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* Department of Medicine, University of Montréal, Montréal, QC, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal, QC, Canada; ** Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN; Pacific Northwest Research Institute, Seattle, WA; and Departments of Medicine and Pharmacology, University of Washington, Seattle, WA
2 To whom correspondence should be addressed. E-mail: vincent.poitout{at}umontreal.ca.
The insulin gene is expressed almost exclusively in pancreatic ß-cells. Metabolic regulation of insulin gene expression enables the ß-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 ß-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/EBPß, 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 ß-cell function in type 2 diabetes.
KEY WORDS: • B-cell • diabetes • insulin
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