Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 364, Issue 1-2, Pages 1-27Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2012.08.003
Keywords
Pancreatic beta-cell glucotoxicity; Type 2 diabetes; Oxidative stress; Endoplasmic reticulum stress; Hypoxia
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Funding
- Societe Francophone du Diabete (SFD, Paris, France)
- European Foundation for the Study of Diabetes
- SFD
- Fonds de la Recherche Scientifique Medicale (Brussels, Belgium)
- General Direction of Scientific Research of the French Community of Belgium
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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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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