Mechanisms by which cocoa flavanols improve metabolic syndrome and related disorders

Journal of Nutritional Biochemistry

Volume 35, September 01, 2016, Pages 1-21

(Review)

Strat, K.M.^a, 

Rowley, T.J.^b, 

Smithson, A.T.^c, 

Tessem, J.S.^b, 

Hulver, M.W.^ad, 

Liu, D.^a, 

Davy, B.M.^a, 

Davy, K.P.^a, 

Neilson, A.P.^c 

 

^a  Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA, United States
^b  Department of Nutrition, Dietetics and Food Science, Brigham Young University, Provo, UT, United States
^c  Department of Food Science and Technology, Virginia Tech, Blacksburg, VA, United States 

View additional affiliations

View references (244)

Abstract

Dietary administration of cocoa flavanols may be an effective complementary strategy for alleviation or prevention of metabolic syndrome, particularly glucose intolerance. The complex flavanol composition of cocoa provides the ability to interact with a variety of molecules, thus allowing numerous opportunities to ameliorate metabolic diseases. These interactions likely occur primarily in the gastrointestinal tract, where native cocoa flavanol concentration is high. Flavanols may antagonize digestive enzymes and glucose transporters, causing a reduction in glucose excursion, which helps patients with metabolic disorders maintain glucose homeostasis. Unabsorbed flavanols, and ones that undergo enterohepatic recycling, will proceed to the colon where they can exert prebiotic effects on the gut microbiota. Interactions with the gut microbiota may improve gut barrier function, resulting in attenuated endotoxin absorption. Cocoa may also positively influence insulin signaling, possibly by relieving insulin-signaling pathways from oxidative stress and inflammation and/or via a heightened incretin response. The purpose of this review is to explore the mechanisms that underlie these outcomes, critically review the current body of literature related to those mechanisms, explore the implications of these mechanisms for therapeutic utility, and identify emerging or needed areas of research that could advance our understanding of the mechanisms of action and therapeutic potential of cocoa flavanols. © 2016 Elsevier Inc.

Author keywords

Diabetes; Endotoxin; Epicatechin; GLP-1; Procyanidins; β-Cells

ISSN: 09552863 CODEN: JNBIESource Type: Journal Original language: English

DOI: 10.1016/j.jnutbio.2015.12.008Document Type: Review

Publisher: Elsevier Inc.

References (244)

View in search results format

• Page
 
• • Export |
  • Print |
  • E-mail |
  • Create bibliography

• 
  1

  Eckel, R.H., Grundy, S.M., Zimmet, P.Z.

  The metabolic syndrome
  (2005) Lancet, 365 (9468), pp. 1415-1428. Cited 3049 times.
  doi: 10.1016/S0140-6736(05)66378-7
  

  • View at Publisher
• 
  2

  Grundy, S.M., Hansen, B., Smith Jr., S.C., Cleeman, J.I., Kahn, R.A.

  Clinical Management of Metabolic Syndrome: Report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on Scientific Issues Related to Management
  (2004) Circulation, 109 (4), pp. 551-556. Cited 502 times.
  doi: 10.1161/01.CIR.0000112379.88385.67
  

  • View at Publisher
• 
  3

  Osakabe, N., Hoshi, J., Kudo, N., Shibata, M.

  The flavan-3-ol fraction of cocoa powder suppressed changes associated with early-stage metabolic syndrome in high-fat diet-fed rats
  (2014) Life Sciences, 114 (1), art. no. 14113, pp. 51-56. Cited 4 times.
  www.elsevier.com/locate/lifescie
  doi: 10.1016/j.lfs.2014.07.041
  

  • View at Publisher
• 
  4

  Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M.

  Prevalence of childhood and adult obesity in the United States, 2011-2012
  (2014) JAMA - Journal of the American Medical Association, 311 (8), pp. 806-814. Cited 1525 times.
  http://jama.jamanetwork.com/data/Journals/JAMA/929800/joi140013.pdf
  doi: 10.1001/jama.2014.732
  

  • View at Publisher
• 
  5

  Guariguata, L., Whiting, D.R., Hambleton, I., Beagley, J., Linnenkamp, U., Shaw, J.E.

  Global estimates of diabetes prevalence for 2013 and projections for 2035
  (2014) Diabetes Research and Clinical Practice, 103 (2), pp. 137-149. Cited 438 times.
  www.elsevier.com/locate/diabres
  doi: 10.1016/j.diabres.2013.11.002
  

  • View at Publisher
• 
  6

  Aguilar, M., Bhuket, T., Torres, S., Liu, B., Wong, R.J.

  Prevalence of the metabolic syndrome in the United States, 2003-2012
  (2015) JAMA, 313 (19), pp. 1973-1974. Cited 19 times.
  doi: 10.1001/jama.2015.4260
  

  • View at Publisher
• 
  7

  Lee, K.W., Kim, Y.J., Lee, H.J., Lee, C.Y.

  Cocoa Has More Phenolic Phytochemicals and a Higher Antioxidant Capacity than Teas and Red Wine
  (2003) Journal of Agricultural and Food Chemistry, 51 (25), pp. 7292-7295. Cited 341 times.
  doi: 10.1021/jf0344385
  

  • View at Publisher
• 
  8

  Beecher, G.R.

  Overview of dietary flavonoids: Nomenclature, occurrence and intake
  (2003) Journal of Nutrition, 133 (10), pp. 3248S-3254S. Cited 443 times.
  

  • View at Publisher
• 
  9

  Ou, K., Gu, L.

  Absorption and metabolism of proanthocyanidins
  (2014) Journal of Functional Foods, 7 (1), pp. 43-53. Cited 32 times.
  http://www.elsevier.com/wps/find/journaldescription.cws_home/717426/description#description
  doi: 10.1016/j.jff.2013.08.004
  

  • View at Publisher
• 
  10

  Gu, L., Kelm, M.A., Hammerstone, J.F., Beecher, G., Holden, J., Haytowitz, D., Prior, R.L.

  Screening of Foods Containing Proanthocyanidins and Their Structural Characterization Using LC-MS/MS and Thiolytic Degradation
  (2003) Journal of Agricultural and Food Chemistry, 51 (25), pp. 7513-7521. Cited 309 times.
  doi: 10.1021/jf034815d
  

  • View at Publisher
• 
  11

  Thilakarathna, S.H., Vasantha Rupasinghe, H.P.

  Flavonoid bioavailability and attempts for bioavailability enhancement
  (2013) Nutrients, 5 (9), pp. 3367-3387. Cited 42 times.
  http://www.mdpi.com/2072-6643/5/9/3367/pdf
  doi: 10.3390/nu5093367
  

  • View at Publisher
• 
  12

  Lau-Cam, C.A.
  The absorption, metabolism, and pharmacokinetics of chocolate polyphenols
  (2013) Chocolate in health and nutrition: springer science + business media, pp. 201-246.
  W. RR (Ed.)
  

  •  
• 
  13

  Neilson, A.P., Ferruzzi, M.G.

  Bioavailability and Metabolism of Bioactive Compounds from Foods
  (2013) Nutrition in the Prevention and Treatment of Disease, pp. 407-423. Cited 4 times.
  http://www.sciencedirect.com.scopeesprx.elsevier.com/science/book/9780123918840
  ISBN: 978-012391884-0
  doi: 10.1016/B978-0-12-391884-0.00022-6
  

  • View at Publisher
• 
  14

  Crozier, S.J., Preston, A.G., Hurst, J.W., Payne, M.J., Mann, J., Hainly, L., Miller, D.L.

  Cacao seeds are a "Super Fruit": A comparative analysis of various fruit powders and products
  (2011) Chemistry Central Journal, 5 (1), art. no. 5. Cited 23 times.
  http://journal.chemistrycentral.com/content/5/1/5
  doi: 10.1186/1752-153X-5-5
  

  • View at Publisher
• 
  15

  Ortega, N., Reguant, J., Romero, M.-P., Macià, A., Motilva, M.-J.

  Effect of fat content on the digestibility and bioaccessibility of cocoa polyphenol by an in vitro digestion model
  (2009) Journal of Agricultural and Food Chemistry, 57 (13), pp. 5743-5749. Cited 50 times.
  http://pubs.acs.org/doi/pdfplus/10.1021/jf900591q
  doi: 10.1021/jf900591q
  

  • View at Publisher
• 
  16

  Andújar, I., Recio, M.C., Giner, R.M., Ríos, J.L.

  Cocoa polyphenols and their potential benefits for human health
  (2012) Oxidative Medicine and Cellular Longevity, art. no. 906252. Cited 23 times.
  doi: 10.1155/2012/906252
  

  • View at Publisher
• 
  17

  Dorenkott, M.R., Griffin, L.E., Goodrich, K.M., Thompson-Witrick, K.A., Fundaro, G., Ye, L., Stevens, J.R., (...), Neilson, A.P.

  Oligomeric cocoa procyanidins possess enhanced bioactivity compared to monomeric and polymeric cocoa procyanidins for preventing the development of obesity, insulin resistance, and impaired glucose tolerance during high-fat feeding
  (2014) Journal of Agricultural and Food Chemistry, 62 (10), pp. 2216-2227. Cited 30 times.
  http://pubs.acs.org/journal/jafcau
  doi: 10.1021/jf500333y
  

  • View at Publisher
• 
  18

  Goodrich, K.M., Dorenkott, M.R., Ye, L., O'Keefe, S.F., Hulver, M.W., Neilson, A.P.

  Dietary supplementation with cocoa flavanols does not alter colon tissue profiles of native flavanols and their microbial metabolites established during habitual dietary exposure in C57BL/6J mice
  (2014) Journal of Agricultural and Food Chemistry, 62 (46), pp. 11190-11199. Cited 5 times.
  http://pubs.acs.org/journal/jafcau
  doi: 10.1021/jf503838q
  

  • View at Publisher
• 
  19

  Zierath, J.R., He, L., Gumà, A., Odegaard Wahlström, E., Klip, A., Wallberg-Henriksson, H.

  Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM
  (1996) Diabetologia, 39 (10), pp. 1180-1189. Cited 250 times.
  

  • View at Publisher
• 
  20

  Liu, K., Zhou, R., Wang, B., Chen, K., Shi, L.-Y., Zhu, J.-D., Mi, M.-T.

  Effect of green tea on glucose control and insulin sensitivity: A meta-analysis of 17 randomized controlled trials
  (2013) American Journal of Clinical Nutrition, 98 (2), pp. 340-348. Cited 22 times.
  http://ajcn.nutrition.org/content/98/2/340.full.pdf+html
  doi: 10.3945/ajcn.112.052746
  

  • View at Publisher
• 
  21

  Sae-Tan, S., Grove, K.A., Lambert, J.D.

  Weight control and prevention of metabolic syndrome by green tea
  (2011) Pharmacological Research, 64 (2), pp. 146-154. Cited 67 times.
  doi: 10.1016/j.phrs.2010.12.013
  

  • View at Publisher
• 
  22

  Rains, T.M., Agarwal, S., Maki, K.C.

  Antiobesity effects of green tea catechins: A mechanistic review
  (2011) Journal of Nutritional Biochemistry, 22 (1), pp. 1-7. Cited 118 times.
  doi: 10.1016/j.jnutbio.2010.06.006
  

  • View at Publisher
• 
  23

  Kennedy, J.W., Hirshman, M.F., Gervino, E.V., Ocel, J.V., Forse, R.A., Hoenig, S.J., Aronson, D., (...), Horton, E.S.

  Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes
  (1999) Diabetes, 48 (5), pp. 1192-1197. Cited 209 times.
  doi: 10.2337/diabetes.48.5.1192
  

  • View at Publisher
• 
  24

  Sanbongi, C., Suzuki, N., Sakane, T.

  Polyphenols in chocolate, which have antioxidant activity, modulate immune functions in humans in vitro
  (1997) Cellular Immunology, 177 (2), pp. 129-136. Cited 166 times.
  doi: 10.1006/cimm.1997.1109
  

  • View at Publisher
• 
  25

  Grassi, D., Desideri, G., Mai, F., Martella, L., De Feo, M., Soddu, D., Fellini, E., (...), Ferri, C.

  Cocoa, Glucose Tolerance, and Insulin Signaling: Cardiometabolic Protection
  (2015) Journal of Agricultural and Food Chemistry, 63 (45), pp. 9919-9926.
  http://pubs.acs.org/journal/jafcau
  doi: 10.1021/acs.jafc.5b00913
  

  • View at Publisher
• 
  26

  Neilson, A.P., Ferruzzi, M.G.

  Influence of formulation and processing on absorption and metabolism of flavan-3-ols from tea and cocoa.
  (2011) Annual review of food science and technology, 2, pp. 125-151. Cited 28 times.
  

  • View at Publisher
• 
  27

  Spencer, J.P.E., Chaudry, F., Pannala, A.S., Srai, S.K., Debnam, E., Rice-Evans, C.

  Decomposition of cocoa procyanidins in the gastric milieu
  (2000) Biochemical and Biophysical Research Communications, 272 (1), pp. 236-241. Cited 158 times.
  doi: 10.1006/bbrc.2000.2749
  

  • View at Publisher
• 
  28

  Rios, L.Y., Bennett, R.N., Lazarus, S.A., Rémésy, C., Scalbert, A., Williamson, G.

  Cocoa procyanidins are stable during gastric transit in humans
  (2002) American Journal of Clinical Nutrition, 76 (5), pp. 1106-1110. Cited 200 times.
  

  • View at Publisher
• 
  29

  Serra, A., MacI, A., Romero, M.-P., Valls, J., Bladé, C., Arola, L., Motilva, M.-J.

  Bioavailability of procyanidin dimers and trimers and matrix food effects in in vitro and in vivo models
  (2010) British Journal of Nutrition, 103 (7), pp. 944-952. Cited 87 times.
  doi: 10.1017/S0007114509992741
  

  • View at Publisher
• 
  30

  Tsang, C., Auger, C., Mullen, W., Bornet, A., Rouanet, J.-M., Crozier, A., Teissedre, P.-L.

  The absorption, metabolism and excretion of flavan-3-ols and procyanidins following the ingestion of a grape seed extract by rats
  (2005) British Journal of Nutrition, 94 (2), pp. 170-181. Cited 176 times.
  doi: 10.1079/BJN20051480
  

  • View at Publisher
• 
  31

  Donovan, J.L., Manach, C., Rios, L., Morand, C., Scalbert, A., Rémésy, C.

  Procyanidins are not bioavailable in rats fed a single meal containing a grapeseed extract or the procyanidin dimer B3
  (2002) British Journal of Nutrition, 87 (4), pp. 299-306. Cited 133 times.
  doi: 10.1079/BJNBJN2001517
  

  • View at Publisher
• 
  32

  Nakamura, Y., Tonogai, Y.

  Metabolism of Grape Seed Polyphenol in the Rat
  (2003) Journal of Agricultural and Food Chemistry, 51 (24), pp. 7215-7225. Cited 32 times.
  doi: 10.1021/jf030250+
  

  • View at Publisher
• 
  33

  Wiese, S., Esatbeyoglu, T., Winterhalter, P., Kruse, H.P., Winkler, S., Bub, A.
  Comparative biokinetics and metabolism of pure monomeric, dimeric and polymeric flavan-3-ols: a randomized cross-over study in humans
  (2014) Mol Nutr Food Res
  

  •  
• 
  34

  Wollgast, J., Anklam, E.

  Polyphenols in chocolate: Is there a contribution to human health?
  (2000) Food Research International, 33 (6), pp. 449-459. Cited 97 times.
  doi: 10.1016/S0963-9969(00)00069-7
  

  • View at Publisher
• 
  35

  Boyer, J., Liu, R.H.

  Apple phytochemicals and their health benefits
  (2004) Nutrition Journal, 3, art. no. 1, pp. 1-45. Cited 486 times.
  http://www.nutritionj.com/content/3/1/5
  doi: 10.1186/1475-2891-3-1
  

  • View at Publisher
• 
  36

  Gu, Y., Hurst, W.J., Stuart, D.A., Lambert, J.D.

  Inhibition of key digestive enzymes by cocoa extracts and procyanidins
  (2011) Journal of Agricultural and Food Chemistry, 59 (10), pp. 5305-5311. Cited 46 times.
  doi: 10.1021/jf200180n
  

  • View at Publisher
• 
  37

  Holt, R.R., Lazarus, S.A., Cameron Sullards, M., Zhu, Q.Y., Schramm, D.D., Hammerstone, J.F., Fraga, C.G., (...), Keen, C.L.

  Procyanidin dimer B2 [epicatechin-(4β-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa
  (2002) American Journal of Clinical Nutrition, 76 (4), pp. 798-804. Cited 339 times.
  

  • View at Publisher
• 
  38

  Donovan, J.L., Crespy, V., Oliveira, M., Cooper, K.A., Gibson, B.B., Williamson, G.

  (+)-Catechin is more bioavailable than (-)-catechin: Relevance to the bioavailability of catechin from cocoa
  (2006) Free Radical Research, 40 (10), pp. 1029-1034. Cited 79 times.
  doi: 10.1080/10715760600868545
  

  • View at Publisher
• 
  39

  Deprez, S., Mila, I., Huneau, J.-F., Tome, D., Scalbert, A.

  Transport of proanthocyanidin dimer, trimer, and polymer across monolayers of human intestinal epithelial Caco-2 cells
  (2001) Antioxidants and Redox Signaling, 3 (6), pp. 957-967. Cited 218 times.
  

  • View at Publisher
• 
  40

  Kosińska, A., Andlauer, W.

  Cocoa polyphenols are absorbed in Caco-2 cell model of intestinal epithelium
  (2012) Food Chemistry, 135 (3), pp. 999-1005. Cited 14 times.
  doi: 10.1016/j.foodchem.2012.05.101
  

  • View at Publisher
• 
  41

  Cardona, F., Andrés-Lacueva, C., Tulipani, S., Tinahones, F.J., Queipo-Ortuño, M.I.

  Benefits of polyphenols on gut microbiota and implications in human health
  (2013) Journal of Nutritional Biochemistry, 24 (8), pp. 1415-1422. Cited 90 times.
  doi: 10.1016/j.jnutbio.2013.05.001
  

  • View at Publisher
• 
  42

  Manach, C., Scalbert, A., Morand, C., Rémésy, C., Jiménez, L.

  Polyphenols: Food sources and bioavailability
  (2004) American Journal of Clinical Nutrition, 79 (5), pp. 727-747. Cited 2594 times.
  

  • View at Publisher
• 
  43

  Neilson, A.P., George, J.C., Janle, E.M., Mattes, R.D., Ralf, R., Matusheski, N.V., Ferruzzi, M.G.

  Influence of chocolate matrix composition on cocoa flavan-3-ol bioaccessibility in vitro and bioavailability in humans
  (2009) Journal of Agricultural and Food Chemistry, 57 (20), pp. 9418-9426. Cited 37 times.
  http://pubs.acs.org/doi/pdfplus/10.1021/jf902919k
  doi: 10.1021/jf902919k
  

  • View at Publisher
• 
  44

  Baba, S., Osakabe, N., Yasuda, A., Natsume, M., Takizawa, T., Nakamura, T., Terao, J.

  Bioavailability of (-)-epicatechin upon intake of chocolate and cocoa in human volunteers
  (2000) Free Radical Research, 33 (5), pp. 635-641. Cited 162 times.
  

  • View at Publisher
• 
  45

  Roura, E., Andrés-Lacueva, C., Estruch, R., Mata-Bilbao, M.L., Izquierdo-Pulido, M., Waterhouse, A.L., Lamuela-Raventós, R.M.

  Milk does not affect the bioavailability of cocoa powder flavonoid in healthy human
  (2007) Annals of Nutrition and Metabolism, 51 (6), pp. 493-498. Cited 58 times.
  doi: 10.1159/000111473
  

  • View at Publisher
• 
  46

  Williamson, G.

  Possible effects of dietary polyphenols on sugar absorption and digestion
  (2013) Molecular Nutrition and Food Research, 57 (1), pp. 48-57. Cited 48 times.
  doi: 10.1002/mnfr.201200511
  

  • View at Publisher
• 
  47

  Tzounis, X., Vulevic, J., Kuhnle, G.G.C., George, T., Leonczak, J., Gibson, G.R., Kwik-Uribe, C., (...), Spencer, J.P.E.

  Flavanol monomer-induced changes to the human faecal microflora
  (2008) British Journal of Nutrition, 99 (4), pp. 782-792. Cited 121 times.
  doi: 10.1017/S0007114507853384
  

  • View at Publisher
• 
  48

  Selma, M.V., Espín, J.C., Tomás-Barberán, F.A.

  Interaction between phenolics and gut microbiota: Role in human health
  (2009) Journal of Agricultural and Food Chemistry, 57 (15), pp. 6485-6501. Cited 320 times.
  http://pubs.acs.org/doi/pdfplus/10.1021/jf902107d
  doi: 10.1021/jf902107d
  

  • View at Publisher
• 
  49

  Goodrich, K.M., Smithson, A.T., Ickes, A.K., Neilson, A.P.

  Pan-colonic pharmacokinetics of catechins and procyanidins in male Sprague-Dawley rats
  (2015) Journal of Nutritional Biochemistry, 26 (10), pp. 1007-1014. Cited 2 times.
  www.elsevier.com/locate/jnutbio
  doi: 10.1016/j.jnutbio.2015.04.008
  

  • View at Publisher
• 
  50

  Ou, K., Sarnoski, P., Schneider, K.R., Song, K., Khoo, C., Gu, L.

  Microbial catabolism of procyanidins by human gut microbiota
  (2014) Molecular Nutrition and Food Research, 58 (11), pp. 2196-2205. Cited 6 times.
  www.mnf-journal.de
  doi: 10.1002/mnfr.201400243
  

  • View at Publisher
• 
  51

  Gonthier, M.-P., Donovan, J.L., Texier, O., Felgines, C., Remesy, C., Scalbert, A.

  Metabolism of dietary procyanidins in rats
  (2003) Free Radical Biology and Medicine, 35 (8), pp. 837-844. Cited 207 times.
  doi: 10.1016/S0891-5849(03)00394-0
  

  • View at Publisher
• 
  52

  Larrosa, M., Luceri, C., Vivoli, E., Pagliuca, C., Lodovici, M., Moneti, G., Dolara, P.

  Polyphenol metabolites from colonic microbiota exert anti-inflammatory activity on different inflammation models
  (2009) Molecular Nutrition and Food Research, 53 (8), pp. 1044-1054. Cited 81 times.
  http://www3.interscience.wiley.com/cgi-bin/fulltext/122466859/PDFSTART
  doi: 10.1002/mnfr.200800446
  

  • View at Publisher
• 
  53

  Wang, D., Williams, B.A., Ferruzzi, M.G., D'Arcy, B.R.

  Microbial metabolites, but not other phenolics derived from grape seed phenolic extract, are transported through differentiated Caco-2 cell monolayers
  (2013) Food Chemistry, 138 (2-3), pp. 1564-1573. Cited 10 times.
  doi: 10.1016/j.foodchem.2012.09.103
  

  • View at Publisher
• 
  54

  Gonthier, M.-P., Cheynier, V., Donovan, J.L., Manach, C., Morand, C., Mila, I., Lapierre, C., (...), Scalbert, A.

  Microbial aromatic acid metabolites formed in the gut account for a major fraction of the polyphenols excreted in urine of rats fed red wine polyphenols
  (2003) Journal of Nutrition, 133 (2), pp. 461-467. Cited 157 times.
  

  • View at Publisher
• 
  55

  Forester, S.C., Waterhouse, A.L.

  Metabolites are key to understanding health effects of wine polyphenolics
  (2009) Journal of Nutrition, 139 (9), pp. 1824S-1831S. Cited 62 times.
  http://jn.nutrition.org/cgi/reprint/139/9/1824S
  doi: 10.3945/jn.109.107664
  

  • View at Publisher
• 
  56

  Williamson, G., Clifford, M.N.

  Colonic metabolites of berry polyphenols: The missing link to biological activity?
  (2010) British Journal of Nutrition, 104 (SUPPL.3), pp. S48-S66. Cited 139 times.
  doi: 10.1017/S0007114510003946
  

  • View at Publisher
• 
  57

  Monagas, M., Urpi-Sarda, M., Sánchez-Patán, F., Llorach, R., Garrido, I., Gómez-Cordovés, C., Andres-Lacueva, C., (...), Bartolomé, B.

  Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites
  (2010) Food and Function, 1 (3), pp. 233-253. Cited 143 times.
  doi: 10.1039/c0fo00132e
  

  • View at Publisher
• 
  58

  Fernández-Millán, E., Ramos, S., Alvarez, C., Bravo, L., Goya, L., Martín, M.T.

  Microbial phenolic metabolites improve glucose-stimulated insulin secretion and protect pancreatic beta cells against tert-butyl hydroperoxide-induced toxicity via ERKs and PKC pathways
  (2014) Food and Chemical Toxicology, 66, pp. 245-253. Cited 9 times.
  doi: 10.1016/j.fct.2014.01.044
  

  • View at Publisher
• 
  59

  Carrasco-Pozo, C., Gotteland, M., Castillo, R.L., Chen, C.

  3,4-dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, protects against pancreatic β-cells dysfunction induced by high cholesterol
  (2015) Experimental Cell Research, 334 (2), pp. 270-282. Cited 2 times.
  http://www.journals.elsevier.com/experimental-cell-research/
  doi: 10.1016/j.yexcr.2015.03.021
  

  • View at Publisher
• 
  60

  Monagas, M., Khan, N., Andrés-Lacueva, C., Urpí-Sardá, M., Vázquez-Agell, M., Lamuela-Raventós, R.M., Estruch, R.

  Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells
  (2009) British Journal of Nutrition, 102 (2), pp. 201-206. Cited 49 times.
  doi: 10.1017/S0007114508162110
  

  • View at Publisher
• 
  61

  Goodrich, K.M., Neilson, A.P.

  Simultaneous UPLC-MS/MS analysis of native catechins and procyanidins and their microbial metabolites in intestinal contents and tissues of male Wistar Furth inbred rats
  (2014) Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 958, pp. 63-74. Cited 9 times.
  www.elsevier.com/inca/publications/store/5/0/2/6/8/9
  doi: 10.1016/j.jchromb.2014.03.011
  

  • View at Publisher
• 
  62

  Yamashita, Y., Okabe, M., Natsume, M., Ashida, H.
  Cacao liquor procyanidin extract improves glucose tolerance by enhancing GLUT4 translocation and glucose uptake in skeletal muscle
  (2012) J Nutr Sci, 1. Cited 6 times.
  

  •  
• 
  63

  Gu, Y., Yu, S., Park, J.Y., Harvatine, K., Lambert, J.D.

  Dietary cocoa reduces metabolic endotoxemia and adipose tissue inflammation in high-fat fed mice
  (2014) Journal of Nutritional Biochemistry, 25 (4), pp. 439-445. Cited 14 times.
  www.elsevier.com/locate/jnutbio
  doi: 10.1016/j.jnutbio.2013.12.004
  

  • View at Publisher
• 
  64

  Yamashita, Y., Okabe, M., Natsume, M., Ashida, H.

  Cinnamtannin A2, a tetrameric procyanidin, increases GLP-1 and insulin secretion in mice
  (2013) Bioscience, Biotechnology and Biochemistry, 77 (4), pp. 888-891. Cited 16 times.
  https://www.jstage.jst.go.jp/article/bbb/77/4/77_130095/_pdf
  doi: 10.1271/bbb.130095
  

  • View at Publisher
• 
  65

  Matsumura, Y., Nakagawa, Y., Mikome, K., Yamamoto, H., Osakabe, N.

  Enhancement of energy expenditure following a single oral dose of flavan-3-ols associated with an increase in catecholamine secretion
  (2014) PLoS ONE, 9 (11), art. no. e112180. Cited 5 times.
  http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0112180&representation=PDF
  doi: 10.1371/journal.pone.0112180
  

  • View at Publisher
• 
  66

  Ruzaidi, A., Amin, I., Nawalyah, A.G., Hamid, M., Faizul, H.A.

  The effect of Malaysian cocoa extract on glucose levels and lipid profiles in diabetic rats
  (2005) Journal of Ethnopharmacology, 98 (1-2), pp. 55-60. Cited 75 times.
  doi: 10.1016/j.jep.2004.12.018
  

  • View at Publisher
• 
  67

  Tomaru, M., Takano, H., Osakabe, N., Yasuda, A., Inoue, K.-i., Yanagisawa, R., Ohwatari, T., (...), Uematsu, H.

  Dietary supplementation with cacao liquor proanthocyanidins prevents elevation of blood glucose levels in diabetic obese mice
  (2007) Nutrition, 23 (4), pp. 351-355. Cited 58 times.
  doi: 10.1016/j.nut.2007.01.007
  

  • View at Publisher
• 
  68

  Jalil, A.M.M., Ismail, A., Pei, P.C., Hamid, M., Kamaruddin, S.H.S.

  Effects of cocoa extract containing polyphenols and methylxanthines on biochemical parameters of obese-diabetic rats
  (2009) Journal of the Science of Food and Agriculture, 89 (1), pp. 130-137. Cited 25 times.
  http://www3.interscience.wiley.com/cgi-bin/fulltext/121481492/PDFSTART
  doi: 10.1002/jsfa.3419
  

  • View at Publisher
• 
  69

  Yamashita, Y., Okabe, M., Natsume, M., Ashida, H.

  Prevention mechanisms of glucose intolerance and obesity by cacao liquor procyanidin extract in high-fat diet-fed C57BL/6 mice
  (2012) Archives of Biochemistry and Biophysics, 527 (2), pp. 95-104. Cited 30 times.
  doi: 10.1016/j.abb.2012.03.018
  

  • View at Publisher
• 
  70

  Watanabe, N., Inagawa, K., Shibata, M., Osakabe, N.

  Flavan-3-ol fraction from cocoa powder promotes mitochondrial biogenesis in skeletal muscle in mice
  (2014) Lipids in Health and Disease, 13 (1), art. no. 64. Cited 6 times.
  doi: 10.1186/1476-511X-13-64
  

  • View at Publisher
• 
  71

  Fernández-Millán, E., Cordero-Herrera, I., Ramos, S., Escrivá, F., Alvarez, C., Goya, L., Martín, M.A.

  Cocoa-rich diet attenuates beta cell mass loss and function in young Zucker diabetic fatty rats by preventing oxidative stress and beta cell apoptosis
  (2015) Molecular Nutrition and Food Research, 59 (4), pp. 820-824. Cited 6 times.
  www.mnf-journal.de
  doi: 10.1002/mnfr.201400746
  

  • View at Publisher
• 
  72

  Gutiérrez-Salmeán, G., Jesús-Torres, E.D., Ortiz-Vilchis, P., Vacaseydel, C., Garduño-Siciliano, L., Meaney, E.
  Cardiometabolic alterations in Wistar rats induced by an obesogenic paigen-like diet: effects of (-) epicatechin
  (2014) Diabetes Metab, 5.
  

  •  
• 
  73

  Si, H., Fu, Z., Babu, P.V.A., Zhen, W., LeRoith, T., Meaney, M.P., Voelker, K.A., (...), Liu, D.

  Dietary epicatechin promotes survival of obese diabetic mice and Drosophila melanogaster
  (2011) Journal of Nutrition, 141 (6), pp. 1095-1100. Cited 32 times.
  http://jn.nutrition.org/content/141/6/1095.full.pdf
  doi: 10.3945/jn.110.134270
  

  • View at Publisher
• 
  74

  de Oliveira, T.B., Genovese, M.I.

  Chemical composition of cupuassu (Theobroma grandiflorum) and cocoa (Theobroma cacao) liquors and their effects on streptozotocin-induced diabetic rats
  (2013) Food Research International, 51 (2), pp. 929-935. Cited 11 times.
  doi: 10.1016/j.foodres.2013.02.019
  

  • View at Publisher
• 
  75

  Gu, Y., Yu, S., Lambert, J.D.

  Dietary cocoa ameliorates obesity-related inflammation in high fat-fed mice
  (2014) European Journal of Nutrition, 53 (1), pp. 149-158. Cited 15 times.
  doi: 10.1007/s00394-013-0510-1
  

  • View at Publisher
• 
  76

  Massot-Cladera, M., Pérez-Berezo, T., Franch, A., Castell, M., Pérez-Cano, F.J.

  Cocoa modulatory effect on rat faecal microbiota and colonic crosstalk
  (2012) Archives of Biochemistry and Biophysics, 527 (2), pp. 105-112. Cited 32 times.
  doi: 10.1016/j.abb.2012.05.015
  

  • View at Publisher
• 
  77

  Brand-Miller, J., Holt, S.H.A., De Jong, V., Petocz, P.

  Cocoa powder increases postprandial insulinemia in lean young adults
  (2003) Journal of Nutrition, 133 (10), pp. 3149-3152. Cited 39 times.
  

  • View at Publisher
• 
  78

  Grassi, D., Lippi, C., Necozione, S., Desideri, G., Ferri, C.

  Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons
  (2005) American Journal of Clinical Nutrition, 81 (3), pp. 611-614. Cited 278 times.
  

  • View at Publisher
• 
  79

  Grassi, D., Necozione, S., Lippi, C., Croce, G., Valeri, L., Pasqualetti, P., Desideri, G., (...), Ferri, C.

  Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives
  (2005) Hypertension, 46 (2), pp. 398-405. Cited 323 times.
  doi: 10.1161/01.HYP.0000174990.46027.70
  

  • View at Publisher
• 
  80

  Grassi, D., Desideri, G., Necozione, S., Lippi, C., Casale, R., Properzi, G., Blumberg, J.B., (...), Ferri, C.

  Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate
  (2008) Journal of Nutrition, 138 (9), pp. 1671-1676. Cited 207 times.
  http://jn.nutrition.org/cgi/reprint/138/9/1671
  

  • View at Publisher

  Neilson, A.P.; 1981 Kraft Dr., United States; email:andrewn@vt.edu
© Copyright 2016 Elsevier B.V., All rights reserved.