Regulation of the insulin gene by glucose and fatty acids

Vincent Poitout, Derek Hagman, Roland Stein, Isabella Artner, R. Paul Robertson, Jamie S. Harmon

Research output: Contribution to journalArticle

149 Scopus citations

Abstract

The insulin gene is expressed almost exclusively in pancreatic β-cells. Metabolic regulation of insulin gene expression enables the β-cell to maintain adequate stores of intracellular insulin to sustain the secretory demand. Glucose is the major physiologic regulator of insulin gene expression; it coordinately controls the recruitment of transcription factors [e.g., pancreatic/duodenal homeobox-1 (PDX-1), mammalian homologue of avian MafA/L-Maf (MafA), Beta2/Neuro D (B2), the rate of transcription, and the stability of insulin mRNA. However, chronically elevated levels of glucose (glucotoxicity) and lipids (lipotoxicity) also contribute to the worsening of β-cell function in type 2 diabetes, in part via inhibition of insulin gene expression. The mechanisms of glucotoxicity, which involve decreased binding activities of PDX-1 and MafA and increased activity of C/EBPβ, are mediated by high-glucose -induced generation of oxidative stress. On the other hand, lipotoxicity is mediated by de novo ceramide synthesis and involves inhibition of PDX-1 nuclear translocation and MafA gene expression. Glucotoxicity and lipotoxicity have common targets, which makes their combination particularly harmful to insulin gene expression and β-cell function in type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)873-876
Number of pages4
JournalJournal of Nutrition
Volume136
Issue number4
DOIs
StatePublished - Apr 2006

Keywords

  • B-cell
  • Diabetes
  • Insulin

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    Poitout, V., Hagman, D., Stein, R., Artner, I., Robertson, R. P., & Harmon, J. S. (2006). Regulation of the insulin gene by glucose and fatty acids. Journal of Nutrition, 136(4), 873-876. https://doi.org/10.1093/jn/136.4.873