and Regeneration.Assay and drug development technologies · 2024Review
- Adjudin improves beta cell maturation, hepatic glucose uptake and glucose homeostasis.Diabetologia · 2024Article
- Review
- Therapeutic Strategies Targeting Pancreatic Islet β-Cell Proliferation, Regeneration, and Replacement.Endocrinology · 2022Article
- In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system.Cell chemical biology · 2022Article
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
Abstract
It is known that β cell proliferation expands the β cell mass during development and under certain hyperglycemic conditions in the adult, a process that may be used for β cell regeneration in diabetes. Here, through a new high-throughput screen using a luminescence ubiquitination-based cell cycle indicator (LUCCI) in zebrafish, we identify HG-9-91-01 as a driver of proliferation and confirm this effect in mouse and human β cells. HG-9-91-01 is an inhibitor of salt-inducible kinases (SIKs), and overexpression of Sik1 specifically in β cells blocks the effect of HG-9-91-01 on β cell proliferation. Single-cell transcriptomic analyses of mouse β cells demonstrate that HG-9-91-01 induces a wave of activating transcription factor (ATF)6-dependent unfolded protein response (UPR) before cell cycle entry. Importantly, the UPR wave is not associated with an increase in insulin expression. Additional mechanistic studies indicate that HG-9-91-01 induces multiple signalling effectors downstream of SIK inhibition, including CRTC1, CRTC2, ATF6, IRE1 and mTOR, which integrate to collectively drive β cell proliferation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.