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

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 12; p. 3328
• Main Authors: Vilas-Boas, Eloisa Aparecida, Almeida, Davidson Correa, Roma, Leticia Prates, Ortis, Fernanda, Carpinelli, Angelo Rafael
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.11.2021; MDPI
• Subjects: Adipocytes; Animals; Beta cells; Carbon; Cell death; Cell survival; Cholesterol; Chronic effects; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - pathology; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; ER stress; Fatty acids; Glucose; Humans; Hyperglycemia; Insulin; Insulin resistance; Insulin secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Lipids; Lipids - chemistry; Lipids - toxicity; lipotoxicity; Liver; Mitochondria; NAD(P)H oxidase; NADPH oxidase; NADPH Oxidases - metabolism; Obesity; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Pancreas; pancreatic β-cell; Phosphorylation; Plasma; Plasma levels; Proteins; Reactive oxygen species; Review; Risk factors; type 2 diabetes; ER stress; pancreatic β-cell; type 2 diabetes; NADPH oxidase; oxidative stress; lipotoxicity
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10123328

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.