Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells.

Shiau-Mei Chen,Shih-Yun Chou,Che-Hong Chen,Daria Mochly-Rosen,Meng-Wei Liu,Siow-Wey Hee,Lee-Ming Chuang,Tien-Jyun Chang

doi:10.3390/biom11101474

Abstract

Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.

Highlights

Insulin resistance and progressive pancreatic beta cell dysfunction are the main features of type 2 diabetes mellitus, most likely owing to a vicious cycle involving the accumulation of toxic aldehydes and relative oxidative stress [1]
The fine balance between the levels of pro-oxidants and antioxidants in pancreatic beta cells is disturbed, which leads to a chronic oxidative stress that subsequently contributes to impaired glucose-stimulated insulin secretion (GSIS) [2,3]
We developed a new strategy of preserving beta cell function and cell viability by activating aldehyde dehydrogenase 2 (ALDH2) to detoxify glucolipotoxicity-induced reactive oxygen species (ROS) production, decreasing mitochondrial function and subsequent beta cell dysfunction, cell apoptosis and death

Summary

Introduction

Insulin resistance and progressive pancreatic beta cell dysfunction are the main features of type 2 diabetes mellitus, most likely owing to a vicious cycle involving the accumulation of toxic aldehydes and relative oxidative stress [1]. It is well known that chronic hyperglycemia and hyperlipidemia, known as glucolipotoxicity, are harmful to beta cell function. The fine balance between the levels of pro-oxidants and antioxidants in pancreatic beta cells is disturbed, which leads to a chronic oxidative stress that subsequently contributes to impaired glucose-stimulated insulin secretion (GSIS) [2,3]. The decreases in antioxidant defense, hyperglycemia, inflammation, and obesity contribute to the accumulation of toxic aldehydes, including glyoxal, methylglyoxal (MG), glycolaldehyde, and 4-hydroxynonenal (4-HNE), among others [5]. The elevated levels of toxic aldehydes can damage carbohydrates, amino acids, and lipids, leading to the formation of reactive carbonyl compounds

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