Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Abstract

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.

Optimization of a GC-MS method for the profiling of microbiota-dependent metabolites in blood samples: An application to type 2 diabetes and prediabetes

“…Among all metabolites used for ROC analysis, SA exhibited the highest AUC value (0.995) (Figure 6). An increased concentration of serum SA plays a fundamental role in the development of beta cell dysfunction and T2DM, as this FA is the major contributor to lipotoxicity in beta cells (Vilas-Boas et al, 2021). It was consistent with the findings of Lu et al (2016) and Zhao et al (2017), who identified FAs as the most important pathogenic factors for insulin resistance and T2DM.…”

Luminal H 2 O 2 promotes ER Ca 2+ dysregulation and toxicity of palmitate in insulin‐secreting INS‐1E cells

“…25,26 However, there is still considerable controversy about the mechanisms of how palmitate promotes the disruption of ER Ca 2+ homeostasis. 54,55 While the molecular mechanisms of ER Ca 2+ dysregulation in response to palmitate in βcells are still unknown, 55 for mouse podocytes it has been proposed that palmitateinduced mobilization of ER Ca 2+ requires the activation of phospholipase C and subsequent activation of the ER 2+ ion channel IP R. proposed mechanisms include alterations ER membrane composition that may lead to ER Ca 2+ -ATPase (SERCA) pump dysfunction, 56,57 as well as downregulation of its expression. 58 In this report, our findings highlight the important role of luminal H 2 O 2 in palmitate-mediated dysregulation of ER Ca 2+ homeostasis.…”

“…Previous studies have shown that palmitate, the most abundant long‐chain saturated FFA in plasma, induces ER Ca 2+ depletion in pancreatic β‐ 21–24 and non‐β‐cells 25,26 . However, there is still considerable controversy about the mechanisms of how palmitate promotes the disruption of ER Ca 2+ homeostasis 54,55 . While the molecular mechanisms of ER Ca 2+ dysregulation in response to palmitate in β‐cells are still unknown, 55 for mouse podocytes it has been proposed that palmitate‐induced mobilization of ER Ca 2+ requires the activation of phospholipase C and subsequent activation of the ER Ca 2+ ion channel IP 3 R 26 .…”

Deep Sea Water Inhibited Pancreatic β-Cell Apoptosis and Regulated Glucose Homeostasis by Affecting Lipid Metabolism in Db/Db Mice

“… 32 Results presented a positive effect of DOMC on adiponectin expression and further on glucose homeostasis. As reported that lipid toxicity accelerates the apoptosis of pancreatic β-cell and leads to the loss of pancreatic mass and function and T2DM progression, 23 , 33 , 34 we further explored the relationship among DOMC, lipid metabolism and glucose metabolism. We measured pancreatic β-cell, however, pathological staining showed no difference in pancreatic islet β-cell between the db/db and db/db+DOMC groups with a 4-week administration of DOMC.…”