Roles of Autophagy in Regulating ER Stress-Mediated Type 2 Diabetes

Type 2 diabetes (T2D) is a metabolic disorder closely associated with endoplasmic reticulum (ER) stress mediated β-cells loss and/or dysfunction and insulin resistance. On the other hand, ER stress and autophagy are strongly interconnected to maintain cellular homeostasis under metabolic stress and environmental cues. Therefore, co-targeting autophagy and ER stress is a promising strategy for T2D treatment.


Introduction
The endoplasmic reticulum (ER) is the main site in the cell for the post-translational modification and secretion of insulin and other proteins. High blood glucose, starvation, lipid toxicity, free fatty acid (FFA), obesity, oxidative stress, insulin resistance, abnormal inflammatory response and Ca2+ concentration increase the burden of insulin synthesis and/or impair the insulin processing step in the ER and lead to ER stress [1][2][3][4][5][6][7][8][9]. Many scientific studies reported that ER stress is implicated in β-cell dysfunction, impaired insulin secretion, and insulin resistance that are considered the main reasons for the pathogenesis of T2D [7,10]. Autophagy plays an important role in regulating ER stress-mediated β-cell dysfunction and insulin resistance, although details mechanism of autophagy in diabetes remains to be elucidated. ER stress-mediated autophagy is usually activated through the ER stress-induced transcription factors such as CCAAT enhancer-binding protein (C/ EBP)-homologous protein (CHOP), X-box-binding protein 1 (XBP1), or other signaling pathways such as via JNK or mTOR [11][12][13][14].  Several studies demonstrate that autophagy has protective roles by reducing ER stress and inflammatory cytokines (IL1 β) production [5,24,25]. Thioredoxin-interacting protein (TXNIP) is considered a potential therapeutic target for diabetes and other ER stress-mediated diseases as it is an important signaling node that links ER stress, inflammation, and autophagy [5]. TXNIP is activated by ER stress via the PERK and the IRE1 pathways, then stimulates IL1 β production by the NLRP3 inflammasome, and increases β-cell death, whereas autophagy is observed to play important protective roles through reducing ER stress, NLRP3-dependent inflammatory cytokine production and PERK/CHOP mediated apoptosis. In contrast, autophagy is also reported to be associated with β-cells damage in T2D and might contribute to β-cells dysfunction [26].
Forced ER stress is found to trigger autophagy-mediated cell death through downregulation of the Akt/TSC/mTOR pathway [13].
Oxidative stress triggers ER stress-mediated β cell dysfunction through impairing di-sulfide bond formation, and accumulation of misfolded proteins [6,27-29]. For instance, human diabetic islets lead to accumulating β-amyloid that is correlated with oxidative stress and apoptosis in the lack of ER stress [30,31]. In addition, autophagy is found to control hyperglycemia by reducing the oxidative stress-mediated accumulation of ubiquitinated-proteins aggregate in the β-cells [32]. ER stress under oxidative conditions suppresses insulin production, decreases β-cell mass, or even leads to β-ubiquitin and p62, degenerate proteins, reduce insulin content, increase β-cell death, and suppress β-cell proliferation, while autophagy plays a crucial role to protect β-cell by clearing insoluble or long-lived large protein aggregates [35,4]. Recent studies demonstrate that autophagy is activated in response to lipotoxic ER stress to protect the β-cell failure [36]. Decrease in Ca 2+ level in the ER leads to progress T2D through increasing the ER stress, promoting store-operated Ca 2+ entry (SOCE), activating calcium-calmodulin kinase II (CaMKII), decreasing lipid removal by autophagy, and increasing insulin resistance [37]. Interestingly, Park HW et al. [38] reported that in obesity and lipotoxicity, an increase in Ca 2+ concentration decreases autophagy, while Ca 2+ channel blocker restores autophagic flux by enhancing autophagosome-lysosome fusion, prevents large proteins or lipid droplets accumulation, reduces inflammation, and suppresses insulin resistance. Impaired autophagy might entail the development of metabolic disorders through dysregulation of ER stress-mediated insulin resistance. For instance, autophagy is reduced in the liver of obese mice; and Atg7 (autophagy related 7) overexpression restores insulin sensitivity and decreases the expression of ER stress marker [39]. Inversely, insulin resistance inhibits Fox1-dependent expression of key autophagy genes [40]. Activation of X box-binding protein-1 (XBP1) transcription factor through ER stress-mediated phosphorylation of inositol requiring enzyme-1α (IRE1α) plays a vital role in insulin resistance. ER stress by obesity/lipid injury or cytokines is found to develop insulin resistance through serine phosphorylation of insulin receptor system-1/2 (IRS-1/2) by c-Jun N-terminal protein kinase (JNK) [7, 41,42].
Autophagy deficiency usually worsens the ER stress-induced inflammatory response. Yoshizaki T et al. [43] found that autophagy is decreased and inflammation is increased in adipose tissue

Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.