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.