A metabolomics approach to investigate the proceedings of mitochondrial dysfunction in rats from prediabetes to diabetes

Chun-Feng Huang; Ann Chen; Siao-Yun Lin; Mei-Ling Cheng; Ming-Shi Shiao; Tso-Yen Mao

doi:10.1016/j.sjbs.2021.04.091

A metabolomics approach to investigate the proceedings of mitochondrial dysfunction in rats from prediabetes to diabetes

Saudi J Biol Sci. 2021 Aug;28(8):4762-4769. doi: 10.1016/j.sjbs.2021.04.091. Epub 2021 May 6.

Authors

Chun-Feng Huang^{1

2}, Ann Chen³, Siao-Yun Lin¹, Mei-Ling Cheng³, Ming-Shi Shiao³, Tso-Yen Mao²

Affiliations

¹ Department of Family Medicine, National Yang Ming Chiao Tung University Hospital, No.152, Xinmin Rd., Yilan City, 260 Yilan County, Taiwan, ROC.
² Department of Leisure Services Management, Chaoyang University of Technology, No.168, Jifeng E. Rd, Wufeng District, 413 Taichung City, Taiwan, ROC.
³ Department of Biomedical Sciences, Chang Gung University, No.259, Wenhua 1st Rd, Guishan Dist, 33302 Taoyuan City, Taiwan, ROC.

Abstract

Diabetes mellitus (DM) is a leading cause of preventable cardiovascular disease, but the metabolic changes from prediabetes to diabetes have not been fully clarified. This study implemented a metabolomics profiling platform to investigate the variations of metabolites and to elucidate their global profiling from metabolic syndrome to DM.

Methods: Male Sprague-Dawley rats (n = 44) were divided into four groups. Three groups were separately fed with a normal diet, a high-fructose diet (HF), or a high-fat (HL) diet while one group was treated with streptozotocin. The HF and HL diet were meant to induce insulin resistance, obesity, and dyslipidemia, which known to induce DM.

Results: The most significant metabolic variations in the DM group's urine samples were the reduced release of citric acid cycle intermediates, the increase in acylcarnitines, and the decrease in urea excretion, all of which indicated energy metabolism abnormalities and mitochondrial dysfunction. Overall, the metabolic analysis revealed tryptophan metabolic pathway variations in the prediabetic phase, even though the mitochondrial function remains unaffected.

Conclusion: This study show that widespread methylations and impaired tryptophan metabolism occur in metabolic syndrome and are then followed by a decline in citric acid cycle intermediates, indicating mitochondrial dysfunction in diabetes.

Keywords: CAN, acetonitrile; DM, diabetes mellitus; Diabetes; GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; HF, high-fructose; HL, high-fat; HMDB, human metabolome database; KEGG, kyoto encyclopedia of genes and genomes; LC-MS, liquid chromatography–mass spectrometry; Metabolic syndrome; Metabolomics; Methylation; Mitochondrial dysfunction; PCA, principal component analysis; Prediabetes; STZ, streptozotocin; TC, total cholesterol; TG, triacylglycerol; Tryptophan.