A small molecule differentiation inducer increases insulin production by pancreatic β cells

Elhadji M. Dioum, Jihan K. Osborne, Sean Goetsch, Jamie Russell, Jay W. Schneider, Melanie H. Cobb

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

New drugs for preserving and restoring pancreatic β-cell function are critically needed for the worldwide epidemic of type 2 diabetes and the cure for type 1 diabetes. We previously identified a family of neurogenic 3,5-disubstituted isoxazoles (Isx) that increased expression of neurogenic differentiation 1 (NeuroD1, also known as BETA2); this transcription factor functions in neuronal and pancreatic β-cell differentiation and is essential for insulin gene transcription. Here, we probed effects of Isx on human cadaveric islets and MIN6 pancreatic β cells. Isx increased the expression and secretion of insulin in islets that made little insulin after prolonged ex vivo culture and increased expression of neurogenic differentiation 1 and other regulators of islet differentiation and insulin gene transcription. Within the first few hours of exposure, Isx caused biphasic activation of ERK1/2 and increased bulk histone acetylation. Although there was little effect on histone deacetylase activity, Isx increased histone acetyl transferase activity in nuclear extracts. Reconstitution assays indicated that Isx increased the activity of the histone acetyl transferase p300 through an ERK1/2-dependent mechanism. In summary, we have identified a small molecule with antidiabetic activity, providing a tool for exploring islet function and a possible lead for therapeutic intervention in diabetes.

Original languageEnglish (US)
Pages (from-to)20713-20718
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number51
DOIs
StatePublished - Dec 20 2011

Keywords

  • Differentiation
  • Glucose-stimulated insulin secretion
  • Human islets
  • p300

ASJC Scopus subject areas

  • General

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