Mulberry leaf extract displays antidiabetic activity in db/db mice via Akt and AMP-activated protein kinase phosphorylation

  • Ui-Jin Bae Chonbuk National University Medical School
  • Eun-Soo Jung Chonbuk National University Hospital
  • Su-Jin Jung Chonbuk National University Hospital
  • Soo-Wan Chae Chonbuk National University Hospital
  • Byung-Hyun Park Chonbuk National University Medical School
Keywords: glucose uptake, muscle, steatosis, insulin, hypertriglyceridemia


Background: Augmenting glucose utilization in skeletal muscle via the phosphatidylinositol-3 kinase (PI3
kinase)/protein kinase B (Akt) pathway or the adenosine monophosphate (AMP)-activated protein kinase
(AMPK) pathway is necessary to regulate hyperglycemia in patients with type 2 diabetes mellitus.

Objective: We investigated the effect of mulberry leaf extract (MLE) on glucose uptake in skeletal muscle cells
and explored its in vivo antidiabetic potential.

Design: Male db/db mice were treated with either MLE (50 mg/kg, 100 mg/kg, and 250 mg/kg) or metformin
(100 mg/kg) for 8 weeks.

Results: MLE treatment stimulated glucose uptake, driven by enhanced translocation of glucose transporter
4 to cell membranes in L6 myotubes. These effects of MLE were synergistic with those of insulin and were
abolished in the presence of PI3K inhibitor or AMPK inhibitor. In db/db mice, supplementation with MLE
decreased fasting blood glucose and insulin levels and enhanced insulin sensitivity, with increases of p-Akt
and p-AMPK in skeletal muscle. Moreover, MLE improved blood lipid parameters and attenuated hepatic
steatosis in diabetic db/db mice.

Discussion: These findings suggest that MLE exerts antidiabetic activity through stimulating glucose disposal
in skeletal muscle cells via the PI3K/Akt and AMPK pathways.

Conclusions: MLE can potentially improve hyperglycemia and hepatic steatosis in patients with type 2 diabetes.


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  1. Carnagarin R, Dharmarajan AM, Dass CR. Molecular aspects of glucose homeostasis in skeletal muscle – A focus on the molecular mechanisms of insulin resistance. Mol Cell Endocrinol 2015; 417: 52–62. doi: 10.1016/j.mce.2015.09.004

  2. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414(6865): 799–806. doi: 10.1038/414799a

  3. Lund S, Holman GD, Schmitz O, O Pedersen. Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin. Proc Natl Acad Sci U S A 1995; 92(13): 5817–5821.

  4. Wang HY, Ducommun S, Quan C, Xie B, Li M, Wasserman DH, et al. AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues. Biochem J 2013; 449(2): 479–489. doi: 10.1042/BJ20120702

  5. Xiong W, Jordens I, Gonzalez E, McGraw TE. GLUT4 is sorted to vesicles whose accumulation beneath and insertion into the plasma membrane are differentially regulated by insulin and selectively affected by insulin resistance. Mol Biol Cell 2010; 21(8): 1375–1386. doi: 10.1091/mbc

  6. Chan EW, Lye PY, Wong SK. Phytochemistry, pharmacology, and clinical trials of Morus alba. Chin J Nat Med 2016; 14(1): 17–30. doi: 10.3724/SP.J.1009.2016.00017

  7. Sheng Y, Zheng S, Ma T, Zhang C, Ou X, He X, et al. Mulberry leaf alleviates streptozotocin-induced diabetic rats by attenuating NEFA signaling and modulating intestinal microflora. Sci Rep 2017; 7(1): 12041. doi: 10.1038/s41598-017-12245-2

  8. Jiao Y, Wang X, Jiang X, Kong F, Wang S, Yan C. Antidiabetic effects of Morus alba fruit polysaccharides on high-fat diet- and streptozotocin-induced type 2 diabetes in rats. J Ethnopharmacol 2017; 199: 119–127. doi: 10.1016/j.jep.2017.02.003

  9. Asai A, Nakagawa K, Higuchi O, Kimura T, Kojima Y, Kariya J, et al. Effect of mulberry leaf extract with enriched 1-deoxynojirimycin content on postprandial glycemic control in subjects with impaired glucose metabolism. J Diabetes Investig 2011; 2(4): 318–323. doi: 10.1111/j.2040-1124.2011.00101.x

  10. Riche DM, Riche KD, East HE, Barrett EK, May WL. Impact of mulberry leaf extract on type 2 diabetes (Mul-DM): a randomized, placebo-controlled pilot study. Complement Ther Med 2017; 32: 105–108. doi: 10.1016/j.ctim.2017.04.006

  11. Liu Y, Li X, Xie C, Luo X, Bao Y, Wu B, et al. Prevention effects and possible molecular mechanism of mulberry leaf extract and its formulation on rats with insulin-insensitivity. PLoS One 2016; 11(4): e0152728. doi: 10.1371/journal.pone.0152728

  12. Liu Q, Li X, Li C, Zheng Y, Peng G. 1-Deoxynojirimycin alleviates insulin resistance via activation of insulin signaling PI3K/AKT pathway in skeletal muscle of db/db mice. Molecules 2015; 20(12): 21700–21714. doi: 10.3390/molecules201219794

  13. Naowaboot J, Pannangpetch P, Kukongviriyapan V, Prawan A, Kukongviriyapan U, Itharat A. Mulberry leaf extract stimulates glucose uptake and GLUT4 translocation in rat adipocytes. Am J Chin Med 2012; 40(1): 163–175. doi: 10.1142/S0192415X12500139

  14. Yan F, Dai G, Zheng X. Mulberry anthocyanin extract ameliorates insulin resistance by regulating PI3K/AKT pathway in HepG2 cells and db/db mice. J Nutr Biochem 2016; 36: 68–80. doi: 10.1016/j.jnutbio.2016.07.004

  15. Naowaboot J, Chung CH, Pannangpetch P, Choi R, Kim BH, Lee MY, et al. Mulberry leaf extract increases adiponectin in murine 3T3-L1 adipocytes. Nutr Res 2012; 32(1): 39–44. doi: 10.1016/j.nutres.2011.12.003

  16. Dkhar B, Khongsti K, Thabah D, Syiem D, Satyamoorthy K, Das B. Genistein represses PEPCK-C expression in an insulin-independent manner in HepG2 cells and in alloxan-induced diabetic mice. J Cell Biochem 2018; 119(2): 1953–1970. doi: 10.1002/jcb.26356

  17. Kim EK, Kwon KB, Song MY, Seo SW, Park SJ, Ka SO, et al. Genistein protects pancreatic β cells against cytokine-mediated toxicity. Mol Cell Endocrinol 2007; 278(1–2): 18–28. doi: 10.1016/j.mce.2007.08.003

  18. Zhang Y, Zhen W, Maechler P, Liu D. Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic β-cell survival and function via CREB. J Nutr Biochem 2013; 24(4): 638–646. doi: 10.1016/j.jnutbio.2012.03.008

  19. Alkhalidy H, Moore W, Zhang Y, McMillan R, Wang A, Ali M, et al. Small molecule kaempferol promotes insulin sensitivity and preserved pancreatic β-cell mass in middle-aged obese diabetic mice. J Diabetes Res 2015; 2015: 532984. doi: 10.1155/2015/532984

  20. Wu C, Zhang X, Zhang X, Luan H, Sun G, Sun X, et al. The caffeoylquinic acid-rich Pandanus tectorius fruit extract increases insulin sensitivity and regulates hepatic glucose and lipid metabolism in diabetic db/db mice. J Nutr Biochem 2014; 25(4): 412–419. doi: 10.1016/j.jnutbio.2013.12.002

  21. Zhao FQ, Keating AF. Functional properties and genomics of glucose transporters. Curr Genomics 2007; 8(2): 113–128.

  22. Ma X, Iwanaka N, Masuda S, Karaike K, Egawa T, Hamada T, et al. Morus alba leaf extract stimulates 5'-AMP-activated protein kinase in isolated rat skeletal muscle. J Ethnopharmacol 2009; 122(1): 54–59. doi: 10.1016/j.jep.2008.11.022

  23. Chan KC, Ho HH, Huang CN, Lin MC, Chen HM, Wang CJ. Mulberry leaf extract inhibits vascular smooth muscle cell migration involving a block of small GTPase and Akt/NF-κB signals. J Agric Food Chem 2009; 57(19): 9147–9153. doi: 10.1021/jf902507k

  24. Wong RH, Sul HS. Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr Opin Pharmacol 2010; 10(6): 684–691. doi: 10.1016/j.coph.2010.08.004

How to Cite
Bae U-J, Jung E-S, Jung S-J, Chae S-W, Park B-H. Mulberry leaf extract displays antidiabetic activity in <em>db/db</em> mice <em>via</em&gt; Akt and AMP-activated protein kinase phosphorylation. Food & Nutrition Research [Internet]. 22Aug.2018 [cited 20Sep.2018];62. Available from:
Original Articles