Preliminary study on the role of AKAP1 in the development of diabetes mellitus
Fengzhou Liu1 Lele JI2 Fei LI1
1.Department of Cardiology, Xijing Hospital, the Fourth Military Medical University
2.State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, the Fourth Military Medical University
Objectives: Diabetes mellitus (DM) is a chronic disease characterized by metabolic disorder. Emerging evidences have showed that mitochondrial dysfunction is associated with diabetes initiation and progression. A kinase anchoring protein1 (AKAP1), located in the mitochondrial outer membrane, has been proved to play an important role in maintaining the functional activity of the mitochondrial respiratory chain, regulating the division and integration of mitochondria. However, to date, the significance of AKAP1 in diabetes mellitus has never been investigated.
Methods: We first constructed AKAP1−/− knockout mice model by CRISPR/Cas9 technology. Then, we systematically explored the role of AKAP1 on the occurrence and development of diabetes mellitus and the underlying mechanism.
Results: Here, we showed that AKAP1−/− knockout mice constructed by CRISPR/Cas9 technology are prone to obesity, hepatic steatosis, and whole-body insulin resistance in diabetes induced by high-fat diet. Moreover, we demonstrated that the up-regulation of AKAP1 can improve the cardiac ejection function, reduce the collagen content of myocardial tissue, alleviate myocardial hypertrophy, and ameliorate myocardial ischemia injury in db/db mice. Finally, our results indicated that AKAP1 deficiency increased the mitochondrial morphological abnormalities in the major tissues of diabetic mice, and up-regulation of AKAP1 expression could significantly improve the mitochondrial morphology of db/db mice.
Conclusions: Our findings demonstrate that AKAP1 plays a critical role in the development of diabetes mellitus. Thereby, AKAP1 may represent an attractive therapeutic target in diabetes.