Regulation of the insulin gene by glucose and fatty acids.
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.
Poitout
Vincent
V
Department of Medicine, University of Montréal, Montréal, QC, Canada. vincent.poitout@umontreal.ca
Hagman
Derek
D
Stein
Roland
R
Artner
Isabella
I
Robertson
R Paul
RP
Harmon
Jamie S
JS
D000818:Animals; D005227:Fatty Acids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology
D005227:Fatty Acids; D007328:Insulin; D014157:Transcription Factors; D005947:Glucose