The molecular mechanisms of pancreatic beta-cell glucotoxicity: Recent findings and future research directions
It is well established that regular physiological stimulation by glucose plays a crucial role in the maintenance of the beta-cell differentiated phenotype. In contrast, prolonged or repeated exposure to elevated glucose concentrations both in vitro and in vivo exerts deleterious or toxic effects on the beta-cell phenotype, a concept termed as glucotoxicity. Evidence indicates that the latter may greatly contribute to the pathogenesis of type 2 diabetes. Through the activation of several mechanisms and signaling pathways, high glucose levels exert deleterious effects on beta-cell function and survival and thereby, lead to the worsening of the disease over time. While the role of high glucose-induced beta-cell overstimulation, oxidative stress, excessive Unfolded Protein Response (UPR) activation, and loss of differentiation in the alteration of the beta-cell phenotype is well ascertained, at least in vitro and in animal models of type 2 diabetes, the role of other mechanisms such as inflammation, O-GlcNacylation, PKC activation, and amyloidogenesis requires further confirmation. On the other hand, protein glycation is an emerging mechanism that may play an important role in the glucotoxic deterioration of the beta-cell phenotype. Finally, our recent evidence suggests that hypoxia may also be a new mechanism of beta-cell glucotoxicity. Deciphering these molecular mechanisms of beta-cell glucotoxicity is a mandatory first step toward the development of therapeutic strategies to protect beta-cells and improve the functional beta-cell mass in type 2 diabetes. Mol Cell Endocrinol. 2012 Nov 25;364(1-2):1-27. doi: 10.1016/j.mce.2012.08.003. Epub 2012 Aug 10.
|ISBN||1872-8057 (Electronic) 0303-7207 (Linking)|
|Authors||Bensellam, M.; Laybutt, D. R.; Jonas, J. C.;|
|Publisher Name||MOL CELL ENDOCRINOL|
|Published Date||2012-01-01 00:00:00|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?11540_12004/12 Bensellam MCE_.pdf|