title: The molecular mechanisms of pancreatic β-cell glucotoxicity: recent findings and future research directions.
abstract: It is well established that regular physiological stimulation by glucose plays a crucial role in the maintenance of the β-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 β-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 β-cell function and survival and thereby, lead to the worsening of the disease over time. While the role of high glucose-induced β-cell overstimulation, oxidative stress, excessive Unfolded Protein Response (UPR) activation, and loss of differentiation in the alteration of the β-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 β-cell phenotype. Finally, our recent evidence suggests that hypoxia may also be a new mechanism of β-cell glucotoxicity. Deciphering these molecular mechanisms of β-cell glucotoxicity is a mandatory first step toward the development of therapeutic strategies to protect β-cells and improve the functional β-cell mass in type 2 diabetes.
authors.affiliation: Université catholique de Louvain, Institut de recherche expérimentale et clinique, Pôle d'endocrinologie, diabète et nutrition, Brussels, Belgium.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bensellam
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Jonas
mesh_terms: D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D057170:Translational Research, Biomedical / Q000639:trends
chemical_list: D007328:Insulin; D005947:Glucose