cells Review Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress Eloisa Aparecida Vilas-Boas 1,2, * , Davidson Correa Almeida 3 , Leticia Prates Roma 4 , Fernanda Ortis 3 and Angelo Rafael Carpinelli 1, *   Citation: Vilas-Boas, E.A.; Almeida, D.C.; Roma, L.P.; Ortis, F.; Carpinelli, A.R. Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress. Cells 2021, 10, 3328. https://doi.org/10.3390/cells10123328 Academic Editor: Adria Giacca Received: 11 October 2021 Accepted: 22 November 2021 Published: 26 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, Brazil 2 Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), São Paulo 05508-900, Brazil 3 Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, Brazil; davidson.almeida@usp.br (D.C.A.); fortis@usp.br (F.O.) 4 Center for Human and Molecular Biology (ZHMB), Department of Biophysics, Saarland University, 66424 Homburg, Germany; leticia.prates-roma@uks.eu * Correspondence: elovilasboas@usp.br (E.A.V.-B.); angelo@icb.usp.br (A.R.C.); Tel.: +55-(11)-3091-7246 (A.R.C.) 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. Keywords: lipotoxicity; pancreatic β-cell; type 2 diabetes; NADPH oxidase; oxidative stress; ER stress 1. Introduction Type 2 diabetes mellitus (T2D) is characterized by a dysfunction in glucose, lipid, and protein metabolism caused by a combination of impaired insulin secretion and insulin sensitivity, resulting in overt hyperglycemia. Of the three major types of diabetes mellitus (type 1, type 2, and gestational), T2D is by far the most prevalent, representing more than 90% of cases [1]. Three major abnormalities contribute to hyperglycemia in T2D: decreased insulin sensitivity in (1) muscle; (2) liver; and (3) impaired insulin secretion. Insulin resistance in muscle is characterized by reduced glucose uptake in the postprandial phase, whereas in the liver, the hallmark of insulin resistance is increased hepatic glucose production (HPG) in the face of hyperinsulinemia [2]. Despite T2D having an important genetic component [3–5], the recent rise in T2D cases can be mostly attributed to the increase in obesity and lack of physical activity; both being insulin resistance-promoting states [1,2]. Moreover, central (or visceral) adiposity is better linked to insulin resistance and plasma levels of glucose, insulin, cholesterol, triglycerides and high-density lipoprotein cholesterol than total adiposity. In persons with prediabetes (impaired fasting glucose, impaired glucose tolerance, without overt hyperglycemia), insulin resistance is compensated by insulin secretion to maintain normoglycemia. It is Cells 2021, 10, 3328. https://doi.org/10.3390/cells10123328 https://www.mdpi.com/journal/cells