The role of anthocyanins as antidiabetic agents: from molecular mechanisms to in vivo and human studies

Abstract

Diabetes mellitus is a chronic metabolic disease characterized by high blood glucose concentration. Nowadays, type 2 diabetes or insulin resistant diabetes is the most common diabetes, mainly due to unhealthy lifestyle. Healthy habits like appropriate nutritional approaches or the consumption of certain natural products or food supplements have been suggested as non-pharmacological strategies for the treatment and prevention of type 2 diabetes. Some of the main bioactive compounds from plant foods are polyphenols, important mainly for their antioxidant capacity in oxidative stress conditions and ageing. Anthocyanins are polyphenols of the flavonoid group, which act as pigments in plants, especially in fruits such as berries. A search of in vitro, in vivo and human studies in relation with antidiabetic properties of anthocyanins has been performed in different electronic databases. Results of this review demonstrate that these compounds have the ability to inhibit different enzymes as well as to influence gene expression and metabolic pathways of glucose, such as AMPK, being able to modulate diabetes and other associated disorders, as hyperlipidaemia, overweight, obesity and cardiovascular diseases. Additionally, human interventional studies have shown that high doses of anthocyanins have potential in the prevention or treatment of type 2 diabetes; nevertheless, anthocyanins used in these studies should be standardized and quantified in order to make general conclusions about its use and to claim benefits for the human population.

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References

  1. 1.

    Akkarachiyasit S, Charoenlertkul P, Yibchok-Anun S, Adisakwattana S (2010) Inhibitory activities of cyanidin and its glycosides and synergistic effect with acarbose against intestinal α-glucosidase and pancreatic α-amylase. Int J Mol Sci 11:3387–3396. https://doi.org/10.3390/ijms11093387

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Akkarachiyasit S, Yibchok-Anun S, Wacharasindhu S, Adisakwattana S (2011) In vitro inhibitory effects of cyandin-3-rutinoside on pancreatic α-amylase and its combined effect with acarbose. Molecules 16:2075–2083. https://doi.org/10.3390/molecules16032075

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Alvarado J, Schoenlau F, Leschot A, Salgado AM, Portales PV (2016) Delphinol® standardized maqui berry extract significantly lowers blood glucose and improves blood lipid profile in prediabetic individuals in three-month clinical trial. Panminerva Med 58:1–6

    PubMed  Google Scholar 

  4. 4.

    Alvarado JL, Leschot A, Olivera-Nappa Á, Salgado A-MM, Rioseco H, Lyon C, Vigil P (2016) Delphinidin-rich maqui berry extract (Delphinol®) lowers fasting and postprandial glycemia and insulinemia in prediabetic individuals during oral glucose tolerance tests. Biomed Res Int 2016:9070537. https://doi.org/10.1155/2016/9070537

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    An JH, Kim DL, Lee TB, Kim KJ, Kim SHSG, Kim NH, Kim HY, Choi DS, Kim SHSG (2016) Effect of Rubus Occidentalis extract on metabolic parameters in subjects with prediabetes: a proof-of-concept, randomized, double-blind, placebo-controlled clinical trial. Phyther Res 30:1634–1640. https://doi.org/10.1002/ptr.5664

    Article  Google Scholar 

  6. 6.

    Anunciação PC, de Morais Cardoso L, Queiroz VAV, de Menezes CB, de Carvalho CWP, Pinheiro-Sant’Ana M, de Cássia Gonçalves Alfenas R (2018) Consumption of a drink containing extruded sorghum reduces glycaemic response of the subsequent meal. Eur J Nutr 57:251–257. https://doi.org/10.1007/s00394-016-1314-x

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Asgary S, Rafieiankopaei M, Sahebkar A, Shamsi F, Goli-malekabadi N (2016) Anti-hyperglycemic and anti-hyperlipidemic effects of Vaccinium myrtillus fruit in experimentally induced diabetes (antidiabetic effect of Vaccinium myrtillus fruit). J Sci Food Agric 96:764–768. https://doi.org/10.1002/jsfa.7144

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Asrafuzzaman M, Cao Y, Afroz R, Kamato D, Gray S, Little PJ (2017) Animal models for assessing the impact of natural products on the aetiology and metabolic pathophysiology of Type 2 diabetes. Biomed Pharmacother 89:1242–1251

    CAS  Article  Google Scholar 

  9. 9.

    Bae IY, An JS, Oh IK, Lee HG (2017) Optimized preparation of anthocyanin-rich extract from black rice and its effects on in vitro digestibility. Food Sci Biotechnol 26:1415–1422. https://doi.org/10.1007/s10068-017-0188-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Banihani S, Swedan S, Alguraan Z (2013) Pomegranate and type 2 diabetes. Nutr Res 33:341–348. https://doi.org/10.1016/j.nutres.2013.03.003

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Batterham RL, Le Roux CW, Cohen MA, Park AJ, Ellis SM, Patterson M, Frost GS, Ghatei MA, Bloom SR (2003) Pancreatic polypeptide reduces appetite and food intake in humans. J Clin Endocrinol Metab 88:3989–3992. https://doi.org/10.1210/jc.2003-030630

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Bell L, Lamport DJ, Butler LT, Williams CM (2017) A study of glycaemic effects following acute anthocyanin-rich blueberry supplementation in healthy young adults. Food Funct 8:3104–3110. https://doi.org/10.1039/c7fo00724h

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Boath AS, Stewart D, McDougall GJ (2012) Berry components inhibit α-glucosidase in vitro: synergies between acarbose and polyphenols from black currant and rowanberry. Food Chem 135:929–936. https://doi.org/10.1016/j.foodchem.2012.06.065

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bonina FP, Leotta C, Scalia G, Puglia C, Trombetta D, Tringali G, Roccazzello AM, Rapisarda P, Saija A (2002) Evaluation of oxidative stress in diabetic patients after supplementation with a standardised red orange extract. Diabetes Nutr Metab 15:14–19

    CAS  PubMed  Google Scholar 

  15. 15.

    Cantos E, Espín JC, Tomás-Barberán FA (2002) Varietal differences among the polyphenol profiles of seven table grape cultivars studied by LC-DAD-MS-MS. J Agric Food Chem 50:5691–5696. https://doi.org/10.1021/jf0204102

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Cásedas G, Les F, Gómez-Serranillos MPMP, Smith C, López V (2016) Bioactive and functional properties of sour cherry juice (Prunus cerasus). Food Funct 7:4675–4682. https://doi.org/10.1039/c6fo01295g

    Article  PubMed  Google Scholar 

  17. 17.

    Cásedas G, Les F, Gómez-Serranillos MP, Smith C, López V (2017) Anthocyanin profile, antioxidant activity and enzyme inhibiting properties of blueberry and cranberry juices: a comparative study. Food Funct 8:4187–4193. https://doi.org/10.1039/c7fo01205e

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Castañeda-Ovando A, de Lourdes Pacheco-Hernández M, Páez-Hernández ME, Rodríguez JA, Galán-Vidal CA (2009) Chemical studies of anthocyanins: a review. Food Chem 113:859–871. https://doi.org/10.1016/j.foodchem.2008.09.001

    CAS  Article  Google Scholar 

  19. 19.

    Castro-Acosta ML, Smith L, Miller RJ, McCarthy DI, Farrimond JA, Hall WL (2016) Drinks containing anthocyanin-rich blackcurrant extract decrease postprandial blood glucose, insulin and incretin concentrations. J Nutr Biochem 38:154–161. https://doi.org/10.1016/j.jnutbio.2016.09.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Castro-Acosta ML, Stone SG, Mok JE, Mhajan RK, Fu C-II, Lenihan-Geels GN, Corpe CP, Hall WL (2017) Apple and blackcurrant polyphenol-rich drinks decrease postprandial glucose, insulin and incretin response to a high-carbohydrate meal in healthy men and women. J Nutr Biochem 49:53–62. https://doi.org/10.1016/j.jnutbio.2017.07.013

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Chamorro MF, Reiner G, Theoduloz C, Ladio A, Schmeda-Hirschmann G, Gómez-Alonso S, Jiménez-Aspee F (2019) Polyphenol composition and (bio)activity of Berberis species and wild strawberry from the Argentinean Patagonia. Molecules 24:3331. https://doi.org/10.3390/molecules24183331

    CAS  Article  PubMed Central  Google Scholar 

  22. 22.

    Chang S, Tan C, Frankel EN, Barrett DM (2000) Low-Density Lipoprotein antioxidant activity of phenolic compounds and polyphenol oxidase activity in selected clingstone peach cultivars. J Agric Food Chem 48:147–151. https://doi.org/10.1021/jf9904564

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Chen L, Magliano DJ, Zimmet PZ (2012) The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol 8:228–236

    CAS  Article  Google Scholar 

  24. 24.

    Chen W, Müller D, Richling E, Wink M (2013) Anthocyanin-rich purple wheat prolongs the life span of Caenorhabditis elegans probably by activating the DAF-16/FOXO transcription factor. J Agric Food Chem 61:3047–3053. https://doi.org/10.1021/jf3054643

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Chen Z, Wang C, Pan Y, Gao X, Chen H (2018) Hypoglycemic and hypolipidemic effects of anthocyanins extract from black soybean seed coat in high fat diet and streptozotocin-induced diabetic mice. Food Funct 9:426–439. https://doi.org/10.1039/c7fo00983f

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Chen J, Wu S, Zhang Q, Yin Z, Zhang L (2020) α-Glucosidase inhibitory effect of anthocyanins from Cinnamomum camphora fruit: inhibition kinetics and mechanistic insights through in vitro and in silico studies. Int J Biol Macromol 143:696–703. https://doi.org/10.1016/j.ijbiomac.2019.09.091

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Choi KH, Lee HA, Park MH, Han JS (2016) Mulberry (Morus alba L.) fruit extract containing anthocyanins improves glycemic control and insulin sensitivity via activation of AMP-activated protein kinase in diabetic C57BL/Ksj-db/db mice. J Med Food 19:737–745. https://doi.org/10.1089/jmf.2016.3665

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Choi KH, Lee HA, Park MH, Han JS (2017) Cyanidin-3-rutinoside increases glucose uptake by activating the PI3K/Akt pathway in 3T3-L1 adipocytes. Environ Toxicol Pharmacol 54:1–6. https://doi.org/10.1016/j.etap.2017.06.007

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Chun OK, Kim DO, Lee CY (2003) Superoxide radical scavenging activity of the major polyphenols in fresh plums. J Agric Food Chem 51:8067–8072. https://doi.org/10.1021/jf034740d

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    D’Urso G, Mes JJ, Montoro P, Hall RD, de Vos RCH (2019) Identification of bioactive phytochemicals in mulberries. Metabolites 10:7. https://doi.org/10.3390/metabo10010007

    CAS  Article  PubMed Central  Google Scholar 

  31. 31.

    Daveri E, Cremonini E, Mastaloudis A, Hester SN, Wood SM, Waterhouse AL, Anderson M, Fraga CG, Oteiza PI (2018) Cyanidin and delphinidin modulate inflammation and altered redox signaling improving insulin resistance in high fat-fed mice. Redox Biol 18:16–24. https://doi.org/10.1016/j.redox.2018.05.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    De Ancos B, Ibañez E, Reglero G, Cano MP (2000) Frozen storage effects on anthocyanins and volatile compounds of raspberry fruit. J Agric Food Chem 48:873–879. https://doi.org/10.1021/jf990747c

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    de Mello VDF, Lankinen MA, Lindström J, Puupponen-Pimiä R, Laaksonen DE, Pihlajamäki J, Lehtonen M, Uusitupa M, Tuomilehto J, Kolehmainen M, Törrönen R, Hanhineva K (2017) 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 61:1–26. https://doi.org/10.1002/mnfr.201700019

    CAS  Article  Google Scholar 

  34. 34.

    De Sun C, Zhang B, Zhang JK, Xu CJ, Wu YL, Li X, Chen KS (2012) Cyanidin-3-glucoside-rich extract from Chinese bayberry fruit protects pancreatic β cells and ameliorates hyperglycemia in streptozotocin-induced diabetic mice. J Med Food 15:288–298. https://doi.org/10.1089/jmf.2011.1806

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    de Villiers A, Vanhoenacker G, Majek P, Sandra P (2004) Determination of anthocyanins in wine by direct injection liquid chromatography-diode array detection-mass spectrometry and classification of wines using discriminant analysis. J Chromatogr A 1054:195–204

    Article  Google Scholar 

  36. 36.

    Djaoudene O, López V, Cásedas G, Les F, Schisano C, Bachir Bey M, Tenore GC (2019) Phoenix dactylifera L. seeds: a by-product as a source of bioactive compounds with antioxidant and enzyme inhibitory properties. Food Funct 10:4953–4965. https://doi.org/10.1039/c9fo01125k

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Du X, Myracle AD (2018) Fermentation alters the bioaccessible phenolic compounds and increases the alpha-glucosidase inhibitory effects of aronia juice in a dairy matrix following: in vitro digestion. Food Funct 9:2998–3007. https://doi.org/10.1039/c8fo00250a

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    DuPont MS, Mondin Z, Williamson G, Price KR (2000) Effect of variety, processing, and storage on the flavonoid glycoside content and composition of lettuce endive. J Agric Food Chem 48:3957–3964. https://doi.org/10.1021/jf0002387

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Esatbeyoglu T, Rodríguez-Werner M, Schlösser A, Liehr M, Ipharraguerre I, Winterhalter P, Rimbach G (2016) Fractionation of plant bioactives from black carrots (Daucus carota subspecies sativus varietas atrorubens Alef.) by adsorptive membrane chromatography and analysis of their potential anti-diabetic activity. J Agric Food Chem 64:5901–5908. https://doi.org/10.1021/acs.jafc.6b02292

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Feshani AM, Kouhsari SM, Mohammadi S (2011) Vaccinium arctostaphylos, a common herbal medicine in Iran: molecular and biochemical study of its antidiabetic effects on alloxan-diabetic Wistar rats. J Ethnopharmacol 133:67–74. https://doi.org/10.1016/j.jep.2010.09.002

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Fitzenberger E, Deusing DJ, Wittkop A, Kler A, Kriesl E, Bonnländer B, Wenzel U (2014) Effects of plant extracts on the reversal of glucose-induced impairment of stress-resistance in Caenorhabditis elegans. Plant Foods Hum Nutr 69:78–84. https://doi.org/10.1007/s11130-013-0399-0

    Article  PubMed  Google Scholar 

  42. 42.

    Gao L, Mazza G (1995) Characterization, quantitation, and distribution of anthocyanins and colorless phenolics in sweet cherries. J Agric Food Chem 43:343–346. https://doi.org/10.1021/jf00050a015

    CAS  Article  Google Scholar 

  43. 43.

    Gennaro L, Leonardi C, Esposito F, Salucci M, Maiani G, Quaglia G, Fogliano V (2002) Flavonoid and carbohydrate contents in tropea red onions: effects of homelike peeling and storage. J Agric Food Chem 50:1904–1910. https://doi.org/10.1021/jf011102r

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Ghosh D, Konishi T (2007) Anthocyanins and anthocyanin-rich extracts: role in diabetes and eye function. Asia Pac J Clin Nutr 16:200–208. https://doi.org/10.3390/ijms13022472

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Gil MI, Tomás-Barberán FA, Hess-Pierce B, Holcroft DM, Kader AA (2000) Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 48:4581–4589

    CAS  Article  Google Scholar 

  46. 46.

    Gironés-Vilaplana A, Villaño D, Moreno DA, García-Viguera C (2013) New isotonic drinks with antioxidant and biological capacities from berries (maqui, açaí and blackthorn) and lemon juice. Int J Food Sci Nutr 64:897–906. https://doi.org/10.3109/09637486.2013.809406

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Guasch-Ferré M, Merino J, Sun Q, Fitó M, Salas-Salvadó J (2017) Dietary polyphenols, Mediterranean diet, prediabetes, and type 2 diabetes: a narrative review of the evidence. Oxidative Med Cell Longev 2017

  48. 48.

    Guo H, Ling W (2015) The update of anthocyanins on obesity and type 2 diabetes: experimental evidence and clinical perspectives. Rev Endocr Metab Disord 16. https://doi.org/10.1007/s11154-014-9302-z

  49. 49.

    Guo H, Xia M, Zou T, Ling W, Zhong R, Zhang W (2012) Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1. J Nutr Biochem 23:349–360. https://doi.org/10.1016/j.jnutbio.2010.12.013

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Gurrola-Díaz CM, García-López PM, Sánchez-Enríquez S, Troyo-Sanromán R, Andrade-González I, Gómez-Leyva JF (2010) Effects of Hibiscus sabdariffa extract powder and preventive treatment (diet) on the lipid profiles of patients with metabolic syndrome (MeSy). Phytomedicine 17:500–505. https://doi.org/10.1016/j.phymed.2009.10.014

    Article  PubMed  Google Scholar 

  51. 51.

    Gutierrez-Albanchez E, Kirakosyan A, Bolling SF, García-Villaraco A, Gutierrez-Mañero J, Ramos-Solano B (2019) Biotic elicitation as a tool to improve strawberry and raspberry extract potential on metabolic syndrome-related enzymes in vitro. J Sci Food Agric 99:2939–2946. https://doi.org/10.1002/jsfa.9507

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Halpern SH, Douglas MJ (2005) Appendix: Jadad scale for reporting randomized controlled trials. In: Halpern SH, Douglas MJ (eds) Evidence-based Obstetric Anesthesia. Blackwell Publishing Ltd, Oxford, pp 237–238

    Chapter  Google Scholar 

  53. 53.

    Hasan MM, Ahmed QU, Mat Soad SZ, Tunna TS (2018) Animal models and natural products to investigate in vivo and in vitro antidiabetic activity. Biomed Pharmacother 101:833–841

    CAS  Article  Google Scholar 

  54. 54.

    Hertweck M, Göbel C, Baumeister R (2004) C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell 6:577–588. https://doi.org/10.1016/S1534-5807(04)00095-4

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Hidalgo J, Flores C, Hidalgo MA, Perez M, Yañez A, Quiñones L, Caceres DD, Burgos RA (2014) Delphinol® standardized maqui berry extract reduces postprandial blood glucose increase in individuals with impaired glucose regulation by novel mechanism of sodium glucose cotransporter inhibition. Panminerva Med 56:1–7

    CAS  PubMed  Google Scholar 

  56. 56.

    Hollands WJ, Armah CN, Doleman JF, Perez-Moral N, Winterbone MS, Kroon PA (2018) 4-Week consumption of anthocyanin-rich blood orange juice does not affect LDL-cholesterol or other biomarkers of CVD risk and glycaemia compared with standard orange juice: a randomised controlled trial. Br J Nutr 119:415–421. https://doi.org/10.1017/S0007114517003865

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Hsu JD, Wu CC, Hung CN, Wang CJ, Huang HP (2016) Myrciaria cauliflora extract improves diabetic nephropathy via suppression of oxidative stress and inflammation in streptozotocin-nicotinamide mice. J Food Drug Anal 24:730–737. https://doi.org/10.1016/j.jfda.2016.03.009

    Article  PubMed  Google Scholar 

  58. 58.

    Huang B, Wang Z, Park JH, Ryu OH, Choi MK, Lee JY, Kang YH, Lim SS (2015) Anti-Diabetic effect of purple corn extract on C57BL/KsJ db/db mice. Nutr Res Pract 9:17–21. https://doi.org/10.4162/nrp.2015.9.1.22

    CAS  Article  Google Scholar 

  59. 59.

    Huang PC, Wang GJ, Fan MJ, Asokan Shibu M, Liu YT, Padma Viswanadha V, Lin YL, Lai CH, Chen YF, Liao HE, Huang CY (2017) Cellular apoptosis and cardiac dysfunction in STZ-induced diabetic rats attenuated by anthocyanins via activation of IGFI-R/PI3K/Akt survival signaling. Environ Toxicol 32:2471–2480. https://doi.org/10.1002/tox.22460

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Iizuka Y, Ozeki A, Tani T, Tsuda T (2018) Blackcurrant extract ameliorates hyperglycemia in type 2 diabetic mice in association with increased basal secretion of glucagon-like peptide-1 and activation of AMP-activated protein kinase. J Nutr Sci Vitaminol (Tokyo) 64:258–264. https://doi.org/10.3177/jnsv.64.258

    CAS  Article  Google Scholar 

  61. 61.

    Inaguma T, Han J, Isoda H (2011) Improvement of insulin resistance by Cyanidin 3-glucoside, anthocyanin from black beans through the up-regulation of GLUT4 gene expression From 22nd European Society for Animal Cell Technology (ESACT) Meeting on Cell Based Technologies Vienna, Austria. 15. BMC Proc 5:P21. doi: https://doi.org/10.1186/1753-6561-5-S8-P21

  62. 62.

    International Diabetes Federation (2019) What is diabetes. In: idf.org. https://www.idf.org/aboutdiabetes/what-is-diabetes.html. Accessed 23 Dec 2019

  63. 63.

    Jeon YD, Kang SH, Moon KH, Lee JH, Kim DG, Kim W, Kim JS, Ahn BY, Jin JS (2018) The Effect of aronia berry on type 1 diabetes in vivo and in vitro. J Med Food 21:244–253. https://doi.org/10.1089/jmf.2017.3939

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Jia Y, Hoang MH, Jun HJ, Lee JH, Lee SJ (2013) Cyanidin, a natural flavonoid, is an agonistic ligand for liver X receptor alpha and beta and reduces cellular lipid accumulation in macrophages and hepatocytes. Bioorganic Med Chem Lett 23:4185–4190. https://doi.org/10.1016/j.bmcl.2013.05.030

    CAS  Article  Google Scholar 

  65. 65.

    Jin Q, Yang J, Ma L, Cai J, Li J (2015) Comparison of polyphenol profile and inhibitory activities against oxidation and α-glucosidase in mulberry (genus morus) cultivars from China. J Food Sci 80:C2440–C2451. https://doi.org/10.1111/1750-3841.13099

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Johnson MH, De Mejia EG (2016) Phenolic compounds from fermented berry beverages modulated gene and protein expression to increase insulin secretion from pancreatic β-cells in vitro. J Agric Food Chem 64:2569–2581. https://doi.org/10.1021/acs.jafc.6b00239

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Johnson MH, De Mejia EG, Fan J, Lila MA, Yousef GG (2013) Anthocyanins and proanthocyanidins from blueberry-blackberry fermented beverages inhibit markers of inflammation in macrophages and carbohydrate-utilizing enzymes in vitro. Mol Nutr Food Res 57:1182–1197. https://doi.org/10.1002/mnfr.201200678

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Kang GG, Francis N, Hill R, Waters D, Blanchard C, Santhakumar AB (2019) Dietary polyphenols and gene expression in molecular pathways associated with type 2 diabetes mellitus: a review. Int J Mol Sci 21:140. https://doi.org/10.3390/ijms21010140

    CAS  Article  PubMed Central  Google Scholar 

  69. 69.

    Karkute SG, Koley TK, Yengkhom BK, Tripathi A, Srivastava S, Maurya A, Singh B (2018) Anti-diabetic phenolic compounds of black carrot (Daucus carota Subspecies sativus var. atrorubens Alef.) inhibit enzymes of glucose metabolism: an in silico and in vitro validation. Med Chem (Los Angeles) 14:641–649. https://doi.org/10.2174/1573406414666180301092819

    CAS  Article  Google Scholar 

  70. 70.

    Kato M, Tani T, Terahara N, Tsuda T (2015) The anthocyanin delphinidin 3-rutinoside stimulates glucagon-like peptide-1 secretion in murine GLUTag cell line via the Ca2+/calmodulin-dependent kinase II pathway. PLoS One 10:e0126157. https://doi.org/10.1371/journal.pone.0126157

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Kebede M, Ferdaoussi M, Mancini A, Alquier T, Kulkarni RN, Walker MD, Poitout V (2012) Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1. Proc Natl Acad Sci U S A 109:2376–2381. https://doi.org/10.1073/pnas.1114350109

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Khalifa I, Xia D, Dutta K, Peng J, Jia Y, Li C (2020) Mulberry anthocyanins exert anti-AGEs effects by selectively trapping glyoxal and structural-dependently blocking the lysyl residues of β-lactoglobulins. Bioorg Chem 96:103615. https://doi.org/10.1016/j.bioorg.2020.103615

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Kianbakht S, Abasi B, Dabaghian FH (2013) Anti-hyperglycemic effect of vaccinium arctostaphylos in type 2 diabetic patients: a randomized controlled trial. Forsch Komplementarmed 20:17–22. https://doi.org/10.1159/000346607

    Article  Google Scholar 

  74. 74.

    Kim JY, Hong JH, Jung HK, Jeong YS, Cho KH (2012) Grape skin and loquat leaf extracts and acai puree have potent anti-atherosclerotic and anti-diabetic activity in vitro and in vivo in hypercholesterolemic zebrafish. Int J Mol Med 30:606–614. https://doi.org/10.3892/ijmm.2012.1045

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, Huypens P, Beckers J, De Angelis MH, Schürmann A, Bakhti M, Klingenspor M, Heiman M, Cherrington AD, Ristow M, Lickert H, Wolf E, Havel PJ, Müller TD, Tschöp MH (2018) Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 14:140–162. https://doi.org/10.1038/nrendo.2017.161

    Article  PubMed  Google Scholar 

  76. 76.

    Koh ES, Lim JH, Kim MY, Chung S, Shin SJ, Choi BS, Kim HW, Hwang SY, Kim SW, Park CW, Chang YS (2015) Anthocyanin-rich Seoritae extract ameliorates renal lipotoxicity via activation of AMP-activated protein kinase in diabetic mice. J Transl Med 13:203. https://doi.org/10.1186/s12967-015-0563-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Kurimoto Y, Shibayama Y, Inoue S, Soga M, Takikawa M, Ito C, Nanba F, Yoshida T, Yamashita Y, Ashida H, Tsuda T (2013) Black soybean seed coat extract ameliorates hyperglycemia and insulin sensitivity via the activation of AMP-activated protein kinase in diabetic mice. J Agric Food Chem 61:5558–5564. https://doi.org/10.1021/jf401190y

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Kusunoki M, Sato D, Tsutsumi K, Tsutsui H, Nakamura T, Oshida Y (2015) Black soybean extract improves lipid profiles in fenofibrate-treated type 2 diabetics with postprandial hyperlipidemia. J Med Food 18:615–618. https://doi.org/10.1089/jmf.2014.3234

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Lai D, Huang M, Zhao L, Tian Y, Li Y, Liu D, Wu Y, Deng F (2019) Delphinidin-induced autophagy protects pancreatic β cells against apoptosis resulting from high-glucose stress via AMPK signaling pathway. Acta Biochim Biophys Sin Shanghai 51:1242–1249. https://doi.org/10.1093/abbs/gmz126

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Lee JS, Kim YR, Park JM, Kim YE, Baek NI, Hong EK (2015) Cyanidin-3-glucoside isolated from mulberry fruits protects pancreatic β-cells against glucotoxicity-induced apoptosis. Mol Med Rep 11:2723–2728. https://doi.org/10.3892/mmr.2014.3078

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Les F, Prieto JM, Arbonés-Mainar JM, Valero MS, López V (2015) Bioactive properties of commercialised pomegranate (Punica granatum) juice: antioxidant, antiproliferative and enzyme inhibiting activities. Food Funct 6:2049–2057. https://doi.org/10.1039/c5fo00426h

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Les F, Carpéné C, Arbonés-Mainar JM, Decaunes P, Valero MS, López V (2017) Pomegranate juice and its main polyphenols exhibit direct effects on amine oxidases from human adipose tissue and inhibit lipid metabolism in adipocytes. J Funct Foods 33:323–331. https://doi.org/10.1016/j.jff.2017.04.006

    CAS  Article  Google Scholar 

  83. 83.

    Les F, Arbonés-Mainar JM, Valero MS, López V (2018) Pomegranate polyphenols and urolithin A inhibit α-glucosidase, dipeptidyl peptidase-4, lipase, triglyceride accumulation and adipogenesis related genes in 3T3-L1 adipocyte-like cells. J Ethnopharmacol 220:67–74. https://doi.org/10.1016/j.jep.2018.03.029

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Li D, Zhang Y, Liu Y, Sun R, Xia M (2015) Purified anthocyanin supplementation reduces dyslipidemia, enhances antioxidant capacity, and prevents insulin resistance in diabetic patients. J Nutr 145:742–748. https://doi.org/10.3945/jn.114.205674

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Li F, Zhang B, Chen G, Fu X (2017) The novel contributors of anti-diabetic potential in mulberry polyphenols revealed by UHPLC-HR-ESI-TOF-MS/MS. Food Res Int 100:873–884. https://doi.org/10.1016/j.foodres.2017.06.052

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Lim SM, Lee HS, Jung JI, Kim SM, Kim NY, Seo TS, Bae JS, Kim EJ (2019) Cyanidin-3-o-galactoside-enriched aronia melanocarpa extract attenuates weight gain and adipogenic pathways in high-fat diet-induced obese C57bl/6 mice. Nutrients 11:1190. https://doi.org/10.3390/nu11051190

    CAS  Article  PubMed Central  Google Scholar 

  87. 87.

    Lindström J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksson J, Uusitupa M, Tuomilehto J (2003) The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 26:3230–3236. https://doi.org/10.2337/diacare.26.12.3230

    Article  PubMed  Google Scholar 

  88. 88.

    Liu Y, Li D, Zhang Y, Sun R, Xia M (2014) Anthocyanin increases adiponectin secretion and protects against diabetes-related endothelial dysfunction. Am J Physiol Metab 306:E975–E988. https://doi.org/10.1152/ajpendo.00699.2013

    CAS  Article  Google Scholar 

  89. 89.

    Luna-Vital DA, De Mejia EG (2018) Anthocyanins from purple corn activate free fatty acid-receptor 1 and glucokinase enhancing in vitro insulin secretion and hepatic glucose uptake. PLoS One 13:e0200449. https://doi.org/10.1371/journal.pone.0200449

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Luna-Vital D, Weiss M, Gonzalez de Mejia E (2017) Anthocyanins from purple corn ameliorated tumor necrosis factor-α-induced inflammation and insulin resistance in 3T3-L1 adipocytes via activation of insulin signaling and enhanced GLUT4 translocation. Mol Nutr Food Res 61. https://doi.org/10.1002/mnfr.201700362

  91. 91.

    Luna-Vital DA, Chatham L, Juvik J, Singh V, Somavat P, De Mejia EG (2019) Activating effects of phenolics from Apache Red Zea mays L. on free fatty acid receptor 1 and glucokinase evaluated with a dual culture system with epithelial, pancreatic, and liver cells. J Agric Food Chem 67:9148–9159. https://doi.org/10.1021/acs.jafc.8b06642

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Määttä-Riihinen KR, Kamal-Eldin A, Törrönen AR (2004) Identification and quantification of phenolic compounds in berries of Fragaria and Rubus species (family rosaceae). J Agric Food Chem 52:6178–6187. https://doi.org/10.1021/jf049450r

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Macz-Pop GA, Rivas-Gonzalo JC, Pérez-Alonso JJ, González-Paramás AM (2006) Natural occurrence of free anthocyanin aglycones in beans (Phaseolus vulgaris L.). Food Chem 94:448–456. https://doi.org/10.1016/j.foodchem.2004.11.038

    CAS  Article  Google Scholar 

  94. 94.

    Matsukawa T, Inaguma T, Han J, Villareal MO, Isoda H (2015) Cyanidin-3-glucoside derived from black soybeans ameliorate type 2 diabetes through the induction of differentiation of preadipocytes into smaller and insulin-sensitive adipocytes. J Nutr Biochem 26:860–867. https://doi.org/10.1016/j.jnutbio.2015.03.006

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Medjakovic S, Jungbauer A (2013) Pomegranate: a fruit that ameliorates metabolic syndrome. Food Funct 4:19–39

    CAS  Article  Google Scholar 

  96. 96.

    Mojica L, Berhow M, Gonzalez de Mejia E (2017) Black bean anthocyanin-rich extracts as food colorants: physicochemical stability and antidiabetes potential. Food Chem 229:628–639. https://doi.org/10.1016/j.foodchem.2017.02.124

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Mylnikov SV, Kokko HI, Kärenlampi SO, Oparina TI, Davies HV, Stewart D (2005) Rubus fruit juices affect lipid peroxidation in a Drosophila melanogaster model in vivo. J Agric Food Chem 53:7728–7733. https://doi.org/10.1021/jf051303l

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Nemes A, Homoki JR, Kiss R, Hegedus C, Kovács DD, Peitl B, Gál F, Stündl L, Szilvássy Z, Remenyik J (2019) Effect of anthocyanin-rich tart cherry extract on inflammatory mediators and adipokines involved in type 2 diabetes in a high fat diet induced obesity mouse model. Nutrients 11:1966. https://doi.org/10.3390/nu11091966

    CAS  Article  PubMed Central  Google Scholar 

  99. 99.

    Nickavar B, Amin G (2010) Bioassay-guided separation of an α-amylase inhibitor anthocyanin from vaccinium arctostaphylos berries. Zeitschrift fur Naturforsch - Sect C J Biosci 65(C):567–570. https://doi.org/10.1515/znc-2010-9-1006

    CAS  Article  Google Scholar 

  100. 100.

    Nielsen KA, Gotfredsen CH, Buch-Pedersen MJ, Ammitzbøll H, Mattsson O, Duus J, Nicholson RL (2004) Inclusions of flavonoid 3-deoxyanthocyanidins in Sorghum bicolor self-organize into spherical structures. Physiol Mol Plant Pathol 65:187–196. https://doi.org/10.1016/j.pmpp.2005.02.001

    CAS  Article  Google Scholar 

  101. 101.

    Nizamutdinova IT, Jin YC, Chung J, Shin SC, Lee SJ, Seo HG, Lee JH, Chang KC, Kim HJ (2009) The anti-diabetic effect of anthocyanins in streptozotocin-induced diabetic rats through glucose transporter 4 regulation and prevention of insulin resistance and pancreatic apoptosis. Mol Nutr Food Res 53:1419–1429. https://doi.org/10.1002/mnfr.200800526

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Novotny JA, Baer DJ, Khoo C, Gebauer SK, Charron CS (2015) Cranberry juice consumption lowers markers of cardiometabolic risk, including blood pressure and circulating C-reactive protein, triglyceride, and glucose concentrations in adults 1-4. J Nutr 145:1185–1193. https://doi.org/10.3945/jn.114.203190

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Ormazabal P, Scazzocchio B, Varì R, Santangelo C, D’Archivio M, Silecchia G, Iacovelli A, Giovannini C, Masella R (2018) Effect of protocatechuic acid on insulin responsiveness and inflammation in visceral adipose tissue from obese individuals: possible role for PTP1B. Int J Obes 42:2012–2021. https://doi.org/10.1038/s41366-018-0075-4

    CAS  Article  Google Scholar 

  104. 104.

    Ostberg-Potthoff JJ, Berger K, Richling E, Winterhalter P (2019) Activity-guided fractionation of red fruit extracts for the identification of compounds influencing glucose metabolism. Nutrients 11:1166. https://doi.org/10.3390/nu11051166

    CAS  Article  PubMed Central  Google Scholar 

  105. 105.

    Peixoto H, Roxo M, Krstin S, Röhrig T, Richling E, Wink M (2016) An Anthocyanin-Rich Extract of Acai (Euterpe precatoria Mart.) Increases Stress Resistance and Retards Aging-Related Markers in Caenorhabditis elegans. J Agric Food Chem 64:1283–1290. https://doi.org/10.1021/acs.jafc.5b05812

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Peixoto H, Roxo M, Krstin S, Wang X, Wink M (2016) Anthocyanin-rich extract of Acai (Euterpe precatoria Mart.) mediates neuroprotective activities in Caenorhabditis elegans. J Funct Foods 26:385–393. https://doi.org/10.1016/j.jff.2016.08.012

    CAS  Article  Google Scholar 

  107. 107.

    Petersen C, Bharat D, Cutler BR, Gholami S, Denetso C, Mueller JE, Cho JM, Kim JS, Symons JD, Anandh Babu PV (2018) Circulating metabolites of strawberry mediate reductions in vascular inflammation and endothelial dysfunction in db/db mice. Int J Cardiol 263:111–117. https://doi.org/10.1016/j.ijcard.2018.04.040

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Petersen C, Wankhade UD, Bharat D, Wong K, Mueller JE, Chintapalli SV, Piccolo BD, Jalili T, Jia Z, Symons JD, Shankar K, Anandh Babu PV (2019) Dietary supplementation with strawberry induces marked changes in the composition and functional potential of the gut microbiome in diabetic mice. J Nutr Biochem 66:63–69. https://doi.org/10.1016/j.jnutbio.2019.01.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Porter Abate J, Blackwell TK (2009) Life is short, if sweet. Cell Metab 10:338–339

    Article  Google Scholar 

  110. 110.

    Qin Y, Xia M, Ma J, Hao YT, Liu J, Mou HY, Cao L, Ling WH (2009) Anthocyanin supplementation improves serum LDL- and HDL-cholesterol concentrations associated with the inhibition of cholesteryl ester transfer protein in dyslipidemic subjects. Am J Clin Nutr 90:485–492. https://doi.org/10.3945/ajcn.2009.27814

    CAS  Article  PubMed  Google Scholar 

  111. 111.

    Qin Y, Zhai Q, Li Y, Cao M, Xu Y, Zhao K, Wang T (2018) Cyanidin-3-O-glucoside ameliorates diabetic nephropathy through regulation of glutathione pool. Biomed Pharmacother 103:1223–1230. https://doi.org/10.1016/j.biopha.2018.04.137

    CAS  Article  PubMed  Google Scholar 

  112. 112.

    Ranilla LG, Huamán-Alvino C, Flores-Báez O, Aquino-Méndez EM, Chirinos R, Campos D, Sevilla R, Fuentealba C, Pedreschi R, Sarkar D, Shetty K (2019) Evaluation of phenolic antioxidant-linked in vitro bioactivity of Peruvian corn (Zea mays L.) diversity targeting for potential management of hyperglycemia and obesity. J Food Sci Technol 56:2909–2924. https://doi.org/10.1007/s13197-019-03748-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Real Hernandez LM, Fan J, Johnson MH, De Mejia EG (2015) Berry phenolic compounds increase expression of hepatocyte nuclear factor-1α (HNF-1α) in Caco-2 and normal colon cells due to high affinities with transcription and dimerization domains of HNF-1α. PLoS One 10:e0138768. https://doi.org/10.1371/journal.pone.0138768

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Rebello CJ, Burton J, Heiman M, Greenway FL (2015) Gastrointestinal microbiome modulator improves glucose tolerance in overweight and obese subjects: a randomized controlled pilot trial. J Diabetes Complicat 29:1272–1276. https://doi.org/10.1016/j.jdiacomp.2015.08.023

    Article  PubMed Central  Google Scholar 

  115. 115.

    Romani A, Mulinacci N, Pinelli P, Vincieri FF, Cimato A (1999) Polyphenolic content in five tuscany cultivars of Olea europaea L. J Agric Food Chem 47:964–967. https://doi.org/10.1021/jf980264t

    CAS  Article  PubMed  Google Scholar 

  116. 116.

    Romani A, Vignolini P, Galardi C, Mulinacci N, Benedettelli S, Heimler D (2004) Germplasm characterization of Zolfino landraces (Phaseolus vulgaris L.) by flavonoid content. J Agric Food Chem 52:3838–3842. https://doi.org/10.1021/jf0307402

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Sánchez-Marzo N, Lozano-Sánchez J, de la Luz Cádiz-Gurrea M, Herranz-López M, Micol V, Segura-Carretero A (2019) Relationships Between Chemical Structure and Antioxidant Activity of Isolated Phytocompounds from Lemon Verbena. Antioxidants 8:324. https://doi.org/10.3390/antiox8080324

    CAS  Article  PubMed Central  Google Scholar 

  118. 118.

    Sandoval V, Femenias A, Martínez-Garza Ú, Sanz-Lamora H, Castagnini JM, Quifer-Rada P, Lamuela-Raventós RM, Marrero PF, Haro D, Relat J (2019) Lyophilized maqui (Aristotelia chilensis) berry induces browning in the subcutaneous white adipose tissue and ameliorates the insulin resistance in high fat diet-induced obese mice. Antioxidants 8:360. https://doi.org/10.3390/antiox8090360

    CAS  Article  PubMed Central  Google Scholar 

  119. 119.

    Sasaki R, Nishimura N, Hoshino H, Isa Y, Kadowaki M, Ichi T, Tanaka A, Nishiumi S, Fukuda I, Ashida H, Horio F, Tsuda T (2007) Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. Biochem Pharmacol 74:1619–1627. https://doi.org/10.1016/j.bcp.2007.08.008

    CAS  Article  PubMed  Google Scholar 

  120. 120.

    Satija A, Bhupathiraju SN, Rimm EB, Spiegelman D, Chiuve SE, Borgi L, Willett WC, Manson JAE, Sun Q, Hu FB (2016) Plant-based dietary patterns and incidence of type 2 diabetes in US men and women: results from three prospective cohort studies. PLoS Med 13. https://doi.org/10.1371/journal.pmed.1002039

  121. 121.

    Scazzocchio B, Varì R, Filesi C, D’Archivio M, Santangelo C, Giovannini C, Iacovelli A, Silecchia G, Volti GL, Galvano F, Masella R (2011) Cyanidin-3-O-β-glucoside and protocatechuic acid exert insulin-like effects by upregulating PPARγ activity in human omental adipocytes. Diabetes 60:2234–2244. https://doi.org/10.2337/db10-1461

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Scazzocchio B, Varì R, Filesi C, Del Gaudio I, D’Archivio M, Santangelo C, Iacovelli A, Galvano F, Pluchinotta FR, Giovannini C, Masella R (2015) Protocatechuic acid activates key components of insulin signaling pathway mimicking insulin activity. Mol Nutr Food Res 59:1472–1481. https://doi.org/10.1002/mnfr.201400816

    CAS  Article  PubMed  Google Scholar 

  123. 123.

    Seymour EM, Tanone II, Urcuyo-Llanes DE, Lewis SK, Kirakosyan A, Kondoleon MG, Kaufman PB, Bolling SF (2011) Blueberry intake alters skeletal muscle and adipose tissue peroxisome proliferator-activated receptor activity and reduces insulin resistance in obese rats. J Med Food 14:1511–1518. https://doi.org/10.1089/jmf.2010.0292

    CAS  Article  PubMed  Google Scholar 

  124. 124.

    Sohrab G, Nasrollahzadeh J, Zand H, Amiri Z, Tohidi M, Kimiagar M (2014) Effects of pomegranate juice consumption on inflammatory markers in patients with type 2 diabetes: a randomized, placebo-controlled trial. J Res Med Sci 19:215–220

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Sohrab G, Angoorani P, Tohidi M, Tabibi H, Kimiagar M, Nasrollahzadeh J (2015) Pomegranate (Punicagranatum) juice decreases lipid peroxidation, but has no effect on plasma advanced glycated end-products in adults with type 2 diabetes: a randomized double-blind clinical trial. Food Nutr Res 59:1–6. https://doi.org/10.3402/fnr.v59.28551

    CAS  Article  Google Scholar 

  126. 126.

    Sohrab G, Ebrahimof S, Sotoudeh G, Neyestani TR, Angoorani P, Hedayati M, Siasi F (2017) Effects of pomegranate juice consumption on oxidative stress in patients with type 2 diabetes: a single-blind, randomized clinical trial. Int J Food Sci Nutr 68:249–255. https://doi.org/10.1080/09637486.2016.1229760

    CAS  Article  PubMed  Google Scholar 

  127. 127.

    Sohrab G, Nasrollahzadeh J, Tohidi M, Zand H, Nikpayam O (2018) Pomegranate juice increases sirtuin1 protein in peripheral blood mononuclear cell from patients with type 2 diabetes: a randomized placebo controlled clinical trial. Metab Syndr Relat Disord 16:446–451. https://doi.org/10.1089/met.2017.0146

    CAS  Article  PubMed  Google Scholar 

  128. 128.

    Sohrab G, Roshan H, Ebrahimof S, Nikpayam O, Sotoudeh G, Siasi F (2019) Effects of pomegranate juice consumption on blood pressure and lipid profile in patients with type 2 diabetes: a single-blind randomized clinical trial. Clin Nutr ESPEN 29:30–35. https://doi.org/10.1016/j.clnesp.2018.11.013

    Article  PubMed  Google Scholar 

  129. 129.

    Solverson PM, Rumpler WV, Leger JL, Redan BW, Ferruzzi MG, Baer DJ, Castonguay TW, Novotny JA (2018) Blackberry feeding increases fat oxidation and improves insulin sensitivity in overweight and obese males. Nutrients 10:1–16. https://doi.org/10.3390/nu10081048

    CAS  Article  Google Scholar 

  130. 130.

    Spínola V, Llorent-Martínez EJ, Castilho PC (2019) Polyphenols of Myrica faya inhibit key enzymes linked to type II diabetes and obesity and formation of advanced glycation end-products (in vitro): potential role in the prevention of diabetic complications. Food Res Int 116:1229–1238. https://doi.org/10.1016/j.foodres.2018.10.010

    CAS  Article  PubMed  Google Scholar 

  131. 131.

    Spínola V, Pinto J, Llorent-Martínez EJ, Tomás H, Castilho PC (2019) Evaluation of Rubus grandifolius L. (wild blackberries) activities targeting management of type-2 diabetes and obesity using in vitro models. Food Chem Toxicol 123:443–452. https://doi.org/10.1016/j.fct.2018.11.006

    CAS  Article  PubMed  Google Scholar 

  132. 132.

    Stote K, Corkum A, Sweeney M, Shakerley N, Kean T, Gottschall-Pass K (2019) Postprandial effects of blueberry (Vaccinium angustifolium) consumption on glucose metabolism, gastrointestinal hormone response, and perceived appetite in healthy adults: a randomized, placebo-controlled crossover trial. Nutrients 11:1–14. https://doi.org/10.3390/nu11010202

    CAS  Article  Google Scholar 

  133. 133.

    Strugała P, Dzydzan O, Brodyak I, Kucharska AZ, Kuropka P, Liuta M, Kaleta-Kuratewicz K, Przewodowska A, Michałowska D, Gabrielska J, Sybirna N (2019) Antidiabetic and antioxidative potential of the blue Congo variety of purple potato extract in streptozotocin-induced diabetic rats. Molecules 24:3126. https://doi.org/10.3390/molecules24173126

    CAS  Article  PubMed Central  Google Scholar 

  134. 134.

    Su H, Xie L, Xu Y, Ke H, Bao T, Li Y (2019) Chen W (2019) Pelargonidin-3- O-glucoside Derived from Wild Raspberry Exerts Antihyperglycemic Effect by Inducing Autophagy and Modulating Gut Microbiota. J Agric Food Chem. https://doi.org/10.1021/acs.jafc.9b03338

  135. 135.

    Sweeny JG, Iacobucci GA (1983) Effect of substitution on the stability of 3-deoxyanthocyanidins in aqueous solutions. J Agric Food Chem 31:531–533. https://doi.org/10.1021/jf00117a017

    CAS  Article  Google Scholar 

  136. 136.

    Tambara AL, de Los Santos Moraes L, Dal Forno AH, Boldori JR, Gonçalves Soares AT, de Freitas RC, Mariutti LRB, Mercadante AZ, de Ávila DS, Denardin CC (2018) Purple pitanga fruit (Eugenia uniflora L.) protects against oxidative stress and increase the lifespan in Caenorhabditis elegans via the DAF-16/FOXO pathway. Food Chem Toxicol 120:639–650. https://doi.org/10.1016/j.fct.2018.07.057

    CAS  Article  PubMed  Google Scholar 

  137. 137.

    Thilavech T, Ngamukote S, Abeywardena M, Adisakwattana S (2015) Protective effects of cyanidin-3-rutinoside against monosaccharides-induced protein glycation and oxidation. Int J Biol Macromol 75:515–520. https://doi.org/10.1016/j.ijbiomac.2015.02.004

    CAS  Article  PubMed  Google Scholar 

  138. 138.

    Thilavech T, Ngamukote S, Belobrajdic D, Abeywardena M, Adisakwattana S (2016) Cyanidin-3-rutinoside attenuates methylglyoxal-induced protein glycation and DNA damage via carbonyl trapping ability and scavenging reactive oxygen species. BMC Complement Altern Med 16:138. https://doi.org/10.1186/s12906-016-1133-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Tian JL, Liao XJ, Wang YH, Si X, Shu C, Gong ES, Xie X, Ran XL, Li B (2019) Identification of Cyanidin-3-arabinoside Extracted from Blueberry as a Selective Protein Tyrosine Phosphatase 1B Inhibitor. J Agric Food Chem 67:13624–13634. https://doi.org/10.1021/acs.jafc.9b06155

    CAS  Article  PubMed  Google Scholar 

  140. 140.

    Tissenbaum HA, Ruvkun G (1998) An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148:703–717

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Tomás-Barberán FA, Gil MI, Cremin P, Waterhouse AL, Hess-Pierce B, Kader AA (2001) HPLC-DAD-ESIMS analysis of phenolic compounds in nectarines, peaches, and plums. J Agric Food Chem 49:4748–4760. https://doi.org/10.1021/jf0104681

    CAS  Article  PubMed  Google Scholar 

  142. 142.

    Tsuda T, Ueno Y, Aoki H, Koda T, Horio F, Takahashi N, Kawada T, Osawa T (2004) Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. Biochem Biophys Res Commun 316:149–157. https://doi.org/10.1016/j.bbrc.2004.02.031

    CAS  Article  PubMed  Google Scholar 

  143. 143.

    Valenza A, Bonfanti C, Pasini ME, Bellosta P (2018) Anthocyanins Function as Anti-Inflammatory Agents in a Drosophila Model for Adipose Tissue Macrophage Infiltration. Biomed Res Int 2018:6413172. https://doi.org/10.1155/2018/6413172

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Van der Sluis AA, Dekker M, De Jager A, Jongen WMF (2001) Activity and concentration of polyphenolic antioxidants in apple: effect of cultivar, harvest year, and storage conditions. J Agric Food Chem 49:3606–3613. https://doi.org/10.1021/jf001493u

    CAS  Article  PubMed  Google Scholar 

  145. 145.

    Wallace T, Giusti M (2015) Anthocyanins. Adv Nutr an Int Rev J 60:620–622. https://doi.org/10.3945/an.115.009233

    Article  Google Scholar 

  146. 146.

    Wang L, Li YM, Lei L, Liu Y, Wang X, Ma KY, Zhang C, Zhu H, Zhao Y, Chen ZY (2016) Purple sweet potato anthocyanin attenuates fat-induced mortality in Drosophila melanogaster. Exp Gerontol 82:95–103. https://doi.org/10.1016/j.exger.2016.06.006

    CAS  Article  PubMed  Google Scholar 

  147. 147.

    Watts JL, Ristow M (2017) Lipid and carbohydrate metabolism in Caenorhabditis elegans. Genetics 207:413–446. https://doi.org/10.1534/genetics.117.300106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148.

    WHO (2019) Diabetes. In: who.int. https://www.who.int/health-topics/diabetes. Accessed 23 Dec 2019

  149. 149.

    Wu X, Gu L, Prior RL, McKay S (2004) Characterization of anthocyanins and proanthocyanidins in some cultivars of Ribes, Aronia, and Sambucus and their antioxidant capacity. J Agric Food Chem 52:7846–7856. https://doi.org/10.1021/jf0486850

    CAS  Article  PubMed  Google Scholar 

  150. 150.

    Xiao JB, Hogger P (2014) Dietary polyphenols and type 2 diabetes: current insights and future perspectives. Curr Med Chem 22:23–38. https://doi.org/10.2174/0929867321666140706130807

    CAS  Article  Google Scholar 

  151. 151.

    Xiao T, Guo Z, Sun B, Zhao Y (2017) Identification of Anthocyanins from Four Kinds of Berries and Their Inhibition Activity to α-Glycosidase and Protein Tyrosine Phosphatase 1B by HPLC-FT-ICR MS/MS. J Agric Food Chem 65:6211–6221. https://doi.org/10.1021/acs.jafc.7b02550

    CAS  Article  PubMed  Google Scholar 

  152. 152.

    Xiong Y, Zhang P, Warner RD, Fang Z (2019) 3-Deoxyanthocyanidin colorant: nature, health, synthesis, and food applications. Compr Rev Food Sci Food Saf 18:1533–1549

    CAS  Article  Google Scholar 

  153. 153.

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

    CAS  Article  PubMed  Google Scholar 

  154. 154.

    Yan F, Chen X, Zheng X (2017) Protective effect of mulberry fruit anthocyanin on human hepatocyte cells (LO2) and Caenorhabditis elegans under hyperglycemic conditions. Food Res Int 102:213–224. https://doi.org/10.1016/j.foodres.2017.10.009

    CAS  Article  PubMed  Google Scholar 

  155. 155.

    Yan F, Chen Y, Azat R, Zheng X (2017) Mulberry Anthocyanin Extract Ameliorates Oxidative Damage in HepG2 Cells and Prolongs the Lifespan of Caenorhabditis elegans through MAPK and Nrf2 Pathways. Oxidative Med Cell Longev 2017:7956158. https://doi.org/10.1155/2017/7956158

    CAS  Article  Google Scholar 

  156. 156.

    Yang LL, Ling W, Yang Y, Chen Y, Tian Z, Du Z, Chen J, Xie Y, Liu Z, Yang LL (2017) Role of purified anthocyanins in improving cardiometabolic risk factors in chinese men and women with prediabetes or early untreated diabetes—A randomized controlled trial. Nutrients 9:1–14. https://doi.org/10.3390/nu9101104

    CAS  Article  Google Scholar 

  157. 157.

    Zhao C, Yang C, Wai STC, Zhang Y, Portillo MP, Paoli P, Wu Y, San Cheang W, Liu B, Carpéné C, Xiao J, Cao H (2019) Regulation of glucose metabolism by bioactive phytochemicals for the management of type 2 diabetes mellitus. Crit Rev Food Sci Nutr 59:830–847

    CAS  Article  Google Scholar 

  158. 158.

    Zheng W, Wang SY (2003) Oxygen radical absorbing capacity of phenolics in blueberries, cranberries, chokeberries, and lingonberries. J Agric Food Chem 51:502–509. https://doi.org/10.1021/jf020728u

    CAS  Article  PubMed  Google Scholar 

  159. 159.

    Zheng YC, He H, Wei X, Ge S, Lu YH (2016) Comparison of regulation mechanisms of five mulberry ingredients on insulin secretion under oxidative stress. J Agric Food Chem 64:8763–8772. https://doi.org/10.1021/acs.jafc.6b03845

    CAS  Article  PubMed  Google Scholar 

  160. 160.

    Zhu W, Jia Q, Wang Y, Zhang Y, Xia M (2012) The anthocyanin cyanidin-3-O-β-glucoside, a flavonoid, increases hepatic glutathione synthesis and protects hepatocytes against reactive oxygen species during hyperglycemia: involvement of a cAMP-PKA-dependent signaling pathway. Free Radic Biol Med 52:314–327. https://doi.org/10.1016/j.freeradbiomed.2011.10.483

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

Universidad San Jorge and Industrias Químicas del Ebro are acknowledged for providing PhD grants to Guillermo Cásedas. Authors acknowledge the mini-network of CTPIOD (Conferences on Trans-Pyrenean Investigations in Obesity and Diabetes) for facilitating inter-laboratories exchanges.

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Correspondence to Víctor López.

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Keypoints

• Anthocyanins are natural polyphenols with antioxidant and antidiabetic properties.

• Human studies reveal the potential of anthocyanins in type 2 diabetes.

• In vitro and in vivo studies reveal that anthocyanins act as pleiotropic agents.

• Different targets and signalling pathways are modulated by anthocyanins.

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Les, F., Cásedas, G., Gómez, C. et al. The role of anthocyanins as antidiabetic agents: from molecular mechanisms to in vivo and human studies. J Physiol Biochem 77, 109–131 (2021). https://doi.org/10.1007/s13105-020-00739-z

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Keywords

  • Dietary polyphenols
  • Diabetes
  • Clinical trials
  • Flavonoids
  • Anthocyanins
  • Functional foods