Anti-Hyperglycemic Effect of Single Administered Gardeniae Fructus in Streptozotocin-Induced Diabetic Mice by Improving Insulin Resistance and Enhancing Glucose Uptake in Skeletal Muscle


The mechanisms of Gardeniae Fructus (GF) for anti-hyperglycemic action were demonstrated in streptozotocin (STZ)-diabetic mice. Six hours after single intraperitoneal administration of GF (300 mg/kg) or H2O into 3 hour-fasted STZ-diabetic mice, glucose and insulin tolerances were assessed by intraperitoneal glucose (1.5 g/kg) tolerance test (IPGTT) and intraperitoneal insulin (0.65 U/kg) tolerance test (IPITT), respectively. Effects of GF on insulin signaling pathways in soleus muscle such as glucose uptake, expression of glucose transporter 4 (GLUT4) in the plasma membrane and phosphorylation of Akt (P-Akt) in cytosolic fraction were examined in STZ-diabetic mice. In IPGTT test, GF significantly accelerated clearance of exogenous glucose and its glucose-lowering action was greater than H2O-treated controlin STZ-diabetic mice. GF also promoted an exogenous glucose-increased insulin level in STZ-diabetic mice. In IPITT test, GF decreased glucose level to the greater extent than H2O-treated control in STZ-diabetic mice. Furthermore, GF significantly decreased high HOMA-IR in STZ-diabetic mice from 21.6 ± 2.4 to 12.4 ± 1.9 (mg/dl × μU/ml). These results implied that GF improved insulin resistance in STZ-diabetic mice. GF increased glucose uptake of soleus muscle 1.5 times greater than H2O-treated control in STZ-diabetic mice. GF enlarged insulin (10 nmol/ml)-increased glucose uptake to 1.8 time-greater. Correspondingly, GF increased expression of GLUT4 in the plasma membrane of soleus muscle to 1.4 time-greater, and P-Akt in the cytosolic fraction of soleus muscle to 1.9 time-greater than those in H2O-treated control. In conclusion, the improvement of GF on insulin resistance is associated with the repair of insulin signaling via P-Akt, GLUT4 and glucose uptake pathway in soleus muscle of STZ-diabetic mice.

Share and Cite:

Q. Yu, T. Takahashi, M. Nomura and S. Kobayashi, "Anti-Hyperglycemic Effect of Single Administered Gardeniae Fructus in Streptozotocin-Induced Diabetic Mice by Improving Insulin Resistance and Enhancing Glucose Uptake in Skeletal Muscle," Chinese Medicine, Vol. 4 No. 4, 2013, pp. 157-165. doi: 10.4236/cm.2013.44019.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] S. Wild, G. Roglic, A. Green, R. Sicree and H. King, “Global Prevalence of Diabetes: Estimates for the Year 2000 and Projections for 2030,” Diabetes Care, Vol. 27, No. 5, 2004, pp. 1047-1053.
[2] M. F. White, “Insulin Signaling in Health and Disease,” Science, Vol. 302, No. 5651, 2003, pp. 1710-1711.
[3] T. Haruta, A. J. Morris, D. W. Rose, J. G. Nelson, M. Mueckler and J. M. Olefsky, “Insulin-Stimulated GLUT4 Translocation Is Mediated by a Divergent Intracellular Signaling Pathway,” The Journal of Biological Chemistry, Vol. 270, No. 47, 1995, pp. 27991-27994.
[4] C. Rerup and F. Tarding, “Streptozotocin and AlloxanDiabetes in Mice,” European Journal of Pharmacology, Vol. 7, No. 1, 1969, pp. 89-96.
[5] M. H. Shanik, Y. Xu, J. Skrha, R. Dankner, Y. Zick and J. Roth, “Insulin Resistance and Hyperinsulinemia: Is Hyperinsulinemia the Cart or the Horse?” Diabetes Care, Vol. 31, Suppl. 2, 2008, pp. 262-268.
[6] C. George, A. Lochner and B. Huisamen, “The efficacy of Prosopis Glandulosa as Antidiabetic Treatment in Rat Models of Diabetes and Insulin Resistance,” Journal of Ethnopharmacology, Vol. 137, No. 1, 2011, pp. 298-304.
[7] O. Pedersen and H. Beck-Nielsen, “Insulin Resistance and Insulin-Dependent Diabetes Mellitus,” Diabetes Care, Vol. 10, No. 4, 1987, pp. 516-523.
[8] A. Zisman, O. D. Peroni, E. D. Abel, M. D. Michael, F. Mauvais-Jarvis, B. B. Lowell, J. F. Wojtaszewski, M. F. Hirshman, A. Virkamaki, L. J. Goodyear, C. R. Kahn and B. B. Kahn, “Targeted Disruption of the Glucose Transporter 4 Selectively in Muscle Causes Insulin Resistance and Glucose Intolerance,” Nature Medicine, Vol. 6, No. 8, 2000, pp. 924-928.
[9] J. E. Pessin, D. C. Thurmound, J. S. Elmendorf, K. J. Coker and S. Okada, “Molecular Basis of Insulin-Stimulated GLUT4 Vesicle Trafficking. Location! Location! Location!” The Journal of Biological Chemistry, Vol. 274, No. 5, 1999, pp. 2593-2596.
[10] N. J. Bryant, R. Govers and D. E. James, “Regulated Transport of the Glucose Transporter GLUT4,” Nature Reviews Molecular Cell Biology, Vol. 3, No. 4, 2002, pp. 267-277.
[11] J. K. Kim, A. Zisman, J. J. Fillmore, O. D. Peroni, K. Kotani, P. Perret, H. Zong, J. Dong, C. R. Kahn, B. B. Kahn and G. I. Shulman, “Glucose Toxicity and the Development of Diabetes in Mice with Muscle-Specific Inactivation of GLUT4,” The Journal of Clinical Investigation, Vol. 108, No. 1, 2001, pp. 153-160.
[12] I. T. Nizamutdinova, Y. C. Jin, J. I. Chung, S. C. Shin, S. J. Lee, H. G. Seo, J. H. Lee, K. C. Chang and H. J. Kim, “The Anti-Diabetic Effect of Anthocyanins in Streptozotocin-Induced Diabetic Rats through Glucose Transporter 4 Regulation and Prevention of Insulin Resistance and Pancreatic Apoptosis,” Molecular Nutrition & Food Research, Vol. 53, No. 11, 2009, pp. 1419-1429.
[13] P. H. Ducluzeau, L. M. Fletcher, G. I. Welsh and J. M. Tavaré, “Functional Consequence of Targeting Protein Kinase B/Akt to GLUT4 Vesicles,” Journal of Cell Science, Vol. 115, No. 14, 2002, pp. 2857-2866.
[14] M. Ueda, S. Nishiumi, H. Nagayasu, I. Fukuda, K. Yoshida and H. Ashida, “Epigallocatechingallate Promotes GLUT4 Translocation in Skeletal Muscle,” Biochemical and Biophysical Research Communications, Vol. 377, No. 1, 2008, pp. 286-290.
[15] A. Junod, A. E. Lambert, L. Orci, R. Pictet, A. E. Gonet and A. E. Renold, “Studies of the Diabetogenic Action of Streptozotocin,” Proceedings of the Society for Experimental Biology and Medicine, Vol. 126, No. 1, 1967, pp. 201-205.
[16] J. Movassat and B. Portha, “Beta-Cell Growth in the Neonatal Goto-Kakisaki Rat and Regeneration after Treatment with Streptozotocin at Birth,” Diabetologia, Vol. 42, No. 9, 1999, pp. 1098-1106.
[17] M. S. Gokhale, D. H. Shah, Z. Hakim, D. D. Santani and R. K. Goyal, “Effect of Chronic Treatment with Amlodipine in Non-Insulin-Dependent Diabetic Rats,” Pharmacological Research, Vol. 37, No. 6, 1998, pp. 455-459.
[18] R. W. Gelling, G. J. Morton, C. D. Morrison, K. D. Niswender, M. G. Myers Jr., C. J. Rhodes and M. W. Schwartz, “Insulin Action in the Brain Contributes to Glucose Lowering during Insulin Treatment of Diabetes,” Cell Metabolism, Vol. 3, No. 1, 2006, pp. 67-73.
[19] P. K. Mukherjee, K. Maiti, K. Mukherjee, P. J. Houghton, “Leads from Indian Medicinal Plants with Hypoglycemic Potentials,” Journal of Ethnopharmacology, Vol. 106, No. 1, 2006, pp. 1-28.
[20] R. Jagadeeswaran, C. Thirunavukkarasu, P. Gunasekaran, N. Ramamurty and D. Sakthisekaran, “In Vitro Studies on the Selective Cytotoxic Effect of Crocetin and Quercetin,” Fitoterapia, Vol. 71, No. 4, 2000, pp. 395-399.
[21] T. H. Tseng, C. Y. Chu, J. M. Huang, S. J. Shiow and C. J. Wang, “Crocetin Protects against Oxidative Damage in rat Primary Hepatocytes,” Cancer Letters, Vol. 97, No. 1, 1995, pp. 61-67.
[22] W. S. Jung, Y. S. Chae, D. Y. Kim, S. W. Seo, H. J. Park, G. S. Bae, T. H. Kim, H. J. Oh, K. J. Yun, R. K. Park, J. S. Kim, E. C. Kim, S. Y. Hwang, S. J. Park and H. J. Song, “Gardenia Jasminoides Protects against Cerulein-Induced Acute Pancreatitis,” World Journal of Gastroenterology, Vol. 14, No. 40, 2008, pp. 6188-6194.
[23] Q.Yu, M. Yasuda, T. Takahashi, M. Nomura, N. Hagino and S. Kobayashi, “Effects of Bofutsushosan and Gardeniae Frutus on Diabetic Serum Parameters in Streptozotocin-Induced Diabetic Mice,” Chinese Medicine, Vol. 2, No. 4, 2011, pp. 130-137.
[24] Q. Yu, T. Takahashi, M. Nomura, M. Yasuda, K. Obatake-Ikeda and S. Kobayashi, “Effects of Single Administered Bofutsushosan-Composed Crude Drugs on Diabetic Serum Parameters in Streptozotocin-Induced Diabetic Mice,” Chinese Medicine, Vol. 4, No. 1, 2013, pp. 24-31.
[25] N. Nakashima, I. Kimura, M. Kimura and H. Matsuura, “Isolation of Pseudoprototimosaponin AIII from Rhizomes of Anemarrhena asphodeloides and Its Hypoglycemic Activity in Streptozotocin-Induced Diabetic Mice,” Journal of Natural Products, Vol. 56, No. 3, 1993, pp. 345-350.
[26] T. Miura, H. Toyoda, M. Miyake, E. Ishihara, M. Usami and K. Tanigawa, “Hypoglycemic Action of Stigma of Zea mays L. in Normal and Diabetic Mice,” Natural Medicines, Vol. 50, No. 5, 1996, pp. 363-365.
[27] D. R. Matthews, J. P. Hosker, A. S. Rudenski, B. A. Naylor, D. F. Treacher and R. C. Turner, “Homeostasis Model Assessment: Insulin Resistance and Beta-Cell Function from Fasting Plasma Glucose and Insulin Concentrations in Man,” Diabetologia, Vol. 28, No. 27, 1985, pp. 412-419.
[28] P. A. Hansen, E. A. Gulve, B. A. Marshall, J. Gao, J. E. Pessin, J. O. Holloszy and M. Mueckler, “Skeletal Muscle Glucose Transport and Metabolism Are Enhanced in Transgenic Mice Overexpressing the Glut4 Glucose Transporter,” The Journal of Biological Chemistry, Vol. 270, No. 4, 1995, pp. 1679-1684.
[29] N. T. Dang, R. Mukai, K. Yoshida and H. Ashida, “DPinitol and Myo-Inositol Stimulate Translocation of Glucose Transporter 4 in Skeletal Muscle of C57BL/6 Mice,” Bioscience, Biotechnology, and Biochemistry, Vol. 74, No. 5, 2010, pp. 1062-1067.
[30] S. Miyasita, “A Historical Study of Chinese Drugs for the Treatment of Jaundice,” The American Journal of Chinese Medicine (Garden City NY), Vol. 4, No. 3, 1976, pp. 239-243.
[31] C. J. Ma, A. F. Nie, Z. J. Zhang, Z. G. Zhang, L. Du, X. Y. Li and G. Ning, “Genipin Stimulates Glucosetransport in C2C12 Myotubes via an IRS-1 and Calcium-Dependent Mechanism,” The Journal of Endocrinology, Vol. 216, No. 3, 2013, pp. 353-362.
[32] H. Aquila, T. A. Link and M. Klingenberg, “The Uncoupling Protein from Brown Fat Mitochondria Is Related to the Mitochondrial ADP/ATP Carrier. Analysis of Sequence Homologies and of Folding of the Protein in the Membrane,” The EMBO Journal, Vol. 4, No. 9, 1985, pp. 2369-2376.
[33] H. Kageyama, A. Suga, M. Kashiba, J. Oka, T. Osaka, T. Kashiwa, T. Hirano, K. Nemoto, Y. Namba, D. Ricquier, J. P. Giacobino and S. Inoue, “Increased Uncoupling Protein-2 and -3 Gene Expressions in Skeletal Muscle of STZ-Induced Diabetic Rats,” The Federation of European Biochemical Societies Letters, Vol. 440, No. 3, 1998, pp. 450-453.
[34] C. B. Chan, D. De Leo, J. W. Joseph, T. S. McQuaid, X. F. Ha, F. Xu, R. G. Tsushima, P. S. Pennefather, A. M. Salapatek and M. B. Wheeler, “Increased Uncoupling Protein-2 Levels in Beta-Cells Are Associated with Impaired Glucose-Stimulated Insulin Secretion: Mechanism of Action,” Diabetes, Vol. 50, No. 6, 2001, pp. 13021310.
[35] C. Y. Zhang, G. Baffy, P. Perret, S. Krauss, O. Peroni, D. Grujic, T. Hagen, A. J. Vidal-Puig, O. Boss, Y. B. Kim, X. X. Zheng, M. B. Wheeler, G. I. Shulman, C. B. Chan and B. B. Lowell, “Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is A Major Link between Obesity, Beta Cell Dysfunction, and Type 2 Diabetes,” Cell, Vol. 105, No. 6, 2001, pp. 745-755.
[36] K. S. Echtay, T. C. Esteves, J. L. Pakay, M. B. Jekabsons, A. J. Lambert, M. Portero-Otini, R. Pamplona, A. J. Vidal-Puig, S. Wang, S. J. Roebuck and M. D. Brand, “A Signaling Role for 4-Hydroxy-2-nonenal in Regulation of Mitochondrial Uncoupling,” The EMBO Journal, Vol. 22, No. 16, 2003, pp. 4103-4110.
[37] C. Y. Zhang, L. E. Parton, C. P. Ye, S. Krauss, R. Shen, C. T. Lin, J. A. Porco Jr. and B. B. Lowell, “Genipin Inhibits UCP2-Mediated Proton Leak and Acutely Reverses Obesityand High Glucose-Induced Beta Cell Dysfunction in Isolated Pancreatic Islets,” Cell Metabolism, Vol. 3, No. 6, 2006, pp. 417-427.
[38] L. X. Guo, Z. N. Xia, X. Gao, F. Yin and J. H. Liu, “Glucagon-Like Peptide 1 Receptor Plays a Critical Role in Geniposide-Regulated Insulin Secretion in INS-1 cells,” Acta Pharmacologica Sinica, Vol. 33, No. 2, 2012, pp. 237-241.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.