Journal Article

Identification of a small molecule that stimulates human β-cell proliferation and insulin secretion, and protects against cytotoxic stress in rat insulinoma cells

Zhang, Lu, Taylor, Brandon, Laffitte, Bryan, Stephens, Samuel, Newgard, Christopher B., Hohmeier, Hans E., Lu, Danhong, McNamara, Peter

2020

Overview

A key event in the development of both major forms of diabetes is the loss of functional pancreatic islet β-cell mass. Strategies aimed at enhancing β-cell regeneration have long been pursued, but methods for reliably inducing human β-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor NKX6.1 stimulates β-cell proliferation, while also enhancing GSIS and providing protection against β-cell cytotoxicity through induction of the VGF prohormone. We developed an NKX6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation, but not expression of NKX6.1 or VGF, suggesting an alternative mechanism of action. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human β-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. GNF-9228 stimulates proliferation via a mechanism distinct from recently emergent DYRK1A inhibitors, as it is unaffected by DYRK1A overexpression and does not activate NFAT translocation. In conclusion, we have identified a small molecule with pleiotropic positive effects on islet biology, including stimulation of human β-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenoviruses / Animals / Beta cells / Biological effects / Biology and Life Sciences / Cell culture / Cell cycle / Cell growth / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cytokines / Cytotoxicity / Diabetes / Diabetes mellitus / Dyrk Kinases / Engineering and Technology / Gene expression / Genomics / Glucagon-Secreting Cells - metabolism / Glucagon-Secreting Cells - pathology / Glucose / Glucose - pharmacology / Homeobox / Homeodomain Proteins - metabolism / Humans / Inflammation / Insulin / Insulin secretion / Insulin Secretion - drug effects / Insulin-Secreting Cells - metabolism / Insulin-Secreting Cells - pathology / Insulinoma / Insulinoma - metabolism / Insulinoma - pathology / Kinases / Medicine and Health Sciences / Metabolism / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - metabolism / Neuroendocrine tumors / NF-AT protein / Nkx6.1 protein / Nutrition / Pancreas / Peptides / Physical Sciences / Physiology / Protein Kinase Inhibitors - pharmacology / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - metabolism / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - metabolism / Rats / Regeneration / Research and Analysis Methods / Stress / Toxicity / Translocation