PDF herunterladen
Planta Med 2020; 86(11): 790-799
DOI: 10.1055/a-1164-8152
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Wild Strawberry, Blackberry, and Blueberry Leaf Extracts Alleviate Starch-Induced Hyperglycemia in Prediabetic and Diabetic Mice

István Takács
1   Department of Microbiology, University of Szeged, Szeged, Hungary
,
András Szekeres
1   Department of Microbiology, University of Szeged, Szeged, Hungary
,
Ákos Takács
2   Department of Food Engineering, University of Szeged, Szeged, Hungary
,
Dávid Rakk
1   Department of Microbiology, University of Szeged, Szeged, Hungary
,
Miklós Mézes
3   Department of Nutrition, Szent István University, Gödöllő, Hungary
,
Ágnes Polyák
4   Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
,
Lóránt Lakatos
5   Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
6   Present address: Biological Research Center, Szeged, Hungary
,
Gyöngyi Gyémánt
7   Department of Inorganic and Analytical Chemistry, University of Debrecen, Debrecen, Hungary
,
Dezső Csupor
8   Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
,
Krisztina J. Kovács   *
4   Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
,
Szilamér Ferenczi   *
4   Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
› InstitutsangabenGefördert durch: GINOP GINOP-2.3.2-15-2016-00012
Gefördert durch: National Research Development and Innovation Office of Hungary 109622
Gefördert durch: National Research Development and Innovation Office of Hungary 109744
Gefördert durch: National Research Development and Innovation Office of Hungary 124424
Gefördert durch: National Research Development and Innovation Office of Hungary NN107787
Gefördert durch: National Research Development and Innovation Office of Hungary NN11024
Weitere Informationen

Publikationsverlauf

received 17. Oktober 2019
revised 15. April 2020

accepted 23. April 2020

Publikationsdatum:
25. Mai 2020 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Intestinal α-glucosidase and α-amylase break down nutritional poly- and oligosaccharides to monosaccharides and their activity significantly contributes to postprandial hyperglycemia. Competitive inhibitors of these enzymes, such as acarbose, are effective antidiabetic drugs, but have unpleasant side effects. In our ethnopharmacology inspired investigations, we found that wild strawberry (Fragaria vesca), blackberry (Rubus fruticosus), and European blueberry (Vaccinium myrtillus) leaf extracts inhibit α-glucosidase and α-amylase enzyme activity in vitro and are effective in preventing postprandial hyperglycemia in vivo. Toxicology tests on H9c2 rat embryonic cardiac muscle cells demonstrated that berry leaf extracts have no cytotoxic effects. Oral administration of these leaf extracts alone or as a mixture to normal (control), obese, prediabetic, and streptozotocin-induced diabetic mice attenuated the starch-induced rise of blood glucose levels. The efficiency was similar to that of acarbose on blood glucose. These results highlight berry leaf extracts as candidates for testing in clinical trials in order to assess the clinical significance of their effects on glycemic control.

Key words

diabetes - α-glucosidase - α-amylase - Fragaria vesca - Rubus fruticosus - Vaccinium myrtillus - Rosaceae - Ericaceae

* Joint senior authors.


Supporting Information

 

  • References

  • 1 Ramlo-Halsted B, Edelman SV. The natural history of type 2 diabetes. Implications for clinical practice. Prim Care 1999; 26: 771-789
    CrossrefPubMedSuche in Google Scholar
  • 2 American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2018. Diabetes Care 2018; 41 (Suppl. 01) S13-S27
    CrossrefPubMedSuche in Google Scholar
  • 3 Leahy JJL, Aleppo G, Fonseca VA, Garg SK, Hirsch IB, McCall AL, McGill JB, Polonsky WH. Optimizing postprandial glucose management in adults with insulin-requiring diabetes: Report and recommendations. J Endocr Soc 2019; 3: 1942-1957
    CrossrefPubMedSuche in Google Scholar
  • 4 Wareham NJ, Pfister R. Diabetes: glycated hemoglobin is a marker of diabetes and CVD risk. Nat Rev Cardiol 2010; 7: 367-368
    CrossrefPubMedSuche in Google Scholar
  • 5 Ceriello A, dello Russo P, Amstad P, Cerutti P. High glucose induces antioxidant enzymes in human endothelial cells in culture. Evidence linking hyperglycemia and oxidative stress. Diabetes 1996; 45: 471-477
    CrossrefPubMedSuche in Google Scholar
  • 6 Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813-820
    CrossrefPubMedSuche in Google Scholar
  • 7 Gerich J. Pathogenesis and management of postprandial hyperglycemia: role of incretin-based therapies. Int J Gen Med 2013; 6: 877-895
    PubMedSuche in Google Scholar
  • 8 Walton RJ, Sherif IT, Noy GA, Alberti KG. Improved metabolic profiles in insulin-treated diabetic patients given an alpha-glucosidehydrolase inhibitor. Br Med J 1979; 1: 220-221
    PubMedSuche in Google Scholar
  • 9 Baron AD. Postprandial hyperglycaemia and alpha-glucosidase inhibitors. Diabetes Res Clin Pract 1998; 40 (Suppl.) S51-S55
    CrossrefPubMedSuche in Google Scholar
  • 10 Folsch UR. Clinical experience with acarbose as first line therapy in NIDDM. Clin Invest Med 1995; 18: 312-317
    PubMedSuche in Google Scholar
  • 11 Kast RE. Acarbose related diarrhea: increased butyrate upregulates prostaglandin E. Inflamm Res 2002; 51: 117-118
    CrossrefPubMedSuche in Google Scholar
  • 12 Hsiao SH, Liao LH, Cheng PN, Wu TJ. Hepatotoxicity associated with acarbose therapy. Ann Pharmacother 2006; 40: 151-154
    CrossrefPubMedSuche in Google Scholar
  • 13 Aoki K, Muraoka T, Ito Y, Togashi Y, Terauchi Y. Comparison of adverse gastrointestinal effects of acarbose and miglitol in healthy men: a crossover study. Intern Med 2010; 49: 1085-1087
    CrossrefPubMedSuche in Google Scholar
  • 14 Fabricant DS, Farnsworth NR. The value of plants used in traditional medicine for drug discovery. Environ Health Perspect 2001; 109 (Suppl. 01) 69-75
    PubMedSuche in Google Scholar
  • 15 de Bock M, Derraik JG, Cutfield WS. Polyphenols and glucose homeostasis in humans. J Acad Nutr Diet 2012; 112: 808-815
    CrossrefPubMedSuche in Google Scholar
  • 16 Helmstadter A, Schuster N. Vaccinium myrtillus as an antidiabetic medicinal plant–research through the ages. Pharmazie 2010; 65: 315-321
    PubMedSuche in Google Scholar
  • 17 Sidorova Y, Shipelin V, Mazo V, Zorin S, Petrov N, Kochetkova A. Hypoglycemic and hypolipidemic effect of Vaccinium myrtillus L. leaf and Phaseolus vulgaris L. seed coat extracts in diabetic rats. Nutrition 2017; 41: 107-112
    CrossrefPubMedSuche in Google Scholar
  • 18 Ştefănescu Braic R, Vari C, Imre S, Huţanu A, Fogarasi E, Todea T, Groşan A, Eşianu S, Laczkó-Zöld E, Dogaru M. Vaccinium extracts as modulators in experimental type 1 diabetes. J Med Food 2018; 21: 1106-1112
    CrossrefPubMedSuche in Google Scholar
  • 19 Bljajić K, Petlevski R, Vujić L, Čačić A, Šoštarić N, Jablan J, Saraiva de Carvalho I, Zovko Končić M. Chemical composition, antioxidant and alpha-glucosidase-inhibiting activities of the aqueous and hydroethanolic extracts of Vaccinium myrtillus leaves. Molecules 2017; 22: E703
    CrossrefPubMedSuche in Google Scholar
  • 20 Karcheva-Bahchevanska DP, Lukova PK, Nikolova MM, Mladenov RD, Iliev IN. Effect of extracts of bilberries (Vaccinium myrtillus L.) on amyloglucosidase and alpha-glucosidase activity. Folia Med (Plovdiv) 2017; 59: 197-202
    PubMedSuche in Google Scholar
  • 21 de Mello VD, Lankinen MA, Lindström J, Puupponen-Pimiä R, Laaksonen DE, Pihlajamäki J, Lehtonen M, Uusitupa M, Tuomilehto J, Kolehmainen M, Törrönen R, Hanhineva K. Fasting serum hippuric acid is elevated after bilberry (Vaccinium myrtillus) consumption and associates with improvement of fasting glucose levels and insulin secretion in persons at high risk of developing type 2 diabetes. Mol Nutr Food Res 2017;
    CrossrefPubMedSuche in Google Scholar
  • 22 Hoggard N, Cruickshank M, Moar KM, Bestwick C, Holst JJ, Russell W, Horgan G. A single supplement of a standardised bilberry (Vaccinium myrtillus L.) extract (36 % wet weight anthocyanins) modifies glycaemic response in individuals with type 2 diabetes controlled by diet and lifestyle. J Nutr Sci 2013; 2: e22
    CrossrefPubMedSuche in Google Scholar
  • 23 Solverson PM, Rumpler WV, Leger JL, Redan BW, Ferruzzi MG, Baer DJ, Castonguay TW, Novotny JA. Blackberry feeding increases fat oxidation and improves insulin sensitivity in overweight and obese males. Nutrients 2018; 10: E1048
    CrossrefPubMedSuche in Google Scholar
  • 24 Ferlemi AV, Lamari FN. Berry leaves: an alternative source of bioactive natural products of nutritional and medicinal value. Antioxidants (Basel) 2016; 5: E17
    CrossrefPubMedSuche in Google Scholar
  • 25 Alonso R, Cadavid I, Calleja JM. A preliminary study of hypoglycemic activity of Rubus fruticosus . Planta Med 1980; Suppl.: 102-106
    Thieme ConnectPubMedSuche in Google Scholar
  • 26 Swanston-Flatt SK, Day C, Bailey CJ, Flatt PR. Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice. Diabetologia 1990; 33: 462-464
    CrossrefPubMedSuche in Google Scholar
  • 27 Mandave P, Khadke S, Karandikar M, Pandit V, Ranjekar P, Kuvalekar A, Mantri N. Antidiabetic, lipid normalizing, and nephroprotective actions of the strawberry: A potent supplementary fruit. Int J Mol Sci 2017; 18: E124
    CrossrefPubMedSuche in Google Scholar
  • 28 Ibrahim DS, Abd El-Maksoud MA. Effect of strawberry (Fragaria x ananassa) leaf extract on diabetic nephropathy in rats. Int J Exp Pathol 2015; 96: 87-93
    CrossrefPubMedSuche in Google Scholar
  • 29 Moazen S, Amani R, Homayouni Rad A, Shahbazian H, Ahmadi K, Taha Jalali M. Effects of freeze-dried strawberry supplementation on metabolic biomarkers of atherosclerosis in subjects with type 2 diabetes: a randomized double-blind controlled trial. Ann Nutr Metab 2013; 63: 256-264
    CrossrefPubMedSuche in Google Scholar
  • 30 Oszmianski J, Wojdyło A, Gorzelany J, Kapusta I. Identification and characterization of low molecular weight polyphenols in berry leaf extracts by HPLC-DAD and LC-ESI/MS. J Agric Food Chem 2011; 59: 12830-12835
    CrossrefPubMedSuche in Google Scholar
  • 31 Aranaz P, Romo-Hualde A, Zabala M, Navarro-Herrera D, Ruiz de Galarreta M, Gil AG, Martinez JA, Milagro FI, González-Navarro CJ. Freeze-dried strawberry and blueberry attenuates diet-induced obesity and insulin resistance in rats by inhibiting adipogenesis and lipogenesis. Food Funct 2017; 8: 3999-4013
    CrossrefPubMedSuche in Google Scholar
  • 32 Paquette M, Medina Larqué AS, Weisnagel SJ, Desjardins Y, Marois J, Pilon G, Dudonné S, Marette A, Jacques H. Strawberry and cranberry polyphenols improve insulin sensitivity in insulin-resistant, non-diabetic adults: a parallel, double-blind, controlled and randomised clinical trial. Br J Nutr 2017; 117: 519-531
    CrossrefPubMedSuche in Google Scholar
  • 33 Ceriello A. Controlling oxidative stress as a novel molecular approach to protecting the vascular wall in diabetes. Curr Opin Lipidol 2006; 17: 510-518
    CrossrefPubMedSuche in Google Scholar
  • 34 Bischoff H. Pharmacology of alpha-glucosidase inhibition. Eur J Clin Invest 1994; 24 (Suppl. 03) 3-10
    CrossrefPubMedSuche in Google Scholar
  • 35 Kumar S, Narwal S, Kumar V, Prakash O. α-glucosidase inhibitors from plants: A natural approach to treat diabetes. Pharmacogn Rev 2011; 5: 19-29
    CrossrefPubMedSuche in Google Scholar
  • 36 Hung HY, Qian K, Morris-Natschke SL, Hsu CS, Lee KH. Recent discovery of plant-derived anti-diabetic natural products. Nat Prod Rep 2012; 29: 580-606
    CrossrefPubMedSuche in Google Scholar
  • 37 Kim GN, Kwon YI, Jang HD. Mulberry leaf extract reduces postprandial hyperglycemia with few side effects by inhibiting alpha-glucosidase in normal rats. J Med Food 2011; 14: 712-717
    CrossrefPubMedSuche in Google Scholar
  • 38 Satoh T, Igarashi M, Yamada S, Takahashi N, Watanabe K. Inhibitory effect of black tea and its combination with acarbose on small intestinal alpha-glucosidase activity. J Ethnopharmacol 2015; 161: 147-155
    CrossrefPubMedSuche in Google Scholar
  • 39 Buchholz T, Melzig MF. Medicinal plants traditionally used for treatment of obesity and diabetes mellitus – screening for pancreatic lipase and alpha-amylase inhibition. Phytother Res 2016; 30: 260-266
    CrossrefPubMedSuche in Google Scholar
  • 40 Sompong W, Muangngam N, Kongpatpharnich A, Manacharoenlarp C, Amorworasin C, Suantawee T, Thilavech T, Adisakwattana S. The inhibitory activity of herbal medicines on the keys enzymes and steps related to carbohydrate and lipid digestion. BMC Complement Altern Med 2016; 16: 439
    CrossrefPubMedSuche in Google Scholar
  • 41 Jo SH, Cho CY, Lee JY, Ha KS, Kwon YI, Apostolidis E. In vitro and in vivo reduction of post-prandial blood glucose levels by ethyl alcohol and water Zingiber mioga extracts through the inhibition of carbohydrate hydrolyzing enzymes. BMC Complement Altern Med 2016; 16: 111
    CrossrefPubMedSuche in Google Scholar
  • 42 Li Y, Peng G, Li Q, Wen S, Huang TH, Roufogalis BD, Yamahara J. Salacia oblonga improves cardiac fibrosis and inhibits postprandial hyperglycemia in obese Zucker rats. Life Sci 2004; 75: 1735-1746
    CrossrefPubMedSuche in Google Scholar
  • 43 Li Y, Wen S, Kota BP, Peng G, Li GQ, Yamahara J, Roufogalis BD. Punica granatum flower extract, a potent alpha-glucosidase inhibitor, improves postprandial hyperglycemia in Zucker diabetic fatty rats. J Ethnopharmacol 2005; 99: 239-244
    CrossrefPubMedSuche in Google Scholar
  • 44 McDougall GJ, Shpiro F, Dobson P, Smith P, Blake A, Stewart D. Different polyphenolic components of soft fruits inhibit alpha-amylase and alpha-glucosidase. J Agric Food Chem 2005; 53: 2760-2766
    CrossrefPubMedSuche in Google Scholar
  • 45 Boath AS, Stewart D, McDougall GJ. Berry components inhibit alpha-glucosidase in vitro: synergies between acarbose and polyphenols from black currant and rowanberry. Food Chem 2012; 135: 929-936
    CrossrefPubMedSuche in Google Scholar
  • 46 Takikawa M, Inoue S, Horio F, Tsuda T. Dietary anthocyanin-rich bilberry extract ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase in diabetic mice. J Nutr 2010; 140: 527-533
    CrossrefPubMedSuche in Google Scholar
  • 47 Jouad H, Maghrani M, Eddouks M. Hypoglycaemic effect of Rubus fructicosis L. and Globularia alypum L. in normal and streptozotocin-induced diabetic rats. J Ethnopharmacol 2002; 81: 351-356
    CrossrefPubMedSuche in Google Scholar
  • 48 Barnaba C, Dellacassa E, Nicolini G, Nardin T, Serra M, Larcher R. Non-targeted glycosidic profiling of international wines using neutral loss-high resolution mass spectrometry. J Chromatogr A 2018; 1557: 75-89
    CrossrefPubMedSuche in Google Scholar
  • 49 Farkas E, Jánossy L, Harangi J, Kandra L, Lipták A. Synthesis of chromogenic substrates of alpha-amylases on a cyclodextrin basis. Carbohydr Res 1997; 303: 407-415
    CrossrefPubMedSuche in Google Scholar
  • 50 Takács I, Takács Á, Pósa A, Gyémánt G. HPLC method for measurement of human salivary alpha-amylase inhibition by aqueous plant extracts. Acta Biol Hung 2017; 68: 127-136
    CrossrefPubMedSuche in Google Scholar