Progress Report
Challenge for Eradication of Diabetes and Comorbidities through Understanding and Manipulating Homeostatic Systems[2] Elucidation and control of the mechanism of multi-organ transformation in diabetes mellitus
Progress until FY2024
1. Outline of the project
This R&D Item is responsible for research within the project to elucidate the mechanisms of multi-organ transformation in diabetes (See figure below) and to develop control methods.
To achieve this goal, we are working on challenging themes in organs such as heart, liver, brain, and kidney, as well as blood vessels, where we must analyze organ transformation from both functional and morphological perspectives. Based on the idea that close interactions are involved between concomitant diseases, which is completely different from the conventional approach, we are working on this project using techniques such as single cell RNA sequencing, flow cytometry, two-photon microscopy, scanning electron microscopy, light sheet microscopy, and tissue clearing techniques.
2. Outcome so far
(1) Elucidating the mechanisms of recurrent heart failure and multimorbidity
Heart failure, known as a major comorbidity of diabetes mellitus, is characterized by the fact that “once a patient develops heart failure, he/she is in and out of the hospital repeatedly” and “it also affects other diseases”. This is a groundbreaking achievement that reveals the mechanism of recurrent and multiple heart failure. It will lead to the development of prevention of recurrence of heart failure.
(2) Established protocols for tissue clearing and analysis of mouse organs
To elucidate the multi-organ transformation in diabetes, we have created a multi-organ whole cell atlas and completed the platform for analysis. This will be used to comprehensively analyze the morphological changes that occur in diabetic model mice in the very early stages of the disease.
(3) Discovery of plasmablasts in adipose tissue
Plasmablasts, which are strongly implicated in inflammatory diseases, were detected in B lymphocytes in the epididymal fat of obese mice. Celastrol, an inhibitor of the COMMD3/8 complex, was found to inhibit plasmablastogenesis. Since celastrol has anti-obesity and glucose tolerance improving effects, inhibition of COMMD3/8 complex function may be able to control the pathogenesis of diabetes mellitus.
3. Future plans
In the future, we will try to analyze single cell RNA sequencing of cardiac tissue macrophages, hematopoietic stem cells, and peripheral blood to clarify the effects of high-fat diet load on hematopoietic and immune systems. This will help to elucidate the mechanisms of how metabolic abnormalities affect the hematopoietic and immune systems, and to identify diagnostic and therapeutic targets for diabetes complications.
Furthermore, to prevent diabetes, it is essential to reduce dietary glucose influx into peripheral circulation by promoting hepatic glucose uptake, and glycogen synthesis. We are working to elucidate the mechanisms involved in the regulation of glucose uptake in the liver and develop efficient strategies.