Autophagy regulates insulin resistance following endoplasmic reticulum stress in diabetes

Autophagy is a kind of cell biological process that maintains the cell’s energy level under nutrient-poor conditions, regulates the turnover of abnormal or aged proteins, and disposes of dysfunctional organelles. The autophagy system is activated as a novel signaling pathway in response to endoplasmic reticulum stress (ER stress)-induced insulin resistance (IR). Defective autophagy may be closely related to insulin resistance. There are at least three mechanistically distinct arms of ER stress that regulate the expression of key genes which not only function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids, and lipids. ER stress-stimulated insulin resistance is mediated by the autophagy-dependent process. In settings of chronic ER stress, the associated autophagy may contribute to pathophysiological processes involved in a number of prevalent diseases, including diabetes. Whether autophagy plays a protective or harmful role in diabetes awaits further analysis. In this review, we will summarize the current knowledge about the emerging role of autophagy in ER stress-induced insulin resistance. Strategies to take advantage of the potential protective effect of autophagy remain important in the overall treatment of insulin resistance and type 2 diabetes

Autophagy regulates insulin resistance following endoplasmic reticulum stress in diabetes.

Autophagy is a kind of cell biological process that maintains the cell's energy level under nutrient-poor conditions, regulates the turnover of abnormal or aged proteins, and disposes of dysfunctional organelles. The autophagy system is activated as a novel signaling pathway in response to endoplasmic reticulum stress (ER stress)-induced insulin resistance (IR). Defective autophagy may be closely related to insulin resistance. There are at least three mechanistically distinct arms of ER stress that regulate the expression of key genes which not only function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids, and lipids. ER stress-stimulated insulin resistance is mediated by the autophagy-dependent process. In settings of chronic ER stress, the associated autophagy may contribute to pathophysiological processes involved in a number of prevalent diseases, including diabetes. Whether autophagy plays a protective or harmful role in diabetes awaits further analysis. In this review, we will summarize the current knowledge about the emerging role of autophagy in ER stress-induced insulin resistance. Strategies to take advantage of the potential protective effect of autophagy remain important in the overall treatment of insulin resistance and type 2 diabetes.

Matrix metalloproteinase-1 (MMP1) polymorphism is associated with lowered risk of nasopharyngeal carcinoma in Asian population.

Data on the association between -1607 1G > 2G polymorphism in the promoter region of matrix metalloproteinase-1 (MMP1) and nasopharyngeal carcinoma (NPC) are conflicting. The aim of this study was to confirm whether this polymorphism was a causative factor of NPC. We searched PubMed, Embase, and China National Knowledge Infrastructure (CNKI) for studies on the present topic. A total of four publications (1,044 NPC patients and 1,284 healthy control subjects) were included and meta-analysis was performed to assess the association between -1607 1G > 2G polymorphism and NPC risk. Odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated for 1G1G versus 2G2G, 1G1G + 1G2G versus 2G2G, 1G1G versus 1G2G + 2G2G, 1G versus 2G, and 1G2G versus 2G2G contrast models. Meta-analysis results showed significantly reduced risk of NPC associated with the 1G1G versus 2G2G, 1G versus 2G and 1G2G versus 2G2G contrast models (OR = 0.61, 95 % CI 0.49-0.77; OR = 0.78, 95 % CI 0.65-0.92; OR = 0.86, 95 % CI 0.74-0.99, respectively). When we continued to perform subgroup analysis by ethnicity, the significant association persisted in Asian population and was most pronounced under the 1G2G versus 2G2G model (OR = 0.85, 95 % CI 0.73-0.99). These data suggested that MMP1 -1607 1G > 2G polymorphism was associated with reduced risk of NPC, particularly in the population of Asian descent.

Endoplasmic reticulum stress is involved in the connection between inflammation and autophagy in type 2 diabetes.

Type 2 diabetes is a chronic inflammatory disease. A number of studies have clearly demonstrated that cytokines such as interleukin 1ß (IL1ß) contribute to pancreatic inflammation, leading to impaired glucose homeostasis and diabetic disease. There are findings which suggest that islet ß-cells can secrete cytokines and cause inflammatory responses. In this process, thioredoxin-interacting protein (TXNIP) is induced by endoplasmic reticulum (ER) stress, which further demonstrates a potential role for ER stress in innate immunity via activation of the NOD-like receptor (NLRP) 3/caspase1 inflammasome and in diabetes pathogenesis via the release of cytokines. Recent developments have also revealed a crucial role for the autophagy pathway during ER stress and inflammation. Autophagy is an intracellular catabolic system that not only plays a crucial role in maintaining the normal islet architecture and intracellular insulin content but also represents a form of programmed cell death. In this review, we focus on the roles of autophagy, inflammation, and ER stress in type 2 diabetes but, above all, on the connections among these factors.

Liraglutide prevents high glucose level induced insulinoma cells apoptosis by targeting autophagy.

BACKGROUND: The pathophysiology of type 2 diabetes is progressive pancreatic beta cell failure with consequential reduced insulin secretion. Glucotoxicity results in the reduction of beta cell mass in type 2 diabetes by inducing apoptosis. Autophagy is essential for the maintenance of normal islet architecture and plays a crucial role in maintaining the intracellular insulin content by accelerating the insulin degradation rate in beta cells. Recently more attention has been paid to the effect of autophagy in type 2 diabetes. The regulatory pathway of autophagy in controlling pancreatic beta cells is still not clear. The aim of our study was to evaluate whether liraglutide can inhibit apoptosis and modulate autophagy in vitro in insulinoma cells (INS-1 cells). METHODS: INS-1 cells were incubated for 24 hours in the presence or absence of high levels of glucose, liraglutide (a long-acting human glucagon-like peptide-1 analogue), or 3-methyadenine (3-MA). Cell viability was measured using the Cell Counting Kit-8 (CCK8) viability assay. Autophagy of INS-1 cells was tested by monodansylcadaverine (MDC) staining, an autophagy fluorescent compound used for the labeling of autophagic vacuoles, and by Western blotting of microtubule-associated protein I light chain 3 (LC3), a biochemical markers of autophagic initiation. RESULTS: The viability of INS-1 cells was reduced after treatment with high levels of glucose. The viability of INS-1 cells was reduced and apoptosis was increased when autophagy was inhibited. The viability of INS-1 cells was significantly increased by adding liraglutide to supplement high glucose level medium compared with the cells treated with high glucose levels alone. CONCLUSIONS: Apoptosis and autophagy were increased in rat INS-1 cells when treated with high level of glucose, and the viability of INS-1 cells was significantly reduced by inhibiting autophagy. Liraglutide protected INS-1 cells from high glucose level-induced apoptosis that is accompanied by a significant increase of autophagy, suggesting that liraglutide plays a role in beta cell apoptosis by targeting autophagy. Thus, autophagy may be a new target for the prevention or treatment of diabetes.

Autophagy regulates inflammation following oxidative injury in diabetes.

T1D (type 1 diabetes) is an autoimmune disease characterized by lymphocytic infiltration, or inflammation in pancreatic islets called 'insulitis.' Comparatively speaking, T2D (type 2 diabetes) is traditionally characterized by insulin resistance and islet ß cell dysfunction; however, a number of studies have clearly demonstrated that chronic tissue inflammation is a key contributing factor to T2D. The NLR (Nod-like receptor) family of innate immune cell sensors such as the NLRP3 inflammasome are implicated in leading to CASP1 activation and subsequent IL1B (interleukin 1, ß) and IL18 secretion in T2D. Recent developments reveal a crucial role for the autophagy pathway under conditions of oxidative stress and inflammation. Increasingly, research on autophagy has begun to focus on its role in interacting with inflammatory processes, and thereby how it potentially affects the outcome of disease progression. In this review, we explore the pathophysiological pathways associated with oxidative stress and inflammation in T2D. We also explore how autophagy influences glucose homeostasis by modulating the inflammatory response. We will provide here a perspective on the current research between autophagy, inflammation and T2D.