Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2017

Open Access 01-12-2017 | Research article

A novel botanical formula prevents diabetes by improving insulin resistance

Authors: Juntao Kan, Rodney A. Velliquette, Kerry Grann, Charlie R. Burns, Jeff Scholten, Feng Tian, Qi Zhang, Min Gui

Published in: BMC Complementary Medicine and Therapies | Issue 1/2017

Login to get access

Abstract

Background

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease, and the prevalence has increased significantly in recent decades to epidemic proportions in China. Individually, fenugreek (Trigonella foenum graecum) seed, mulberry (Morus alba L.) leaf and American ginseng (Panax quinquefolius) root can improve glycemia in various animal models and humans with impaired glucose metabolism and T2DM. The aim of this study was to design an optimized botanical formula containing these herbal extracts as a nutritional strategy for the prevention of insulin resistance and T2DM.

Methods

Cell-free α-amylase and α-glucosidase enzyme assays were used to determine inhibitory potential of extracts. Glucose uptake was examined in differentiated human adipocytes using radiolabeled 2-deoxyglucose. Male Sprague Dawley rats were divided and glycemia balanced into 5 groups: two controls (naïve and model) and three doses of the botanical test formula containing standardized fenugreek seed, mulberry leaf and American ginseng extracts (42.33, 84.66 and 169.33 mg/kg BW). Insulin resistance and T2DM was induced by feeding animals a high fat diet and with an alloxan injection. Glucose tolerance was examined by measuring serum glucose levels following an oral glucose load.

Results

Fenugreek seed and mulberry leaf dose dependently inhibited α-amylase (IC50 = 73.2 μg/mL) and α-glucosidase (IC50 = 111.8 ng/mL), respectively. All three botanical extracts improved insulin sensitivity and glucose uptake in human adipocytes, which lead to the design of an optimized botanical test formula. In a rat model of insulin resistance and T2DM, the optimized botanical test formula improved fasting serum glucose levels, fasting insulin resistance and the development of impaired glucose tolerance. The reduction in epididymal adipose tissue GLUT4 and PDK1 expression induced by high fat diet and alloxan was blunted by the botanical test formula.

Conclusions

A novel botanical formula containing standardized extracts of mulberry leaf, fenugreek seed and American ginseng at a ratio of 1:1.3:3.4 prevented the development of insulin resistance, impaired glucose tolerance and T2DM. Given the rising need for effective non-drug targeting of insulin resistance and progression to T2DM, complementary and alternative nutritional strategies without intolerable side effects could have meaningful impact on metabolic health and diabetes risks.
Literature
1.
Association AD: 2. Classification and diagnosis of diabetes. Diabetes Care 2015, 38(Supplement 1):S8-S16.
2.
Xu Y, Wang L, He J, Bi Y, Li M, Wang T, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310(9):948–59.CrossRefPubMed
3.
Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, et al. Prevalence of diabetes among men and women in China. N Engl J Med. 2010;362(12):1090–101.CrossRefPubMed
4.
Hashempur MH, Heydari M, Mosavat SH, Heydari ST, Shams M. Complementary and alternative medicine use in Iranian patients with diabetes mellitus. J Integr Med. 2015;13(5):319–25.CrossRefPubMed
5.
Pumthong G, Nathason A, Tuseewan M, Pinthong P, Klangprapun S, Thepsuriyanon D, et al. Complementary and alternative medicines for diabetes mellitus management in ASEAN countries. Complement Ther Med. 2015;23(4):617–25.CrossRefPubMed
6.
Ching SM, Zakaria ZA, Paimin F, Jalalian M. Complementary alternative medicine use among patients with type 2 diabetes mellitus in the primary care setting: a cross-sectional study in Malaysia. BMC Complement Altern Med. 2013;13:148.CrossRefPubMedPubMedCentral
7.
Manya K, Champion B, Dunning T. The use of complementary and alternative medicine among people living with diabetes in Sydney. BMC Complement Altern Med. 2012;12:2.CrossRefPubMedPubMedCentral
8.
Nguyen H, Sorkin DH, Billimek J, Kaplan SH, Greenfield S, Ngo-Metzger Q. Complementary and alternative medicine (CAM) use among non-Hispanic white, Mexican American, and Vietnamese American patients with type 2 diabetes. J Health Care Poor Underserved. 2014;25(4):1941–55.CrossRefPubMed
9.
Calixto J. Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents). Braz J Med Biol Res. 2000;33(2):179–89.CrossRefPubMed
10.
Valli G, Giardina E-GV. Benefits, adverse effects and drug interactionsof herbal therapies with cardiovascular effects. J Am Coll Cardiol. 2002;39(7):1083–95.CrossRefPubMed
11.
Chang CL, Lin Y, Bartolome AP, Chen YC, Chiu SC, Yang WC. Herbal therapies for type 2 diabetes mellitus: chemistry, biology, and potential application of selected plants and compounds. Evid Based Complement Alternat Med. 2013;2013:378657.PubMedPubMedCentral
12.
Bahmani M, Shirzad H, Mirhosseini M, Mesripour A, Rafieian-Kopaei M. A review on ethnobotanical and therapeutic uses of fenugreek (Trigonella foenum-graceum L). J Evid Based Complement Alternat Med. 2016;21(1):53–62.CrossRef
13.
Mucalo I, Rahelic D, Jovanovski E, Bozikov V, Romic Z, Vuksan V. Effect of American ginseng (Panax quinquefolius L.) on glycemic control in type 2 diabetes. Coll Antropol. 2012;36(4):1435–40.PubMed
14.
Shin SO, Seo HJ, Park H, Song HJ. Effects of mulberry leaf extract on blood glucose and serum lipid profiles in patients with type 2 diabetes mellitus: a systematic review. Eur J Integr Med. 2016;8(5):602–8.CrossRef
15.
Zohary D, Hopf M. Domestication of plants in the old world : the origin and spread of cultivated plants in West Asia, Europe, and the Nile Valley. 3rd ed. Oxford New York: Oxford University Press; 2000.
16.
Mishkinsky JS, Goldschmied A, Joseph B, Ahronson Z, Sulman FG. Hypoglycaemic effect of Trigonella foenum graecum and Lupinus termis (leguminosae) seeds and their major alkaloids in alloxan-diabetic and normal rats. Arch Int Pharmacodyn Ther. 1974;210(1):27–37.PubMed
17.
Gong J, Fang K, Dong H, Wang D, Hu M, Lu F. Effect of fenugreek on hyperglycaemia and hyperlipidemia in diabetes and prediabetes: a meta-analysis. J Ethnopharmacol. 2016;194:260–8.CrossRefPubMed
18.
Ribes G, Sauvaire Y, Da Costa C, Baccou JC, Loubatieres-Mariani MM. Antidiabetic effects of subfractions from fenugreek seeds in diabetic dogs. P Soc Exp Biol Med. 1986;182(2):159–66.CrossRef
19.
Ribes G, Sauvaire Y, Baccou JC, Valette G, Chenon D, Trimble ER, et al. Effects of fenugreek seeds on endocrine pancreatic secretions in dogs. Ann Nutr Metab. 1984;28(1):37–43.CrossRefPubMed
20.
Kumar P, Kale RK, Baquer NZ. Antihyperglycemic and protective effects of Trigonella foenum graecum seed powder on biochemical alterations in alloxan diabetic rats. Eur Rev Med Pharmacol. 2012;16(Suppl 3):18–27.
21.
Moorthy R, Prabhu KM, Murthy PS. Mechanism of anti-diabetic action, efficacy and safety profile of GII purified from fenugreek (Trigonella foenum-graceum Linn.) seeds in diabetic animals. Indian J Exp Biol. 2010;48(11):1119–22.PubMed
22.
Khosla P, Gupta DD, Nagpal RK. Effect of Trigonella foenum graecum (fenugreek) on blood glucose in normal and diabetic rats. Indian J Physiol Pharmacol. 1995;39(2):173–4.PubMed
23.
Kassaian N, Azadbakht L, Forghani B, Amini M. Effect of fenugreek seeds on blood glucose and lipid profiles in type 2 diabetic patients. Int J Vitam Nutr Res. 2009;79(1):34–9.CrossRefPubMed
24.
Zafar MI, Feng G. 4-Hydroxyisoleucine: a potential new treatment for type 2 diabetes mellitus. BioDrugs. 2016:1–8.
25.
Broca C, Gross R, Petit P, Sauvaire Y, Manteghetti M, Tournier M, et al. 4-Hydroxyisoleucine: experimental evidence of its insulinotropic and antidiabetic properties. Am J Physiology. 1999;277(4 Pt 1):E617–23.
26.
Sauvaire Y, Petit P, Broca C, Manteghetti M, Baissac Y, Fernandez-Alvarez J, et al. 4-Hydroxyisoleucine: a novel amino acid potentiator of insulin secretion. Diabetes. 1998;47(2):206–10.CrossRefPubMed
27.
Broca C, Manteghetti M, Gross R, Baissac Y, Jacob M, Petit P, et al. 4-Hydroxyisoleucine: effects of synthetic and natural analogues on insulin secretion. Eur J Pharmacol. 2000;390(3):339–45.CrossRefPubMed
28.
Lu F-r, Shen L, Qin Y, Gao L, Li H, Dai Y. Clinical observation on Trigonella foenum-graecum L. total saponins in combination with sulfonylureas in the treatment of type 2 diabetes mellitus. Chin J Integr Med. 2008;14:56–60.CrossRefPubMed
29.
Hajizadeh MR, Eftekhar E, Zal F, Jafarian A, Mostafavi-Pour Z. Mulberry leaf extract attenuates oxidative stress-mediated testosterone depletion in streptozotocin-induced diabetic rats. Iran J Basic Med Sci. 2014;39(2):123–9.
30.
Park JM, Bong HY, Jeong HI, Kim YK, Kim JY, Kwon O. Postprandial hypoglycemic effect of mulberry leaf in Goto-Kakizaki rats and counterpart control Wistar rats. Nutr Res Pract. 2009;3(4):272–8.CrossRefPubMedPubMedCentral
31.
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.CrossRefPubMedPubMedCentral
32.
Naowaboot J, Pannangpetch P, Kukongviriyapan V, Kongyingyoes B, Kukongviriyapan U. Antihyperglycemic, antioxidant and antiglycation activities of mulberry leaf extract in streptozotocin-induced chronic diabetic rats. Plant Food Hum Nutr. 2009;64(2):116–21.CrossRef
33.
34.
Yatsunami K, Ichida M, Onodera S. The relationship between 1-deoxynojirimycin content and alpha-glucosidase inhibitory activity in leaves of 276 mulberry cultivars (Morus spp.) in Kyoto, Japan. J Nat Med. 2008;62(1):63–6.CrossRefPubMed
35.
Mudra M, Ercan-Fang N, Zhong L, Furne J, Levitt M. Influence of mulberry leaf extract on the blood glucose and breath hydrogen response to ingestion of 75 g sucrose by type 2 diabetic and control subjects. Diabetes Care. 2007;30(5):1272–4.CrossRefPubMed
36.
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 Invest. 2011;2(4):318–23.CrossRef
37.
Kimura T, Nakagawa K, Kubota H, Kojima Y, Goto Y, Yamagishi K, et al. Food-grade mulberry powder enriched with 1-deoxynojirimycin suppresses the elevation of postprandial blood glucose in humans. J Agric Food Chem. 2007;55(14):5869–74.CrossRefPubMed
38.
Kim JY, Ok HM, Kim J, Park SW, Kwon SW, Kwon O. Mulberry leaf extract improves postprandial glucose response in prediabetic subjects: a randomized, double-blind placebo-controlled trial. J Med Food. 2015;18(3):306–13.CrossRefPubMed
39.
Wang X, Sakuma T, Asafu-Adjaye E, Shiu GK. Determination of ginsenosides in plant extracts from Panax ginseng and Panax quinquefolius L. by LC/MS/MS. Anal Chem. 1999;71(8):1579–84.CrossRefPubMed
40.
Sen S, Querques MA, Chakrabarti S. North American ginseng (Panax quinquefolius) prevents hyperglycemia and associated pancreatic abnormalities in diabetes. J Med Food. 2013;16(7):587–92.CrossRefPubMed
41.
Yoo KM, Lee C, Lo YM, Moon B. The hypoglycemic effects of American red ginseng (Panax quinquefolius L.) on a diabetic mouse model. J Food Sci. 2012;77(7):H147–52.CrossRefPubMed
42.
Xie JT, Wang CZ, Li XL, Ni M, Fishbein A, Yuan CS. Anti-diabetic effect of American ginseng may not be linked to antioxidant activity: comparison between American ginseng and Scutellaria Baicalensis using an ob/ob mice model. Fitoterapia. 2009;80(5):306–11.CrossRefPubMed
43.
Vuksan V, Sievenpiper JL, Wong J, Xu Z, Beljan-Zdravkovic U, Arnason JT, et al. American ginseng (Panax quinquefolius L.) attenuates postprandial glycemia in a time-dependent but not dose-dependent manner in healthy individuals. Am J Clin Nutr. 2001;73(4):753–8.PubMed
44.
Vuksan V, Stavro MP, Sievenpiper JL, Beljan-Zdravkovic U, Leiter LA, Josse RG, et al. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care. 2000;23(9):1221–6.CrossRefPubMed
45.
De Souza LR, Jenkins AL, Jovanovski E, Rahelic D, Vuksan V. Ethanol extraction preparation of American ginseng (Panax quinquefolius L) and Korean red ginseng (Panax ginseng C.A. Meyer): differential effects on postprandial insulinemia in healthy individuals. J Ethnopharmacol. 2015;159:55–61.CrossRefPubMed
46.
CFDA: Technical standards for testing and assessment of health food. People's Medical Publishing House 2003, 1: 38–40.
47.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.CrossRefPubMed
48.
Phielix E, Szendroedi J, Roden M. The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact. Trends Pharmacol Sci. 2011;32(10):607–16.CrossRefPubMed
49.
Joshi SR, Standl E, Tong N, Shah P, Kalra S, Rathod R. Therapeutic potential of α-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review. Expert Opin Pharmacother. 2015;16(13):1959–81.CrossRefPubMed
50.
Hu R, Yi L, Lv Q, Wu T, Tong N. Acarbose monotherapy and type 2 diabetes prevention in eastern and western prediabetes: an ethnicity-specific meta-analysis. Clin Ther. 2015;37(8):1798–812.CrossRefPubMed
51.
Kwon HJ, Ji YC, Ji YK, Kwon O. Comparison of 1-deoxynojirimycin and aqueous mulberry leaf extract with emphasis on postprandial hypoglycemic effects: in vivo and in vitro studies. J Agric Food Chem. 2011;59(7):3014–9.CrossRefPubMed
52.
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(01):163–75.CrossRefPubMed
53.
Lee SM, Shin MJ, Hwang KY, Kwon O, Chung JH. 1-Deoxynojirimycin isolated from a Bacillus Subtilis stimulates adiponectin and GLUT4 expressions in 3T3-L1 adipocytes. J Microbiol Biotechnol. 2013;23(5):637–43.CrossRefPubMed
54.
Jaiswal N, Maurya CK, Venkateswarlu K, Sukanya P, Srivastava AK, Narender T, et al. 4-Hydroxyisoleucine stimulates glucose uptake by increasing surface GLUT4 level in skeletal muscle cells via phosphatidylinositol-3-kinase-dependent pathway. Eur J Nutr. 2012;51(7):893–8.CrossRefPubMed
55.
Shang W, Yang Y, Zhou L, Jiang B, Jin H, Chen M. Ginsenoside Rb1 stimulates glucose uptake through insulin-like signaling pathway in 3T3-L1 adipocytes. J Endocrinol. 2008;198(3):561–9.CrossRefPubMed
56.
Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol. 2002;3(4):267–77.CrossRefPubMed
57.
Leto D, Saltiel AR. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol. 2012;13(6):383–96.CrossRefPubMed
58.
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799–806.CrossRefPubMed
59.
Cohen P, Alessi DR, Cross DA. PDK1, one of the missing links in insulin signal transduction? FEBS Lett. 1997;410(1):3–10.CrossRefPubMed
60.
Sakaue H, Nishizawa A, Ogawa W, Teshigawara K, Mori T, Takashima Y, et al. Requirement for 3-phosphoinositide-dependent kinase-1 (PDK-1) in insulin-induced glucose uptake in immortalized brown adipocytes. J Biol Chem. 2003;278(40):38870–4.CrossRefPubMed
61.
Bandyopadhyay G, Standaert ML, Sajan MP, Karnitz LM, Cong L, Quon MJ, et al. Dependence of insulin-stimulated glucose transporter 4 translocation on 3-phosphoinositide-dependent protein kinase-1 and its target threonine-410 in the activation loop of protein kinase C-zeta. Mol Endocrinol. 1999;13(10):1766–72.PubMed
62.
Mora A, Komander D, Aalten DMFV, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15(2):161–70.CrossRefPubMed
63.
Lim S, Yoon JW, Choi SH, Cho BJ, Kim JT, Chang HS, et al. Effect of ginsam, a vinegar extract from Panax ginseng, on body weight and glucose homeostasis in an obese insulin-resistant rat model. Metabolism. 2009;58(1):8–15.CrossRefPubMed
64.
Han KL, Jung MH, Sohn JH, Hwang J-K. Ginsenoside 20 (S)-protopanaxatriol (PPT) activates peroxisome proliferator-activated receptor (PPAR) in 3T3-L1 adipocytes. Biol Pharm Bull. 2006;29(1):110–3.CrossRefPubMed
65.
Gad MZ, El-Sawalhi MM, Ismail MF, El-Tanbouly ND. Biochemical study of the anti-diabetic action of the Egyptian plants fenugreek and Balanites. Mol Cell Biochem. 2006;281(1–2):173–83.CrossRefPubMed
66.
Hansawasdi C, Kawabata J. α-Glucosidase inhibitory effect of mulberry (Morus alba) leaves on Caco-2. Fitoterapia. 2006;77(7):568–73.CrossRefPubMed
67.
Kim G-N, Kwon Y-I, Jang H-D. Mulberry leaf extract reduces postprandial hyperglycemia with few side effects by inhibiting α-glucosidase in normal rats. J Med Food. 2011;14(7–8):712–7.CrossRefPubMed
Metadata
Title
A novel botanical formula prevents diabetes by improving insulin resistance
Authors
Juntao Kan
Rodney A. Velliquette
Kerry Grann
Charlie R. Burns
Jeff Scholten
Feng Tian
Qi Zhang
Min Gui
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2017
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-017-1848-3

Other articles of this Issue 1/2017

BMC Complementary Medicine and Therapies 1/2017 Go to the issue

Research article

Chemical constituents, antibacterial and antioxidant properties of the essential oil flower of Tagetes minuta grown in Cala community Eastern Cape, South Africa

Research article

Comparison of chemical profiles between the root and aerial parts from three Bupleurum species based on a UHPLC-QTOF-MS metabolomics approach

Research article

Anti-cancer effects of Ajwa dates (Phoenix dactylifera L.) in diethylnitrosamine induced hepatocellular carcinoma in Wistar rats

Research article

Anti-inflammatory potential of Capparis spinosa L. in vivo in mice through inhibition of cell infiltration and cytokine gene expression

Software

DisArticle: a web server for SVM-based discrimination of articles on traditional medicine

Research article

Community pharmacists’ perceptions about pharmaceutical service of over-the-counter traditional Chinese medicine: a survey study in Harbin of China