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Review
. 2006 Apr;136(4):873-6.
doi: 10.1093/jn/136.4.873.

Regulation of the insulin gene by glucose and fatty acids

Vincent Poitout  1 , Derek Hagman, Roland Stein, Isabella Artner, R Paul Robertson, Jamie S Harmon
Affiliations
Review

Regulation of the insulin gene by glucose and fatty acids

Vincent Poitout et al. J Nutr. 2006 Apr.

Abstract

The insulin gene is expressed almost exclusively in pancreatic beta-cells. Metabolic regulation of insulin gene expression enables the beta-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 beta-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/EBPbeta, 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 beta-cell function in type 2 diabetes.

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Figures

FIGURE 1
FIGURE 1
Schematic representation of the proximal region of the rat insulin 2 promoter showing the key elements and trans-activating factors involved in glucose regulation of insulin gene transcription.
FIGURE 2
FIGURE 2
Proposed intracellular mechanisms by which chronically elevated glucose and fatty acids impair insulin gene transcription.
See this image and copyright information in PMC

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