Unraveling the Mechanism behind Obesity-Induced Pancreatic β-Cell Dysfunction
Obesity is known to have adverse effects on various organs. In particular, pancreatic β-cells, which are responsible for insulin secretion, are severely affected by obesity, and the resultant β-cell dysfunction leads to the development of diabetes mellitus. Notably, researchers from the University of Tsukuba reported that the degradation of the metabolite sensor CtBP2 protein is the primary mechanism behind this obesity-associated pathology.
Tsukuba, Japan—Obesity not only increases the risk of metabolic syndrome-related diseases, such as diabetes, fatty liver, and atherosclerosis, but also remarkably impacts seemingly unrelated conditions, such as cancer, psychiatric disorders, and immune function. To understand this wide range of diseases and develop therapeutic approaches for the same, it is important to elucidate the mechanisms by which various organ and cell functions are impaired in the pathogenesis of obesity.
Moreover, the function of pancreatic β-cells is known to be progressively impaired during obesity. Furthermore, impaired insulin secretion is causally associated with the development of diabetes mellitus. However, previous studies primarily focused on mechanisms specific to pancreatic β-cells, thereby overlooking potential factors that commonly affect the whole body in obesity-related diseases. Thus, understanding the common factors in obesity will facilitate the development of effective therapeutic strategies. The research group from the University of Tsukuba has extensively studied the role of CtBP2 protein—a sensor molecule that assesses the quality and quantity of metabolites—in obesity. In the present study, they revealed that obesity-induced oxidative stress in pancreatic β-cells causes the degradation of CtBP2 protein, which results in the inability to maintain pancreatic β-cell function, thereby leading to decreased insulin secretion and diabetes mellitus.
Overall, the results of this and previous studies indicate that the loss of CtBP2 function in obesity plays an important role in the development and pathogenesis of metabolic syndrome. Hence, targeting CtBP2 may be a potential therapeutic strategy for obesity-related diseases in the future.
This research was supported by Japan Promotion of Science (Grant Number 20K08855), the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18gm5910007 and JP22ek0210175, Takeda Science Foundation, Ono Medical Research Foundation and Japan Diabetes Foundation.
- Title of original paper:
- Loss of CtBP2 may be a mechanistic link between metabolic derangements and the progressive impairment of pancreatic β-cell function
- Cell Reports