, Volume 31, Issue 5, pp 891–908 | Cite as

Chromium malate alleviates high-glucose and insulin resistance in L6 skeletal muscle cells by regulating glucose uptake and insulin sensitivity signaling pathways

  • Weiwei Feng
  • Yangyang Ding
  • Weijie Zhang
  • Yao Chen
  • Qian Li
  • Wei Wang
  • Hui Chen
  • Yun Feng
  • Ting Zhao
  • Guanghua Mao
  • Liuqing YangEmail author
  • Xiangyang WuEmail author


Previous study revealed that chromium malate improved the regulation of fasting blood glucose and insulin resistance in type 2 diabetic rats. In this study, the effect of chromium malate on anti-high-glucose and improve insulin resistance activities in L6 skeletal muscle cells with insulin resistance and its acting mechanism were investigated. Chromium malate showed direct anti-high-glucose activity in vitro. The glucose levels had a significant downward trend compared to chromium trichloride. Compared with model group, chromium malate could significantly promote the secretion levels of GLUT-4, Akt, Irs-1, PPARγ, PI3K and p38-MAPK, promote AMPKβ1 phosphorylation, and reduced the level of p-Irs-1 in L6 cells with insulin resistance. And the relate mRNA expression of chromium malate was significantly increased. Chromium malate is more effective at improving the related proteins and mRNA expression than those of chromium trichloride and chromium picolinate. Pretreatment with the specific p38MAPK inhibitor completely inhibited the GLUT-4 and Irs-1 proteins and mRNA expression induced by the chromium malate when compared with model group, but GLUT-4 and Irs-1 proteins and mRNA expression was partially inhibited after inhibiting p38MAPK/PI3K expression. The results suggested that chromium malate had a beneficial influence on the improvement of controlling glucose levels and insulin resistance in L6 cells with insulin resistance by regulating proteins production and genes expression in glucose uptake and insulin sensitivity signaling pathways.

Graphical abstract

The signaling pathways of glucose uptake and insulin sensitivity. This study shown that chromium malate could significant increase in the production levels of GLUT-4, p-AMPKβ1, Akt, Irs-1, PPARγ, PI3K and p38-MAPK proteins and mRNA in L6 cells with insulin resistant. Pretreatment with the specific p38MAPK inhibitor completely inhibited the GLUT-4 and Irs-1 proteins and mRNA expression induced by the chromium malate compared to model group, but the proteins and mRNA were partially inhibited after inhibiting p38MAPK/PI3K. Therefore, chromium malate had beneficial influence on improvement of controlling glucose levels and insulin resistant in L6 cells by regulating proteins production and genes expression in glucose uptake and insulin sensitivity signaling pathways. The key proteins of glucose uptake and insulin sensitivity signaling pathways were p38MAPK, PI3K and PPARγ.


Chromium malate Insulin resistance Glucose uptake Signaling pathway 



This work was supported by the Specialized Research Fund for the Natural Science Foundation of China (Grant Numbers 31271850) and Research Foundation for Advanced Talents of Jiangsu University (Grant Numbers 15JDG146).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no competing interests.

Supplementary material

10534_2018_132_MOESM1_ESM.xlsx (13 kb)
Supplementary material 1 (XLSX 13 kb)


  1. Aghdassi E, Arendt BM, Salit IE, Mohammed SS, Jalali P, Bondar H, Allard JP (2018) In patients with HIV-infection, chromium supplementation improves insulin resistance and other metabolic abnormalities: a randomized, double-blind, placebo controlled trial. Curr HIV Res 8:113–120CrossRefGoogle Scholar
  2. Al-Zoairy R, Pedrini MT, Khan MI, Engl J, Tschoner A, Ebenbichler C, Gstraunthaler G, Salzmann K, Bakry R, Niederwanger A (2017) Serotonin improves glucose metabolism by serotonylation of the small GTPase Rab4 in L6 skeletal muscle cells. Diabetol Metab Syndr. PubMedPubMedCentralCrossRefGoogle Scholar
  3. Andersson MA, Grawe KVP, Karlsson OM, Abramsson-Zetterberg LAG, Hellman BE (2007) Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro. Food Chem Toxicol 45:1097–1106CrossRefPubMedGoogle Scholar
  4. Atila G, Yuce A (2016) Effects of the Trigonella foenum-graecum L. seed extract and chromium picolinate supplementation in streptozotocin induced diabetes in rats. Indian J Tradit Know 15:447–452Google Scholar
  5. Bai Y, Zhao X, Qi C, Wang L, Cheng Z, Liu M, Liu J, Yang D, Wang S, Chai T (2014) Effects of chromium picolinate on the viability of chick embryo fibroblast. Hum Exp Toxicol 33:403–413CrossRefPubMedGoogle Scholar
  6. Blue EK, Sheehan BM, Nuss ZV, Boyle FA, Hocutt CM, Gohn CR, Varberg KM, McClintick JN, Haneline LS (2015) Epigenetic regulation of placenta-specific 8 contributes to altered function of endothelial colony-forming cells exposed to intrauterine gestational diabetes mellitus. Diabetes 64:2664–2675CrossRefPubMedPubMedCentralGoogle Scholar
  7. Dhanya R, Arya AD, Nisha P, Jayamurthy P (2017) Quercetin, a lead compound against type 2 diabetes ameliorates glucose uptake via AMPK pathway in skeletal muscle cell line. Front Pharmacol. PubMedPubMedCentralCrossRefGoogle Scholar
  8. Diaz M, Garcia C, Sebastiani G, de Zegher F, Lopez-Bermejo A, Ibanez L (2017) Placental and cord blood methylation of genes involved in energy homeostasis: association with fetal growth and neonatal body composition. Diabetes 66:779–784CrossRefPubMedGoogle Scholar
  9. Feng WW, Zhao T, Mao GH, Wang W, Feng Y, Li F, Zheng DH, Wu HY, Jin D, Yang LQ (2015) Type 2 diabetic rats on diet supplemented with chromium malate show improved glycometabolism, glycometabolism-related enzyme levels and lipid metabolism. PLoS ONE. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Gannon NP, Conn CA, Vaughan RA (2015) Dietary stimulators of GLUT4 expression and translocation in skeletal muscle: a mini-review. Mol Nutr Food Res 59:48–64CrossRefPubMedGoogle Scholar
  11. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence in adults for 2013 and projections for 2035. Diabetes Res Clin Pract 103:137–149CrossRefPubMedGoogle Scholar
  12. Hininger I, Benaraba R, Osman M, Faure H, Roussel AM, Anderson RA (2007) Safety of trivalent chromium complexes: no evidence for DNA damage in human HaCaT keratinocytes. Free Radic Biol Med 42:1759–1765CrossRefPubMedGoogle Scholar
  13. Huang S, Peng WF, Jiang XH, Shao K, Xia LL, Tang YB, Qiu JY (2014) The effect of chromium picolinate supplementation on the pancreas and macroangiopathy in type II diabetes mellitus rats. J Diabetes Res. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Jiao YK, Zhang ML, Wang SM, Yan CY (2017) Consumption of guava may have beneficial effects in type 2 diabetes: a bioactive perspective. Int J Biol Macromol 101:543–552CrossRefPubMedGoogle Scholar
  15. Krol E, Krejpcio Z, Byks H, Bogdanski P, Pupek-Musialik D (2011) Effects of chromium brewer’s yeast supplementation on body mass, blood carbohydrates, and lipids and minerals in type 2 diabetic patients. Biol Trace Elem Res 143:726–737CrossRefPubMedGoogle Scholar
  16. Kumar N, Shaw P, Uhm HS, Choi EH, Attri P (2017) Influence of Nitric Oxide generated through microwave plasma on L6 skeletal muscle cell myogenesis via oxidative signaling pathways. Sci Rep. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lee SY, Lai FY, Shi LS, Chou YC, Yen IC, Chang TC (2015) Rhodiola crenulata extract suppresses hepatic gluconeogenesis via activation of the AMPK pathway. Phytomedicine 22:477–486CrossRefPubMedGoogle Scholar
  18. Li F, Wu XY, Zhao T, Zhang M, Zhao JL, Mao GH, Yang LQ (2011) Anti-diabetic properties of chromium citrate complex in alloxan-induced diabetic rats. J Trace Elem Med Biol 25:218–224CrossRefPubMedGoogle Scholar
  19. Liu YX, Song A, Zang SS, Wang C, Song GY, Li XL, Zhu YJ, Yu X, Li L, Wang Y, Duan LY (2015) Jinlida reduces insulin resistance and ameliorates liver oxidative stress in high-fat fed rats. J Ethnopharmacol 162:244–252CrossRefPubMedGoogle Scholar
  20. Mao XQ, Zhang L, Xia Q, Sun ZF, Zhao XM, Cai HX, Yang XD, Xia ZL, Tang YJ (2008) Vanadium-enriched chickpea sprout ameliorated hyperglycemia and impaired memory in streptozotocin-induced diabetes rats. Biometals 21:563–570CrossRefPubMedGoogle Scholar
  21. Mao GH, Ren Y, Feng WW, Li Q, Wu HY, Jin D, Zhao T, Xu CQ, Yang LQ, Wu XY (2015) Antitumor and immunomodulatory activity of a water-soluble polysaccharide from Grifola frondosa. Carbohyd Polym 134:406–412CrossRefGoogle Scholar
  22. Martins FF, Bargut TCL, Aguila MB, Mandarim-de-Lacerda CA (2017) Thermogenesis, fatty acid synthesis with oxidation, and inflammation in the brown adipose tissue of ob/ob (−/−) mice. Ann Anat 210:44–51CrossRefPubMedGoogle Scholar
  23. Mokashi P, Khanna A, Pandita N (2017) Flavonoids from Enicostema littorale blume enhances glucose uptake of cells in insulin resistant human liver cancer (HepG2) cell line via IRS-1/PI3K/Akt pathway. Biomed Pharmacother 90:268–277CrossRefPubMedGoogle Scholar
  24. Mozaffari MS, Baban B, Abdelsayed R, Liu JY, Wimborne H, Rodriguez N, Abebe W (2012) Renal and glycemic effects of high-dose chromium picolinate in db/db mice: assessment of DNA damage. J Nutr Biochem 23:977–985CrossRefPubMedGoogle Scholar
  25. Nagarjun S, Dhadde SB, Veerapur VP, Thippeswamy BS, Chandakavathe BN (2017) Ameliorative effect of chromium-d-phenylalanine complex on indomethacin-induced inflammatory bowel disease in rats. Biomed Pharmacother 89:1061–1066CrossRefPubMedGoogle Scholar
  26. Ooi DJ, Adamu HA, Imam MU, Ithnin H, Ismail M (2018) Polyphenol-rich ethyl acetate fraction isolated from Molineria latifolia ameliorates insulin resistance in experimental diabetic rats via IRS1/AKT activation. Biomed Pharmacother 98:125–133CrossRefPubMedGoogle Scholar
  27. Paiva AN, de Lima JG, de Medeiros ACQ, Figueiredo HAO, de Andrade RL, Ururahy MAG, Rezende AA, Brandao-Neto J, Almeida MD (2015) Beneficial effects of oral chromium picolinate supplementation on glycemic control in patients with type 2 diabetes: a randomized clinical study. J Trace Elem Med Biol 32:66–72CrossRefPubMedGoogle Scholar
  28. Panchal SK, Wanyonyi S, Brown L (2017) Selenium, vanadium, and chromium as micronutrients to improve metabolic syndrome. Curr Hypertens Rep. PubMedCrossRefGoogle Scholar
  29. Qiao W, Peng ZL, Wang ZS, Wei J, Zhou A (2009) Chromium improves glucose uptake and metabolism through upregulating the mRNA levels of IR, GLUT4, GS, and UCP3 in skeletal muscle cells. Biol Trace Elem Res 131:133–142CrossRefPubMedGoogle Scholar
  30. Refaie FM, Esmat AY, Mohamed AF, Nour WHA (2009) Effect of chromium supplementation on the diabetes induced-oxidative stress in liver and brain of adult rats. Biometals 22:1075–1087CrossRefPubMedGoogle Scholar
  31. Sahin K, Tuzcu M, Orhan C, Sahin N, Kucuk O, Ozercan IH, Juturu V, Komorowski JR (2013) Anti-diabetic activity of chromium picolinate and biotin in rats with type 2 diabetes induced by high-fat diet and streptozotocin. Brit J Nutr 110:197–205CrossRefPubMedGoogle Scholar
  32. Song EK, Lee YR, Kim YR, Yeom JH, Yoo CH, Kim HK, Park HM, Kang HS, Kim JS, Kim UH, Han MK (2012) NAADP mediates insulin-stimulated glucose uptake and insulin sensitization by PPAR gamma in adipocytes. Cell Rep 2:1607–1619CrossRefPubMedGoogle Scholar
  33. Veerapur VP, Prabhakar KR, Thippeswamy BS, Bansal P, Srinivasan KK, Unnikrishnan MK (2012) Antidiabetic effect of Ficus racemosa Linn. stem bark in high-fat diet and low-dose streptozotocin-induced type 2 diabetic rats: a mechanistic study. Food Chem 132:186–193CrossRefPubMedGoogle Scholar
  34. Wang S, Wang J, Zhang XN, Hu LL, Fang ZJ, Huang ZW, Shi P (2016) Trivalent chromium alleviates oleic acid induced steatosis in SMMC-7721 cells by decreasing fatty acid uptake and triglyceride synthesis. Biometals 29:881–892CrossRefPubMedGoogle Scholar
  35. World Health Organization (2016) Global report on diabetes. Accessed Nov 2016
  36. Wu XY, Li F, Xu WD, Zhao JL, Zhao T, Liang LH, Yang LQ (2011) Anti-hyperglycemic activity of chromium(III) malate complex in alloxan-induced diabetic Rats. Biol Trace Elem Res 143:1031–1043CrossRefPubMedGoogle Scholar
  37. Wu X, Wang J, Shi YQ, Chen S, Yan QJ, Jiang ZQ, Jing H (2017) N-Acetyl-chitobiose ameliorates metabolism dysfunction through Erk/p38 MAPK and histone H3 phosphorylation in type 2 diabetes mice. J Funct Foods 28:96–105CrossRefGoogle Scholar
  38. Yang JJ, Xu YY, Qian K, Zhang W, Wu D, Wang CL (2016) Effects of chromium-enriched Bacillus subtilis KT260179 supplementation on growth performance, caecal microbiology, tissue chromium level, insulin receptor expression and plasma biochemical profile of mice under heat stress. Brit J Nutr 115:774–781CrossRefPubMedGoogle Scholar
  39. Yu N, Fang X, Zhao DD, Mu QQ, Zuo JC, Ma Y, Zhang Y, Mo FF, Zhang DW, Jiang GJ, Wu R, Gao SH (2017) Anti-diabetic effects of Jiang Tang Xiao Ke granule via PI3K/Akt signalling pathway in type 2 diabetes KKAy mice. PLoS ONE. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Zhang Q, Xiao XH, Zheng J, Li M, Yu M, Ping F, Wang ZX, Qi CJ, Wang T, Wang XJ (2017) Maternal chromium restriction modulates miRNA profiles related to lipid metabolism disorder in mice offspring. Exp Biol Med 242:1444–1452CrossRefGoogle Scholar
  41. Zhou Q, Yang XZ, Xiong MR, Xu XL, Zhen L, Chen WW, Wang Y, Shen JH, Zhao P, Liu QH (2016) Chloroquine increases glucose uptake via enhancing GLUT4 translocation and fusion with the plasma membrane in L6 cells. Cell Physiol Biochem 38:2030–2040CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.School of the Environment and Safety EngineeringJiangsu UniversityZhenjiangChina
  2. 2.Institute of Environmental Health and Ecological SecurityJiangsu UniversityZhenjiangChina
  3. 3.School of Food and Biological EngineeringJiangsu UniversityZhenjiangChina
  4. 4.School of Medical Science and Laboratory MedicineJiangsu UniversityZhenjiangChina
  5. 5.School of Chemistry and Chemical EngineeringJiangsu UniversityZhenjiangChina

Personalised recommendations