1731-P: The Involvement of Glutaminolysis in ß-Cell Differentiation and Its Clinical Application for Type 1 Diabetes

Abstract

Objective: B cells play a crucial role in type 1 diabetes (1DM). Recently, “Immunometabolism” attract much attention. In this study, we examined the role of mitochondrial function and glutaminolysis in B cell differentiation and its relevance to 1DM. Methods: Peripheral blood mononuclear cells were obtained from healthy controls (HCs) and 1DM patients and assessed by FACS. In addition, CD19+ cells were isolated from HCs and change of mitochondrial function and glutaminolysis were assessed in the absence of glucose or glutamine, by metformin in vitro. Results: Initially, mitochondrial function in B cells from 1DM patients was assessed using DiOc6 as a marker of depolarization-activated mitochondrial membrane. CD24-DiOc6+ cells in IgD-CD27- memory B cell from 1DM patients were significantly higher than those of HCs. Next, we assessed the role of mitochondrial function and glutaminolysis in human B cell differentiation in vitro. Stimulation with CpG (TLR9 ligand) and IFN-α, 1) increased the area of cytoplasm including many expanded mitochondrial cristae with slightly wider and loosely organized intermembrane space in electric microscopy, accompanied with ROS production and DiOc6 up-regulation, 2) induced CD27hiCD38hi plasmablasts differentiation and immunoglobulin production. Interestingly, ROS production and DiOc6 expression were significantly decreased in the absence of glutamine, leading to inhibition of plasmablasts differentiation and immunoglobulin production. This tendency was not shown in the absence of glucose. Metformin, which is known as AMPK activator, abrogated glutamine uptake, resulting in suppression of ROS production, DiOc6 expression, plasmablast differentiation and immunoglobulin production. Conclusion: These results suggest that mitochondrial activation via glutaminolysis may play an important role in the differentiation from IgD-CD27- double negative B cells to plasmablasts and production of immunoglobulins in 1DM patients. Disclosure M. Hajime: None. S. Iwata: None. M. Zhang: None. S. Nakayamada: None. Y. Okada: None. Y. Tanaka: None.