期刊
JOURNAL OF NUTRITION
卷 136, 期 4, 页码 873-876出版社
AMER SOCIETY NUTRITIONAL SCIENCE
DOI: 10.1093/jn/136.4.873
关键词
B-cell; diabetes; insulin
资金
- Canadian Institutes of Health Research [77686] Funding Source: Medline
- NIDDK NIH HHS [R01 DK038325, R01 DK38325, R01 DK58096, R01 DK058096, F32 DK070406, R01 DK050203, R01 DK50203] Funding Source: Medline
The insulin gene is expressed almost exclusively in pancreatic G-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/EBP beta, 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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