β-cell autophagy: Mechanism and role in β-cell dysfunction

Abstract

Background: Elucidation of the basic molecular mechanism of autophagy was a breakthrough in understanding various physiological events and pathogenesis of diverse diseases. In the fields of diabetes and metabolism, many cellular events associated with the development of disease or its treatment cannot be explained well without taking autophagy into account. While a grand picture of autophagy has been established, detailed aspects of autophagy, particularly that of selective autophagy responsible for homeostasis of specific organelles or metabolic intermediates, are still ambiguous and currently under intensive research.

Scope of review: Here, results from previous and current studies on the role of autophagy and its dysregulation in the physiology of metabolism and pathogenesis of diabetes are summarized, with an emphasis on the pancreatic β-cell autophagy. In addition to nonselective (bulk) autophagy, machinery and significance of selective autophagy such as mitophagy of pancreatic β-cells is discussed. Novel findings regarding autophagy types other than macroautophagy are also covered, since several types of autophagy or lysosomal degradation pathways other than macroautophagy coexist in pancreatic β-cells.

Major conclusion: Autophagy plays a critical role in cellular metabolism, homeostasis of the intracellular environment and function of organelles such as mitochondria and endoplasmic reticulum. Impaired autophagic activity due to aging, obesity or genetic predisposition could be a factor in the development of β-cell dysfunction and diabetes associated with lipid overload or human-type diabetes characterized by islet amyloid deposition. Modulation of autophagy of pancreatic β-cells is likely to be possible in the near future, which would be valuable in the treatment of diabetes associated with lipid overload or accumulation of islet amyloid.

Keywords: Autophagy; Crinophagy; Islet-associated polypeptide (IAPP); Lysosome; Mitophagy; β-cells.

Figure 1

Molecular pathways of autophagy. (1) Initiation/Nucleation: Autophagy inducers such as nutrient deprivation or rapamycin reduce mTORC1 phosphorylation, which liberates the ULK1/2 complex. The ULK1/2 complex increases activity of the Beclin1/Vps34 complex through phosphorylation of Ambra1 and Beclin 1. PI3P, produced by Vps34, recruits effector proteins such as DFCP1 and WIPI2 to promote formation of isolation membrane and to constitute the nucleation step. (2) Expansion/Completion: Expansion of autophagosome is mediated by two conjugated systems comprising Atg12-Atg5-Atg16L and LC3-Atg3 which lead to the formation of LC3-PE (LC3-II). (3) Degradation/Retrieval: After completion, mature autophagosome fuses with lysosome forming autophagolysosome, wherein the sequestered materials or organelles are degraded by lysosomal enzymes. After digestion of entrapped materials, nutrients become available and mTORC1 is reactivated. Proto-lysosomal tubules are then formed which mature into functional lysosome, constituting the retrieval process.

Figure 2

Machinery of selective autophagy. (1) Mitophagy: When mitochondrial potential is dissipated by mitochondrial stressors, PINK1 is stabilized on the outer membrane of mitochondria and recruits Parkin. Parkin, as an E3 ligase, ubiquitinates several substrates in mitochondria and induces mitophagy together with autophagy receptors including p62, optineurin, NDP52 and NBR1. In addition to Parkin-mediated ubiquitin-dependent mitophagy, Parkin-independent receptor-mediated autophagy and piecemeal-type mitophagy has also been described. (2) ER-phagy: An ER membrane protein, FAM134B, has been shown to mediate ER-phagy through the interaction of the LIR domain of FAM134B and LC3. In addition to FAM134B, Sec62 and RTN3 can also interact with LC3 through their LIR domains. FAM134B and Sec62 mediate ER-phagy of ER cistern, while RTN3 mediates that of ER tubule. (3) Lipophagy: Small GTPases such as Rab7 or Rab10 have been shown to mediate the formation of the ‘lipophagic synapse’ and autophagic degradation of LD. LC3 may also facilitate recruitment of ATGL to LD via the interaction with the LIR domain of ATGL, leading to lipolysis by cytosolic lipases. Autophagy may also contribute to the DGAT-1-dependent formation of LD by providing free fatty acids (FFAs) (green arrows), which may favor efficient oxidative degradation of FFAs through β-oxidation after transfer to mitochondria and reduce lipotoxicity of FFAs.

Figure 3

A model for autophagic clearance of pro-hIAPP oligomer. Pro-hIAPP dimer is formed in the membrane-rich fraction after binding of pro-hIAPP to the membrane fraction. Some pro-hIAPP dimers are translocated to the soluble fraction, while other pro-hIAPP dimers proceed to form pro-hIAPP timers. pro-hIAPP dimer and trimer are targets of autophagic clearance. high-n or fibrillary hIAPP oligomer could also be targets of autophagy. Autophagy enhancers may be able to expedite clearance of pro-hIAPP dimer, pro-trimer and hIAPP oligomer.

Figure 4

Lysosomal autophagic degradation pathways other than macroautophagy in pancreatic β-cells. (1) SINGD: In starvation, PKD is inactivated at the Golgi area and nascent insulin secretory granules generated in Golgi apparatus directly fuse with lysosomes. Amino acids released from lysosomal degradation of insulin secretory granules inhibit autophagy through mTORC1. (2) Vesicophagy: Insulin granules are sequestered in autophagosome, and autophagosome containing insulin secretory granules as an autophagy cargo fuses with lysosome for degradation of insulin secretory granules. (3) Microautophagy: β-cell granules are engulfed by late endosome or multivesicular body in a manner similar to phagocytosis for degradation of the granule components. (4) GOMED: When the insulin secretory process from the Golgi apparatus is suppressed in autophagy-deficient β-cells, autophagosome-like double-membrane compartment is formed from Golgi membrane in an Atg5/7-independent but Rab9-dependent manner.