Metabonomic study of metformin in type Ⅱ diabetic rats

ZENG Xiao-hui1,2 ZHUO Jun-cheng1,2,3 XIE Kai-feng1,2,3 LI Yu-ting1,2,3 ZHAN Xin-yi1,2,3 CHEN Yu-xing1,2 GAN Hai-ning1,2 HUANG Xue-jun1,2 HUANG Dan-e1,2

(1.Guangdong Province Engineering Technology Research Institute of TCM, Guangzhou, China 510095)
(2.Guangdong Provincial Key Lab of Research and Development in Traditional Chinese Medicine, Guangzhou, China 510095)
(3.Fifth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China 510405)

【Abstract】 Aim To study the mechanism of metformin in the treatment of type 2 diabetic mellitus (T2DM) rats. Methods Rats were randomly divided into normal group, model group and metformin group with 10 rats in each group. Four weeks after induction with HFSD, 35 mg·kg−1 STZ was injected intramuscularly, and the experiment was completed after eight weeks of administration. UPLC/ESI-TOF-MS was used to study the effects of metformin on metabolites in serum of T2DM rats, and qPCR was used to find its target. Results Compared with normal group, the body weight, pancreatic index and insulin level in model group decreased significantly (P < 0.05), the liver index, GLU, TC, TG and FFA levels increased significantly (P < 0.01), OGTT was significantly impaired, while metformin could significantly increase the body weight, pancreatic index and insulin level (P < 0.05), reduce the liver index, GLU, TC, TG and FFA levels (P < 0.05), and improve OGTT. After metabonomics, 17 biomarkers were obtained. After verification, metformin was found to regulate the synthesis and metabolism of cholesterol, fatty acids, bile acids and phospholipids. Conclusions Metformin can improve the lipid metabolism disorder of T2 DM by regulating the synthesis and metabolism of cholesterol, fatty acids, bile acids and phospholipids.

【Keywords】 metabolic profile; biomarker; type 2 diabetic mellitus; metformin; bile acids; fatty acid;

【DOI】

【Funds】 National Major Scientific and Technological Special Project for “Significant New Drugs Development” of the Ministry of Science and Technology (2016ZX09101076, 2018ZX09301011-002)

Download this article

    References

    [1] Kiebish M A, Han X, Cheng H, et al. Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer [J]. J Lipid Res, 2008, 49 (12): 2545–56.

    [2] Guariguata L, Whiting D R, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035 [J]. Diabetes Res Clin Practice, 2014, 103 (2): 137–49.

    [3] Devanathan S, Nemanich S T, Kovacs A, et al. Genomic and metabolic disposition of non-obese type 2 diabetic rats to increased myocardial fatty acid metabolism [J]. PLoS One, 2013, 8 (10): e78477.

    [4] Zhang H M, Wang X, Wu Z H, et al. Beneficial effect of farnesoid X receptor activation on metabolism in a diabetic rat model [J]. Mol Med Rep, 2016, 13 (3): 2135–42.

    [5] Li X X, Yu Q, Guo C. 二甲双胍的临床应用新进展 [J]. New progress in clinical application of metformin [J]. China Pharmacy, 2014, (8): 760–3 (in Chinese).

    [6] Wrobel M P, Marek B, Kajdaniuk D, et al. Metformin—a new old drug [J]. Endokrynol Polska, 2017, 68 (4): 482–96.

    [7] Abu Bakar Sajak A, Mediani A, Maulidiani, et al. Metabolite variation in lean and obese streptozotocin (STZ)-induced diabetic rats via 1H NMR-based metabolomics approach [J]. Appl Biochem Biotechnol, 2017, 182 (2): 653–68.

    [8] Liu X, Gao J, Chen J, et al. Identification of metabolic biomarkers in patients with type 2 diabetic coronary heart diseases based on metabolomic approach [J]. Sci Rep, 2016, 6 (1): 30785.

    [9] Zhuo J C, Zeng X H, Zeng Q H, et al. Study on hyperlipidemia mice models induced by Triton WR-1399 via VLDL-C metabolic pathway and reverse cholesterol transport [J]. Chinese Pharmacological Bulletin, 2017, 33 (3): 433–9 (in Chinese).

    [10] Zhang Q. Effects of exercise combined with ketogenic diet on glucose homeosstasis and hepatic lipid metabolism in STZ-induced T2DM mice [D]. Shanghai: East China Normal University, 2017 (in Chinese).

    [11] Duan W L, Li W J, Yu M H, et al. Plasma pyruvic acid and fat metabolism in diabetic patients [J]. Shanghai Medical Journal, 1994, (12): 689–92 (in Chinese).

    [12] Noel O F, Still C D, Argyropoulos G, et al.Bile acids, FXR, and metabolic effects of Bariatric surgery [J]. J Obes, 2016, 2016: 1–8.

    [13] Chen P, Li J J, Chen J. Nuclear receptors as drug targets in cholestasis [J]. Chinese Pharmacological Bulletin, 2015, 31 (9): 1195–8 (in Chinese).

    [14] Li T, Chiang J Y. Bile acid signaling in metabolic disease and drug therapy [J]. Pharmacol Rev, 2014, 66 (4): 948–83.

    [15] Meikle P J, Summers S A. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders [J]. Nat Rev Endocrinol, 2016, 13 (2): 79–91.

    [16] Standl E, Schnell O, McGuire D K. Heart failure considerations of antihyperglycemic medications for type 2 diabetes [J]. Circ Res, 2016, 118 (11): 1830–43.

    [17] Aggarwal N T, Gauthier K M, Campbell W B. Endothelial nitric oxide and 15-lipoxygenase-1 metabolites independently mediate relaxation of the rabbit aorta [J]. Vasc Pharmacol, 2012, 56 (1–2): 106–12.

    [18] Campbell W B, Gauthier K M. Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway [J]. J Cardiovasc Pharmacol, 2013, 61 (3): 176–87.

This Article

ISSN:1001-1978

CN: 34-1086/R

Vol 35, No. 09, Pages 1212-1220

September 2019

Downloads:2

Share
Article Outline

Abstract

  • 1 Materials
  • 2 Methods
  • 3 Results
  • 4 Discussion
  • References