Autophagy, Pyroptosis and Ferroptosis are Rising Stars in the Pathogenesis of Diabetic Nephropathy.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes and can potentially develop into end-stage renal disease. Its pathogenesis is complex and not fully understood. Podocytes, glomerular endothelial cells (GECs), glomerular mesangial cells (GMCs) and renal tubular epithelial cells (TECs) play important roles in the normal function of glomerulus and renal tubules, and their injury is involved in the progression of DN. Although our understanding of the mechanisms leading to DN has substantially improved, we still need to find more effective therapeutic targets. Autophagy, pyroptosis and ferroptosis are programmed cell death processes that are associated with inflammation and are closely related to a variety of diseases. Recently, a growing number of studies have reported that autophagy, pyroptosis and ferroptosis regulate the function of podocytes, GECs, GMCs and TECs. This review highlights the contributions of autophagy, pyroptosis, and ferroptosis to DN injury in these cells, offering potential therapeutic targets for DN treatment.

Overexpression of TRIM32 promotes pancreatic ß-cell autophagic cell death through Akt/mTOR pathway under high glucose conditions.

Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic and is characterized by progressive pancreatic ß-cell dysfunction and insulin resistance. Tripartite motif protein 32 (TRIM32) belongs to the TRIM family protein and has been shown to be involve in insulin resistance in skeletal muscle and the liver. However, the effect of TRIM32 on pancreatic ß-cell dysfunction and its mechanism remains unknown. In the current study, we found that serum TRIM32 concentrations of T2DM in patients were significantly elevated compared to those in healthy controls, which indicated that TRIM32 might be used as a diagnostic biomarker in T2DM patients. In INS-1 cells, exposure to high glucose (HG) conditions caused a significant elevation in TRIM32 expression and TRIM32 was located in the nucleus. Overexpression of TRIM32 in INS-1 cells exacerbated the effects of HG-induced autophagy and impaired insulin secretion. In contrast, the silencing of TRIM32 produced the opposite effect. Furthermore, TRIM32 overexpression decreased the phosphorylation levels of Akt and mTOR under HG conditions. However, the activation of Akt/mTOR by MHY1485 reversed the effects of TRIM32 on HG-treated INS-1 cells. Collectively, the present results suggested that TRIM32 participates in the development of T2DM by modulating autophagic cell death and insulin secretion, which might occur through the Akt/mTOR pathway. Thus, TRIM32 might be a promising target in T2DM therapy.

LncRNA MEG3 regulates autophagy and pyroptosis via FOXO1 in pancreatic ß-cells.

Diabetes mellitus (DM) is a chronic metabolic disease, and its exact pathogenesis remains unclear. Autophagy and pyroptosis play an important role in pancreatic ß-cells inflammation and death. Recent advances revealed that LncRNA MEG3 (MEG3) promotes insulin secretion and inhibits pancreatic ß-cells apoptosis in DM. However, its effect on pancreatic ß-cells autophagy and pyroptosis remains elusive. This study investigated whether MEG3 can regulate autophagy and pyroptosis through FOXO1 in pancreatic ß-cells. Here, a significant reduction of MEG3 and FOXO1 expression was found in the DM group of mouse model, in company with, autophagy dysfunction and pyroptosis hyperactivity. In the cell model, the level of autophagy was increased in high-glucose (HG) induced INS-1 cells. Besides, we found that MEG3 or FOXO1 knockdown leads to decreased autophagy, and up-regulated pyroptosis in HG-induced INS-1 cells. Furthermore, the deficiency of MEG3 significantly decreased FOXO1 expression. In addition, the specific inhibitors of autophagy also increased pyroptosis-related protein expression. These results demonstrate that MEG3 may adjust both autophagy and pyroptosis through FOXO1 in pancreatic ß-cells. Moreover, we also first verified that inhibiting autophagy can promote pyroptosis in HG-induced INS-1 cells.

Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (Review).

Type 2 diabetes mellitus (T2DM) is a major chronic disease that is characterized by pancreatic ß-cell dysfunction and insulin resistance. Autophagy is a highly conserved intracellular recycling pathway and is involved in regulating intracellular homeostasis. Transcription factor Forkhead box O1 (FoxO1) also regulates fundamental cellular processes, including cell differentiation, metabolism and apoptosis, and proliferation to cellular stress. Increasing evidence suggest that autophagy and FoxO1 are involved in the pathogenesis of T2DM, including ß-cell viability, apoptosis, insulin secretion and peripheral insulin resistance. Recent studies have demonstrated that FoxO1 improves insulin resistance by regulating target tissue autophagy. The present review summarizes current literature on the role of autophagy and FoxO1 in T2DM. The participation of FoxO1 in the development and occurrence of T2DM via autophagy is also discussed.

The role of TRIM family proteins in autophagy, pyroptosis, and diabetes mellitus.

The ubiquitin-proteasome system, which is one of the systems for cell protein homeostasis and degradation, happens through the ordered and coordinated action of three types of enzymes, E1 ubiquitin-activating enzyme, E2 ubiquitin-carrier enzyme, E3 ubiquitin-protein ligase. Tripartite motif-containing (TRIM) family proteins are the richest subfamily of really interesting new gene E3 ubiquitin ligases, which play a critical role not only in many biological processes, including proliferation, apoptosis, pyroptosis, innate immunity, and autophagy, but also many diseases like cancer, diabetes mellitus, and neurodegenerative disease. Increasing evidence suggests that TRIM family proteins play a vital role in modulating autophagy, pyroptosis, and diabetes mellitus. The aim of this review is to discuss the role of TRIM proteins in the regulation of autophagy, pyroptosis, diabetes mellitus, and diabetic complications.

Liraglutide protects palmitate-induced INS-1 cell injury by enhancing autophagy mediated via FoxO1.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and a progressive loss in mass and function of pancreatic ß-cells. In T2DM, lipotoxicity leads to ß-cells dysfunction and decreases its number. Autophagy serves a crucial role in maintaining the normal islet architecture and the function of ß-cells. Moreover, glucagon-like peptide-1 (GLP-1) and its analogs have beneficial roles in pancreatic ß-cells. However, the protective effects of GLP-1 agents on palmitate (PA)-induced pancreatic ß-cells and their underlying mechanisms are not fully elucidated. Forkhead box O1 (FoxO1) can prevent pancreatic ß-cells from apoptosis. Whether GLP-1 protects against PA-induced ß-cells injury via FoxO1 remains unknown. The present study exposed INS-1 cells to PA to establish a T2DM injury model. Cell viability was evaluated using a Cell Counting Kit-8 assay, and apoptosis was determined via western blotting. Furthermore, autophagy was examined using western blotting, immunofluorescence and transmission electron microscopy. Silencing FoxO1 was used to inhibit the activities of FoxO1. The results suggested that the GLP-1 analog liraglutide enhanced the cell viability, inhibited the protein expression of cleaved caspase-3 and increased the expression levels of microtubule-associated protein 1 light chain3 (LC3) II/I, and FoxO1 in INS-1 cells. The autophagy inhibitor chloroquine inhibited the protective effects of liraglutide on INS-1 cells. Silencing of FoxO1 decreased the expression levels of LC3-II and attenuated the protection of liraglutide on the viability of INS-1 cells. In conclusion, the results indicated that liraglutide ameliorated the PA-induced islet ß-cells injury via the upregulation of autophagy-mediated by FoxO1.