Minireview: Autophagy in pancreatic β-cells and its implication in diabetes

Abstract

Autophagy is a conserved system for the degradation of cytoplasmic proteins and organelles. During insulin resistance, in which insulin secretion is enhanced and β-cell mass is increased owing to changes in the expression and function of various proteins in pancreatic β-cells, autophagic activity appears to also be enhanced to adapt to the dynamic changes occurring in β-cells. Indeed, defective autophagy in β-cells recapitulates several features that are observed in islets during the development of type 2 diabetes mellitus. In addition, the dyregulation of autophagic activity appears to occur in the β-cells of type 2 diabetic model mice and type 2 diabetes mellitus patients. These lines of evidence suggest that autophagic failure may be implicated in the pathophysiology of type 2 diabetes mellitus. In this review, we summarized the recent findings regarding how autophagy in β-cells is regulated and how dysfunction of the autophagic machinery may lead to the dysfunction of β-cells.

Figure 1.. Signaling pathway regulating the initiation of autophagy and the formation of autophagosomes.

Macroautophagy consists of distinct stages: phagophore formation, vesicle elongation and completion, and fusion of the double-membrane autophagosome with the lysosome to form an autolysosome. The ULK1 complex and Vps34 complex are key regulators for the initiation of autophagy. The ULK1 complex is composed of ULK1, Atg13, Atg101, and FIP200. Under normal conditions, mTORC1 interacts with the ULK1 complex and inactivates it. In the presence of autophagy inducers, mTORC1 dissociates from the complex. This results in increased ULK1 kinase activity and the phosphorylation of Atg13 and FIP200. The Vps34 complex is composed of Vps34, Beclin-1, Vps15, Atg14L, and Ambra1. Phosphatidylinositol 3-phosphate, the product of ULK1, recruits the double FYVE domain-containing protein 1 (DFCP1) and WD-repeated protein interacting with phosphoinositides (WIPI) family proteins. Wortmannin and 3-methyladenine inhibit ULK1. ULK1 phosphorylates Beclin-1 at Ser14 and enhances PI(3)K activity of the Vps34 complex. This phosphorylation is essential for the full induction of autophagy. In addition, AMP-activated protein kinase (AMPK) phosphorylates Beclin-1 and activates Vps34 lipid kinase. On the other hand, Akt phosphorylates Beclin-1 and suppresses its kinase activity. Vesicle elongation and the formation of double-membrane vesicles are mediated by 2 ubiquitin-like conjugation systems involving ATG proteins. The first system is the ATG12-ATG5 conjugation reaction. The ATG12-ATG5 conjugates form a multimeric complex with ATG16L1 through ATG7 and ATG10. The second system is the conjugation reaction of LC3, the mammalian homologue of ATG8. LC3-I is generated from pro-LC3 by the Atg4 protease. Then, through ATG7, ATG3, and the ATG12-ATG5-ATG16L complex, LC3 conjugates to the phospholipid phosphatidylethanolamine to form LC3-II. During the formation of the autophagosome from the preautophagosome, ATG12-ATG5 complexes are released from the membranes, and LC3-II localizes on them.