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Effect of metformin on global gene expression in liver of KKAy mice

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Abstract

Background

Metformin is a first-line drug for treating type 2 diabetes mellitus, yet its mechanism remains only partially understood and controversial. In this study we assessed a global gene expression profiling in liver of KKAy mice affected by metformin. This study aimed to identify the novel anti-diabetic mechanisms of metformin.

Methods

After KKAy mice were administered metformin for 5 weeks, the gene changes profile in the livers of KKAy mice were assessed by using the Agilent whole mice genome oligo microarray.

Results

Metformin altered the gene expression profiles in liver of KKAy mice. To our best knowledge, some genes have not been reported until now, such as Anxa2, Atf6, and so on. These genes were involved in many pathways, such as peroxisome proliferator activated receptor signaling pathway.

Conclusions

Gene expression changes induced by metformin were in support of the improvement of glucolipid metabolism and insulin resistance in KKAy mice. These findings expanded our knowledge of pharmacological action of metformin, and provided the potential novel insights and interesting information about the molecules involved in the antidiabetic effects of metformin.

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References

  1. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108(8):1167–74.

    Article  CAS  Google Scholar 

  2. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348(Pt. 3):607–14.

    Article  CAS  Google Scholar 

  3. Yuan L, Ziegler R, Hamann A. Metformin modulates insulin post-receptor signaling transduction in chronically insulin-treated HepG2 cells. Acta Pharmacol Sin 2003;24(1):55–60.

    CAS  PubMed  Google Scholar 

  4. Heishi M, Ichihara J, Teramoto R, Itakura Y, Hayashi K, Ishikawa H, et al. Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin. Diabetologia 2006;49(7):1647–55.

    Article  CAS  Google Scholar 

  5. Liu ZQ, Liu T, Chen C, Li MY, Wang ZY, Chen RS, et al. Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice. Toxicol Appl Pharmacol 2015;285(1):61–70.

    Article  CAS  Google Scholar 

  6. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) method. Methods 2001;25(4):402–8.

    Article  CAS  Google Scholar 

  7. Tahara A, Matsuyama-Yokono A, Shibasaki M. Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice. Eur J Pharmacol 2011;655(1–3):108–16.

    Article  CAS  Google Scholar 

  8. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012;122(6):253–70.

    Article  CAS  Google Scholar 

  9. Mithieux G, Guignot L, Bordet JC, Wiernsperger N. Intrahepatic mechanisms underlying the effect of metformin in decreasing basal glucose production in rats fed a high-fat diet. Diabetes 2002;51(1):139–43.

    Article  CAS  Google Scholar 

  10. Ghatak SB, Dhamecha PS, Bhadada SV, Panchal SJ. Investigation of the potential effects of metformin on atherothrombotic risk factors in hyperlipidemic rats. Eur J Pharmacol 2011;659(2–3):213–23.

    Article  CAS  Google Scholar 

  11. Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 1996;98(7):1575–84.

    Article  CAS  Google Scholar 

  12. Ide T, Shimano H, Yahagi N, Matsuzaka T, Nakakuki M, Yamamoto T, et al. SREBPs suppress IRS-2-mediated insulin signalling in the liver. Nat Cell Biol 2004;6(4):351–7.

    Article  CAS  Google Scholar 

  13. Matsuzaka T, Shimano H, Yahagi N, Yoshikawa T, Amemiya-Kudo M, Hasty AH, et al. Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs. J Lipid Res 2002;43(6):911–20.

    CAS  PubMed  Google Scholar 

  14. Chu X, Liu L, Na L, Lu H, Li S, Li Y, et al. Sterol regulatory element-binding protein-1c mediates increase of postprandial stearic acid, a potential target for improving insulin resistance, in hyperlipidemia. Diabetes 2013;62(2):561–71.

    Article  CAS  Google Scholar 

  15. Matsuzaka T, Shimano H. Elovl6: a new player in fatty acid metabolism and insulin sensitivity. J Mol Med (Berl) 2009;87(4):379–84.

    Article  CAS  Google Scholar 

  16. Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med 2004;10(6):625–32.

    Article  CAS  Google Scholar 

  17. Parray HA, Yun JW. Proteomic identification of target proteins of thiodigalactoside in white adipose tissue from diet-induced obese rats. Int J Mol Sci 2015;16(7):14441–63.

    Article  CAS  Google Scholar 

  18. Song YB, An YR, Kim SJ, Park HW, Jung JW, Kyung JS, et al. Lipid metabolic effect of Korean red ginseng extract in mice fed on a high-fat diet. J Sci Food Agric 2012;92(2):388–96.

    Article  CAS  Google Scholar 

  19. Yuzefovych LV, Musiyenko SI, Wilson GL, Rachek LI. Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS One 2013;8(1):e54059.

    Article  CAS  Google Scholar 

  20. Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 2006;172(3):383–93.

    Article  CAS  Google Scholar 

  21. Seo HY, Kim MK, Min AK, Kim HS, Ryu SY, Kim NK, et al. Endoplasmic reticulum stress induced activation of activating transcription factor 6 decreases cAMP-stimulated hepatic gluconeogenesis via inhibition of CREB. Endocrinology 2010;151(2):561–8.

    Article  CAS  Google Scholar 

  22. Usui M, Yamaguchi S, Tanji Y, Tominaga R, Ishigaki Y, Fukumoto M, et al. Atf6α-null mice are glucose intolerant due to pancreatic α-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 2012;61(8):1118–28.

    Article  CAS  Google Scholar 

  23. Han CY, Lim SW, Koo JH, Kim W, Kim SG. PHLDA3 overexpression in hepatocytes by endoplasmic reticulum stress via IRE1-Xbp1s pathway expedites liver injury. Gut 2015, doi:https://doi.org/10.1136/gutjnl-2014-308506.

    Google Scholar 

  24. Simon-Szabó L, Kokas M, Mandl J, Kéri G, Csala M. Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells. PLoS One 2014;9(6):e97868.

    Article  Google Scholar 

  25. Lin WH, Chiu KC, Chang HM, Lee KC, Tai TY, Chuang LM. Molecular scanning of the human sorbin and SH3-domain-containing-1 (SORBS1) gene: positive association of the T228A polymorphism with obesity and type 2 diabetes. Hum Mol Genet 2001;10(17):1753–60.

    Article  CAS  Google Scholar 

  26. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, et al. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 2000;407(6801):202–7.

    Article  CAS  Google Scholar 

  27. Kim SJ, Chae S, Kim H, Mun DG, Back S, Choi HY, et al. A protein profile of visceral adipose tissues linked to early pathogenesis of type 2 diabetes mellitus. Mol Cell Proteom 2014;13(3):811–22.

    Article  CAS  Google Scholar 

  28. Liu X, Feng Q, Chen Y, Zuo J, Gupta N, Chang Y, et al. Proteomics-based identification of differentially-expressed proteins including galectin-1 in the blood plasma of type 2 diabetic patients. J Proteome Res 2009;8(3):1255–62.

    Article  CAS  Google Scholar 

  29. Dzeja P, Terzic A. Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci 2009;10(4):1729–72.

    Article  CAS  Google Scholar 

  30. Tilstone C. DNA microarrays: vital statistics. Nature 2003;424(6949):610–2.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, 071002, PR China

    Zhi-Qin Liu, Xiao-Mei Song, Ting Liu, Ji-Tao Teng, Kun Zhou & Du-Qiang Luo

  2. College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, 071002, PR China

    Zhi-Qin Liu

  3. Affiliated Hospital of Hebei University, Baoding, 071002, PR China

    Que-Ting Chen

Authors
  1. Zhi-Qin Liu
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  2. Xiao-Mei Song
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  3. Que-Ting Chen
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  4. Ting Liu
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  5. Ji-Tao Teng
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  6. Kun Zhou
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  7. Du-Qiang Luo
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Correspondence to Du-Qiang Luo.

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Liu, ZQ., Song, XM., Chen, QT. et al. Effect of metformin on global gene expression in liver of KKAy mice. Pharmacol. Rep 68, 1332–1338 (2016). https://doi.org/10.1016/j.pharep.2016.09.004

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  • DOI: https://doi.org/10.1016/j.pharep.2016.09.004

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