The role of autophagy in β-cell lipotoxicity and type 2 diabetes

Abstract

Autophagy, a ubiquitous catabolic pathway involved in both cell survival and cell death, has been implicated in many age-associated diseases. Recent findings have shown autophagy to be crucial for proper insulin secretion and β-cell viability. Transgenic mice lacking autophagy in their β-cells showed decreased β-cell mass and suppressed glucose-stimulated insulin secretion. Several studies showed that stress can stimulate autophagy in β-cells: the number of autophagosomes is increased in different in vivo models for diabetes, such as db/db mice, mice fed high-fat diet, pdx-1 knockout mice, as well as in in vitro models of glucotoxicity and lipotoxicity. Pharmacological and molecular inhibition of autophagy increases the susceptibility to cell stress, suggesting that autophagy protects against diabetes-relevant stresses. Recent findings, however, question these conclusions. Pancreases of diabetics and β-cells exposed to fatty acids show accumulation of abnormal autophagosome morphology and suppression of lysosomal gene expression suggesting impairment in autophagic turnover. In this review we attempt to give an overview of the data generated by others and by us in view of the possible role of autophagy in diabetes, a role which depending on the conditions, could be beneficial or detrimental in coping with stress.

Figure 1

Autophagy can be stimulated by starvation, radical oxygen species (ROS), endoplasmic reticulum (ER) stress, infection and rapamycin. The initiation of autophagy is marked by the generation of the isolation membrane to which LC3 is recruited. The isolation membrane is engulfing the organelle/s to be digested. The process proceeds with the fusion of the lysosome to the autophagosome (AP) to form the autophagolysosome (APL). Acidification of the autophagolysosome allows for the digestion of its content. The process can be inhibited at the stage of formation of the phagophore using ATG5DN or 3MA. Acidification as well as fusion of AP with lysosomes can be inhibited by chloroquine, bafilomycin, and digestion of the APL content can be inhibited by protease inhibitors such as pepstatin and E64D.

Figure 2

A schematic model of the life cycle of mitochondria and the roles of mitochondrial dynamics and autophagy in the segregation of dysfunctional mitochondria. Each mitochondrion cyclically shifts between a post-fusion state (Network Period) and a post-fission state (Solitary Period). A fusion event commonly lasts less than 2 min and is terminated by a fission event. Following a fission event, each daughter mitochondrion may either maintain intact membrane potential (yellow) or depolarize (purple). If it depolarizes, it is six times less likely to re-engage in further fusion events for the entire depolarization interval. A fraction of the daughter mitochondria that depolarize do recover and their fusion capacity is then restored (re-entering the cycle). However, if membrane potential depolarization is sustained, reduction in OPA1, a mitochondrial fusion protein, follows and elimination by autophagy occurs (for details see [22]).