Role of β-cell autophagy in β-cell physiology and the development of diabetes

Abstract

Elucidating the molecular mechanism of autophagy was a landmark in understanding not only the physiology of cells and tissues, but also the pathogenesis of diverse diseases, including diabetes and metabolic disorders. Autophagy of pancreatic β-cells plays a pivotal role in the maintenance of the mass, structure and function of β-cells, whose dysregulation can lead to abnormal metabolic profiles or diabetes. Modulators of autophagy are being developed to improve metabolic profile and β-cell function through the removal of harmful materials and rejuvenation of organelles, such as mitochondria and endoplasmic reticulum. Among the known antidiabetic drugs, glucagon-like peptide-1 receptor agonists enhance the autophagic activity of β-cells, which might contribute to the profound effects of glucagon-like peptide-1 receptor agonists on systemic metabolism. In this review, the results from studies on the role of autophagy in β-cells and their implication in the development of diabetes are discussed. In addition to non-selective (macro)autophagy, the role and mechanisms of selective autophagy and other minor forms of autophagy that might occur in β-cells are discussed. As β-cell failure is the ultimate cause of diabetes and unresponsiveness to conventional therapy, modulation of β-cell autophagy might represent a future antidiabetic treatment approach, particularly in patients who are not well managed with current antidiabetic therapy.

Keywords: Autophagy; Lysosome; β‐Cells.

Figure 1

Selective autophagy in pancreatic β‐cells. (①) When mitochondrial stress occurs, PTEN‐induced putative kinase (PINK) accumulates on the outer mitochondrial membrane of depolarized mitochondria and induces ubiquitin phosphorylation and PARKIN recruitment. PARKIN, an E3 ligase, induces the ubiquitination of target proteins recognized by mitophagy receptors, such as NDP52 or OPTN, to initiate autophagosome formation. (②) Receptor‐mediated mitophagy occurs by direct binding of LC3 to mitophagy receptor molecules on the outer mitochondrial membrane harboring LC3‐interacting region domains, such as FUNDC1. (③) Aggregates of misfolded proteins are formed and degraded by endoplasmic reticulum (ER)‐phage, which is mediated by ER‐phagy receptors, such as RTN3 when ERAD (see ⑥) is impaired or insufficient. (④) Metabolic or mitochondrial stress induces mitochondrial reactive oxygen species production that can activate lysosomal Ca²⁺ channels and induce lysosomal Ca²⁺ release. Transcription factor EB (TFEB) is activated by Ca²⁺/calcineurin‐mediated dephosphorylation, and then moves to the nuclei to promote expression of target genes including mitophagy receptor genes, such as Ndp52 or Optn. Mitophagy receptors interact with LC3 and mitophagy cargos. Lysosomal Ca²⁺ release is replenished by Ca²⁺ from ER, the largest Ca²⁺ reservoir (dark blue arrow). (⑤) Mitophagy through the CLEC16A–NRDP1–USP8 complex can occur. CLEC16A protects NRDP1, which degrades PARKIN. CLEC16A and NRDP1 also participate in autophagosome‐lysosome fusion. The inhibition of CLEC16A–NRDP1–USP8‐dependent mitophagy by palmitic acid (PA) might play a role in mitochondrial dysfunction caused by metabolic stress. (⑥) ER‐associated degradation (ERAD) induces the degradation of misfolded proteins, such as mutant proinsulin, through the p97‐mediated extraction of ubiquitinated proteins. mtROS, mitochondrial reactive oxygen species.

Figure 2

Lysosomal autophagic degradation pathways other than macroautophagy that can occur in β‐cells. (①) Crinophagy: β‐cell granules directly fuse with lysosomal membrane for insulin degradation. (②) Stress‐induced nascent granule degradation (SINGD): When protein kinase D (PKD) is inactivated during starvation in the Golgi area, nascent insulin secretory granules generated in the Golgi complex directly fuse with lysosomes. Amino acids released by lysosomal degradation of insulin granules activate mammalian target of rapamycin complex 1 and thereby inhibit autophagy. (③) Vesicophagy: Insulin granules are surrounded by autophagosome. Autophagosome containing insulin secretory granules fuses with lysosome for degradation of insulin secretory granules. (④) Golgi membrane‐associated degradation (GOMED): When the insulin secretory process from the Golgi complex is abrogated in β‐cells, which are deficient in autophagy, an autophagosome‐like double‐membrane structure is formed from the Golgi membrane in an Atg5/7‐independent and Rab9‐dependent manner. (⑤) Microautophagy: β‐cell granules are engulfed by late endosome or multivesicular body (MVB) in a manner similar to phagocytosis of foreign or endogenous materials. (⑥) Chaperone‐assisted endosomal microautophagy (CAEMI): Target molecules or structures are conjugated to chaperones and co‐chaperones for engulfment by endosome. (⑦) Chaperone‐assisted selective autophagy (CASA): Target molecules or structures are conjugated to chaperones and co‐chaperones for autophagic degradation.

Figure 3

Autophagy activation by current antidiabetic drugs. Metformin can enhance autophagy through direct activation of adenosine monophosphate‐activated protein kinase (AMPK), which phosphorylates transcription factor EB (TFEB) and enhances transcriptional activity. Metformin‐mediated inhibition of mitochondrial complex I would contribute to AMPK activation by metformin. Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists induce cyclic adenosine monophosphate (cAMP) production through activation of Gα_s and adenylate cyclase. cAMP produced by adenylate cyclase activates EPAC2, which can induce Ca²⁺ release from intracellular sources and subsequent Ca²⁺/calcineurin‐dependent nuclear translocation of TFEB, a master regulator of lysosomal biogenesis and autophagy gene expression. Ca²⁺/calcineurin^– can also induce the growth of juvenile β‐cells through the dephosphorylation of NFATc, and induction of CDK and cyclin. SGLT2 inhibitor can activate AMPK and sirtuin 1 (SIRT1). SIRT1 induces autophagy gene expression through deacetylation of PGC‐1α. Dipeptidyl peptidase‐4 (DPP4) inhibitor increases the serum GLP‐1 levels.