IDF21-0478 Activation of Aldehyde Dehydrogenase 2 (ALDH2) Ameliorates Glucolipotoxicity of the Pancreatic Beta Cells

• Published in: Diabetes research and clinical practice 2022-04, Vol.186, p.109549, Article 109549
• Main Authors: Chen, S.M., Chuang, L.M., Cho, H.Y., Chang, T.J.
• Format: Article
• Language: English
• ISSN: 0168-8227; 1872-8227
• DOI: 10.1016/j.diabres.2022.109549

Background: The prevalence of type 2 diabetes mellitus surges rapidly, especially in developing countries. Excessive aldehydes, formed endogenously by lipid peroxidation and carbohydrate metabolism, exhibit high reactivity to biomolecules, such as protein, DNA, and lipids through formation of intra- or intermolecular covalent adducts, which form advanced glycation end-products (AGEs) or advanced lipoxidation end products (ALEs) and lead to a variety of pathological conditions. Aldehyde dehydrogenase 2 (ALDH2), a mitocondrion-resident enzyme is the most important enzymes metabolizing toxic aldehydes such as acetaldehydes and 4-hydroxynonenal (4-HNE). Beta-cell failure owing to vicious cycle involving oxidative stress. Our team preliminarily found that ALDH2 activator could reduce oxidative-stress-induced beta-cell death and ameliorate insulin secretory function of islet beta cells. Aim: In this study, we investigated the impacts and mechanisms of reactive aldehydes and ALDH2 on beta cell dysfunction & death. We will also study the efficacy and mechanisms of ALDH2 activators on alleviating pancreatic beta cell dysfunction & death. Method: We generated knock-down ALDH2 MIN6 cells (mouse insulinoma cells) by lipofectamin transfection. We compared glucose-stimulated insulin secretion (GSIS), and mitochondrial function between scramble control and ALDH2 knock-down MIN6 cells in the presence or absence of novel ALDH2 activators. We also compared the effect of intermediate metabolites of glucose (methylglyoxal, MG) and lipids (4-hydroxynonenal, 4-HNE) on cell viability, apoptosis, production of reactive oxygen species (ROS), signal transduction, and mitochondrial function of scramble control and ALDH2 knock-down MIN6 cells in the presence or absence of novel ALDH2 activators. Results: ALDH2 activator, Alda-1, enhanced glucose-stimulated Insulin (GSIS) in MIN6 cells and primary islets. The potentiation effect of Alda-1 on GSIS is through improving mitochondrial function presented by increased intracellular ATP concentration and oxygen consumption rate (OCR) in MIN6 cells. Alda-1 rescued MIN6 cells from MG and 4-HNE induced beta cell death and apoptosis through restoration of mitochondrial function. Furthermore, Alda-1 ameliorated MG and 4-HNE increased oxidative stress in mitochondria and cytoplasm in beta cells. On the other hand, the potentiation effect on GSIS and mitochondrial function of ALDH2 activator was abolished in Aldh2 knock-down MIN6 cells. Consistentl