β Cell and Autophagy: What Do We Know?

Abstract

Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure.

Keywords: autophagy; autophagy modulators; insulin homeostasis; type 1 diabetes; type 2 diabetes; β cell.

Figure 1

The four major types of autophagy. (a) Macroautophagy, generally termed autophagy; autophagosomes are formed and engulf cellular components, e.g., secretory granules. Autophagosomes finally fuse with lysosomes, after which the lysosomal hydrolases degrade the sequestered contents. (b) Microautophagy, in which cellular components are directly engulfed by the lysosomal membrane. (c) Chaperone-mediated autophagy, where specific amino acid sequence motifs of cytosolic proteins are recognized via the chaperone protein hsc70 and directly targeted to lysosomes for degradation. (d) Crinophagy, where secretory vesicles directly fuse with lysosomes [6].

Figure 2

Inhibition and induction of autophagy. (a) Nutrient availability: when nutrients are available, mTORC1 is activated and forms a complex accompanied by ULK1, Atg13, Atg101, and FIP200 (200 kDa FAK-family interacting protein) [23]. The developed complex inactivates ULK1 through its phosphorylation, which inhibits autophagy. (b) In starvation conditions, mTORC1 is inhibited by dissociation from the ULK1 complex. Meanwhile, the ULK1 is dephosphorylated and activated by AMPK. The activated ULK1 induces autophagy by phosphorylation of Atg13 and FIP200. Then, the Beclin-1 (Bcl-2-interacting protein) is released from Bcl-2 to form a complex with a set of proteins, including Vps34, Vps15, and Atg14L, resulting in autophagosome formation/maturation [23]. This process is accomplished via the Atg proteins in two ubiquitin-like conjugation pathways [24]. Finally, the lipidated LC3 (LC3-II) is localized to the autophagolysosome membrane [25]. LC3 interacts with p62 to engulf ubiquitinated proteins, and within the autophagolysosomes, the lysosomal hydrolases will then degrade the contents.

Figure 3

Molecular mechanism of proinsulin and insulin relation with autophagy in ER-Golgi pathway. The degradation mechanism of insulin and proinsulin by lysosomes seem to be different. Proinsulin is mainly degraded via macroautophagy, while insulin granule degradation is through microautophagy and crinophagy. Induction of autophagy by pharmacological stimulators (rapamycin and trehalose) and genetic interference using Tat-beclin-1 exhibited reduced proinsulin content in β cells without affecting the insulin amount.

Figure 4

Proposed ER-related mechanisms in the induction of autophagy and UPR in β cells. The ER stress can induce autophagy through PERK, IRE1α, and the ATF6α signaling pathway. The ER stress pathway is caused by hyperglycemia and upon accumulation of misfolded and unfolded proteins in the ER lumen. Activation of IRE1α results in the generation of active sXBP1. The ATF6α is transported to the Golgi apparatus, where it is activated. sXBP1 and the activated ATF6α cause decreased protein burden in the ER. Activation of IRE1α also triggers the JNK signaling cascade, which in turn leads to disruption of the Bcl-2/Beclin-1 interaction through phosphorylation of Bcl-2 and, therefore, induces autophagy. The IRE1α branch of UPR activation of JNK causes phosphorylation of Bcl2, which results in the dissociation of Beclin-1 and, thus, autophagy induction. Another arm of UPR-activated PERK induces autophagy via expression of ATG12 and ATG16L via ATF4 transcription factor; similarly, CHOP activates TRIB3, which blocks the activity of AKT/mTOR pathway-induced autophagy. ATF6α branch of UPR can also induce autophagy by inhibiting phosphorylation at AKT and mTOR pathways.

Figure 5

The possible role of autophagy (crinophagy) in insulin production, physiological conditions, and the pathological onset of T1D. (a) Glucose metabolism in the mitochondria generates ATP and ROS, which are two important insulin production and secretion stimulators. Hyperglycemia can lead to excessive ROS levels, leading to oxidative stress and the increased burden of chronically high levels of insulin secretion on the ER, resulting in ER stress and oxidative stress, which autophagy can alleviate to protect the β cells against apoptosis. As an alternative, it may be possible that stimulated crinophagy leads to direct insulin granules fusion to lysosomes instead of autophagy. In the physiological condition, protein degradation generated peptides tailored in the ideal length for binding to MHC-I and recognized as self and tolerated. This occurs through the ubiquitin/proteasome system or alternative processes such as autophagy. (b) In the early stages of T1D pathogenesis, environmental factors can cause the breakdown of self-proteins to target β cells. Autoantigens are trimmed to modified peptides in β cells and loaded into MHC-I molecules. The pMHCI reaches the progenitor membrane and is recognized by the TCR on CD8 + T cells, causing T cell activation and eventually insulitis.