Theranostics 2020; 10(6):2675-2695. doi:10.7150/thno.40735

Research Paper

Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus

Xinghui Li1,2#, Yandi Wu1,2#, Jingjing Zhao1,3#, Haiping Wang1,2, Jing Tan1,2, Ming Yang1,2, Yuanlong Li1,2, Shijie Deng1,2, Saifei Gao1, Hui Li1, Zhenyu Yang1, Fengmin Yang1,2, Jianxing Ma4, Jianding Cheng5*✉, Weibin Cai1,2*✉

1. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
2. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
3. NHC Key Laboratory on Assisted Circulation, Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
4. Department of Physiology, Health Sciences Center, University of Oklahoma, Oklahoma City, OK 73104, USA.
5. Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
# These authors contributed equally to this work and are joint first authors.
* These authors contributed equally to this work and are joint corresponding authors.

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Citation:
Li X, Wu Y, Zhao J, Wang H, Tan J, Yang M, Li Y, Deng S, Gao S, Li H, Yang Z, Yang F, Ma J, Cheng J, Cai W. Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus. Theranostics 2020; 10(6):2675-2695. doi:10.7150/thno.40735. Available from http://www.thno.org/v10p2675.htm

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Abstract

Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans.

Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests.

Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPARα) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPARα pathway and GLUT4, sustained inhibition of p-GSK-3β and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples.

Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.