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DOI: 10.1055/s-0042-108340
The Metabolic Plant Feedback Hypothesis: How Plant Secondary Metabolites Nonspecifically Impact Human Health[*]
Publication History
received 23 March 2016
revised 24 April 2016
accepted 29 April 2016
Publication Date:
10 June 2016 (online)
Abstract
Humans can ingest gram amounts of plant secondary metabolites daily through diet. Many of these phytochemicals are bioactive beyond our current understanding because they act through weak negative biological feedback mechanisms, undetectable in vitro. Homeostatic-type assessments shed light on the evolutionary implications of the human diet from plants, giving rise to the metabolic plant feedback hypothesis. The hypothesis states that ancient diets rich in carbohydrates coincide with bulk dietary phytochemicals that act as nonspecific inhibitors of metabolic and inflammatory processes. Consequently, food-derived phytochemicals are likely to be equally effective as herbal medicines for these indications. In addition to the ubiquitous flavonoids, terpenoids, and fatty acids in the diet, the likely impact of chronic chlorophyll ingestion on human health is discussed, and data on its modulation of blood glucose levels are presented. A major deduction of this hypothesis is that starchy diets lacking plant secondary metabolites are associated with multimorbidity (lifestyle diseases) including obesity, type 2 diabetes, and cardiovascular disease. It is proposed that the intake of leafy vegetables, spices, and herbal remedies rich in phytochemicals matches the transition and genetic adaptation to early agriculture, playing a compensatory role in the mismatch of old genes and new diets.
Key words
evolution of diet - glucotoxicity - chlorophyll - paleolithic diet - natural products - diabetes* Dedicated to Professor Dr. Dr. h. c. mult. Kurt Hostettmann in recognition of his outstanding contribution to natural product research.
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References
- 1 Gertsch J. From ethnobotany to molecular pharmacognosy: a transdisciplinary approach. Ethnobotany of the Yanomamï-Amerindians in Venezuela, phytochemical and biological investigations on selected plants, development of a real-time PCR-based functional transcriptomics assay (FTA) [dissertation]. Zürich: ETH Zürich; 2002
- 2 Gertsch J, Stauffer W, Narváez A, Sticher O. Use and significance of palms (Arecaceae) among the Yanomamï in southern Venezuela. J Ethnobiol 2002; 22: 219-246
- 3 Headland TN. The wild yam question: How well could independent hunter-gatherers live in a tropical rain forest ecosystem?. Hum Ecol 1987; 15: 463-491
- 4 Hardy K, Brand-Miller J, Brown KD, Thomas MG, Copeland L. The importance of dietary carbohydrate in human evolution. Q Rev Biol 2015; 90: 251-268
- 5 Perry GH, Dominy NJ, Claw KG, Lee AS, Fiegler H, Redon R, Werner J, Villanea FA, Mountain JL, Misra R, Carter NP, Lee C, Stone AC. Diet and the evolution of human amylase gene copy number variation. Nat Genet 2007; 39: 1256-1260
- 6 Blum K, Thanos PK, Gold MS. Dopamine and glucose, obesity, and reward deficiency syndrome. Front Psychol 2014; 5: 919
- 7 Voegtlin WL. The Stone Age Diet: based on in-depth Studies of human Ecology and the Diet of Man. New York: Vantage Press; 1975
- 8 Tapsell LC, Hemphill I, Cobiac L, Patch CS, Sullivan DR, Fenech M, Roodenrys S, Keogh JB, Clifton PM, Williams PG, Fazio VA, Inge KE. Health benefits of herbs and spices: the past, the present, the future. Med J Aust 2006; 185: S4-S24
- 9 Aggarwal BB, Van Kuiken ME, Iyer LH, Harikumar KB, Sung B. Molecular targets of nutraceuticals derived from dietary spices: potential role in suppression of inflammation and tumorigenesis. Exp Biol Med (Maywood) 2009; 234: 825-849
- 10 Diamond J. Evolution, consequences and future of plant and animal domestication. Nature 2002; 418: 700-707
- 11 Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med 1985; 312: 283-289
- 12 Lindeberg S. Food and Western Disease: Health and Nutrition from an evolutionary Perspective. Oxford (UK): Wiley-Blackwell; 2009
- 13 Fairweather-Tait SJ. Human nutrition and food research: opportunities and challenges in the post-genomic era. Philos Trans R Soc Lond B Biol Sci 2003; 358: 1709-1727
- 14 Hunter P. We are what we eat. The link between diet, evolution and non-genetic inheritance. EMBO Rep 2008; 9: 413-415
- 15 Lillycrop KA, Burdge GC. Maternal diet as a modifier of offspring epigenetics. J Dev Orig Health Dis 2015; 6: 88-95
- 16 Acton KJ, Burrows NR, Moore K, Querec L, Geiss LS, Engelgau MM. Trends in diabetes prevalence among American Indian and Alaska native children, adolescents, and young adults. Am J Public Health 2002; 92: 1485-1490
- 17 Wendorf M. Diabetes, the ice free corridor, and the Paleoindian settlement of North America. Am J Phys Anthropol 1989; 79: 503-520
- 18 Lindgärde F, Ercilla MB, Correa LR, Ahrén B. Body adiposity, insulin, and leptin in subgroups of Peruvian Amerindians. High Alt Med Biol 2004; 5: 27-31
- 19 Hanley AJ, Harris SB, Gittelsohn J, Wolever TM, Saksvig B, Zinman B. Overweight among children and adolescents in a Native Canadian community: prevalence and associated factors. Am J Clin Nutr 2000; 71: 693-700
- 20 Bradshaw BS, Blanchard S, Thompson GH. Emergence of diabetes mellitus in a Mexican-origin population: a multiple cause-of-death analysis. Soc Biol 1995; 42: 36-49
- 21 Gracey M. New World syndrome in Western Australian aborigines. Clin Exp Pharmacol Physiol 1995; 22: 220-225
- 22 London DS, Beezhold B. A phytochemical-rich diet may explain the absence of age-related decline in visual acuity of Amazonian hunter-gatherers in Ecuador. Nutr Res 2015; 35: 107-117
- 23 Evans-Pritchard EE. Witchcraft, Oracles and Magic among the Azande. Oxford, UK: Clarendon Press; 1937
- 24 Eliade M. Le Chamanisme et les Techniques archaïques de lʼExtase. Paris: Payot; 1951
- 25 Voeks RA, Sercombe P. The scope of hunter-gatherer ethnomedicine. Soc Sci Med 2000; 51: 679-690
- 26 Zerries O, Schuster M. Mahekodotedi: Monographie eines Dorfes der Waika-Indianer (Yanoama) am oberen Orinoco (Venezuela). München: K. Renner Verlag; 1974
- 27 Milliken W, Albert B. The use of medicinal plants by the Yanomami Indians of Brazil. Econ Bot 1996; 50: 10-25
- 28 Alexiadis MN. Ethnobotany of the Ese Eja: plants, health, and change in an Amazonian society [dissertation]. City University of New York; 1999
- 29 Kahlheber S, Neumann K. The development of plant cultivation in semi-arid West Africa. In: Denham T, Iriarte J, Vrydaghs L, editors Rethinking agriculture: archaeological and ethnoarchaeological perspectives (One World Archaeology 51). Walnut Creek, CA: Left Coast Press; 2007: 320-346
- 30 Cordain L, Eaton SB, Miller JB, Mann N, Hill K. The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr 2002; 56: 42-52
- 31 Etkin NL, Ross PJ. Food as medicine and medicine as food: an adaptive framework for the interpretation of plant utilization among the Hausa of northern Nigeria. Soc Sci Med 1982; 16: 1559-1573
- 32 Johns T. With bitter Herbs they shall eat it: chemical Ecology and the Origins of human Diet and Medicine (Arizona Studies in Human Ecology). Tucson, AZ: University of Arizona Press; 1990
- 33 Leonti M. The co-evolutionary perspective of the food-medicine continuum and wild gathered and cultivated vegetables. Genet Resour Crop Evol 2012; 59: 1295-1302
- 34 Hou Y, Jiang JG. Origin and concept of medicine food homology and its application in modern functional foods. Food Funct 2013; 4: 1727-1741
- 35 Bisson J, McAlpine JB, Friesen JB, Chen SN, Graham J, Pauli GF. Can invalid bioactives undermine natural product-based drug discovery?. J Med Chem 2016; 59: 1671-1690
- 36 Baell JB. Feeling natureʼs PAINS: natural products, natural product drugs, and pan assay interference compounds (PAINS). J Nat Prod DOI: 10.1021/acs.jnatprod.5b00947. advance online publication 22 February 2016
- 37 Ingólfsson HI, Thakur P, Herold KF, Hobart EA, Ramsey NB, Periole X, de Jong DH, Zwama M, Yilmaz D, Hall K, Maretzky T, Hemmings Jr. HC, Blobel C, Marrink SJ, Koçer A, Sack JT, Andersen OS. Phytochemicals perturb membranes and promiscuously alter protein function. ACS Chem Biol 2014; 9: 1788-1798
- 38 Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, Schuster D, Kopp B, Bauer R, Stuppner H, Dirsch VM, Atanasov AG. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem Pharmacol 2014; 92: 73-89
- 39 Li L, Bonneton F, Chen XY, Laudet V. Botanical compounds and their regulation of nuclear receptor action: the case of traditional Chinese medicine. Mol Cell Endocrinol 2015; 401: 221-237
- 40 Mandlekar S, Hong JL, Kong AN. Modulation of metabolic enzymes by dietary phytochemicals: a review of mechanisms underlying beneficial versus unfavorable effects. Curr Drug Metab 2006; 7: 661-675
- 41 Ohnishi K, Ohkura S, Nakahata E, Ishisaka A, Kawai Y, Terao J, Mori T, Ishii T, Nakayama T, Kioka N, Matsumoto S, Ikeda Y, Akiyama M, Irie K, Murakami A. Non-specific protein modifications by a phytochemical induce heat shock response for self-defense. PLoS One 2013; 8: e58641
- 42 Virgili F, Marino M. Regulation of cellular signals from nutritional molecules: a specific role for phytochemicals, beyond antioxidant activity. Free Radic Biol Med 2008; 45: 1205-1216
- 43 Remely M, Lovrecic L, de la Garza AL, Migliore L, Peterlin B, Milagro FI, Martinez AJ, Haslberger AG. Therapeutic perspectives of epigenetically active nutrients. Br J Pharmacol 2015; 172: 2756-2768
- 44 Joven J, Micol V, Segura-Carretero A, Alonso-Villaverde C, Menéndez JA. Bioactive Food Components Platform. Polyphenols and the modulation of gene expression pathways: can we eat our way out of the danger of chronic disease?. Crit Rev Food Sci Nutr 2014; 54: 985-1001
- 45 Szarc vel Szic K, Declerck K, Vidaković M, Vanden Berghe W. From inflammaging to healthy aging by dietary lifestyle choices: is epigenetics the key to personalized nutrition?. Clin Epigenetics 2015; 7: 33
- 46 Gertsch J, Viveros-Paredes JM, Taylor P. Plant immunostimulants–scientific paradigm or myth?. J Ethnopharmacol 2011; 136: 385-391
- 47 Nathan R, Schurr FM, Spiegel O, Steinitz O, Trakhtenbrot A, Tsoar A. Mechanisms of long-distance seed dispersal. Trends Ecol Evol 2008; 23: 638-647
- 48 Fuller DQ. Contrasting patterns in crop domestication and domestication rates: recent archaeobotanical insights from the Old World. Ann Bot 2007; 100: 903-924
- 49 Linus Pauling Institute, Micronutrient Information Center. Phytochemicals. Available at. http://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals Accessed March 10, 2016
- 50 Gertsch J. How scientific is the science in ethnopharmacology? Historical perspectives and epistemological problems. J Ethnopharmacol 2009; 122: 177-183
- 51 Gertsch J. Botanical drugs, synergy, and network pharmacology: forth and back to intelligent mixtures. Planta Med 2011; 77: 1086-1098
- 52 Butterweck V, Nahrstedt A. What is the best strategy for preclinical testing of botanicals? A critical perspective. Planta Med 2012; 78: 747-754
- 53 Terahara N. Flavonoids in foods: a review. Nat Prod Commun 2015; 10: 521-528
- 54 Tholl D. Biosynthesis and biological functions of terpenoids in plants. Adv Biochem Eng Biotechnol 2015; 148: 63-106
- 55 Liu RH. Health-promoting components of fruits and vegetables in the diet. Adv Nutr 2013; 4: 384S-392S
- 56 Gerber LM, Williams GC, Gray SJ. The nutrient-toxin dosage continuum in human evolution and modern health. Q Rev Biol 1999; 74: 273-289
- 57 Parsons PA. The metabolic cost of multiple environmental stresses: Implications for climatic change and conservation. Trends Ecol Evol 1990; 5: 315-317
- 58 Heinrich M, Prieto JM. Diet and healthy ageing 2100: will we globalise local knowledge systems?. Ageing Res Rev 2008; 7: 249-274
- 59 Gostner JM, Becker K, Ueberall F, Fuchs D. The good and bad of antioxidant foods: An immunological perspective. Food Chem Toxicol 2015; 80: 72-79
- 60 De Roos B, Duthie GG. Role of dietary pro-oxidants in the maintenance of health and resilience to oxidative stress. Mol Nutr Food Res 2015; 59: 1229-1248
- 61 Benzie IF. Evolution of dietary antioxidants. Comp Biochem Physiol A Mol Integr Physiol 2003; 136: 113-126
- 62 González-Castejón M, Rodriguez-Casado A. Dietary phytochemicals and their potential effects on obesity: a review. Pharmacol Res 2011; 64: 438-455
- 63 Cicero AF, Colletti A. Role of phytochemicals in the management of metabolic syndrome. Phytomedicine DOI: 10.1016/j.phymed.2015.11.009. advance online publication 11 December 2015
- 64 Li YH, Niu YB, Sun Y, Zhang F, Liu CX, Fan L, Mei QB. Role of phytochemicals in colorectal cancer prevention. World J Gastroenterol 2015; 21: 9262-9272
- 65 Alasalvar C, Bolling BW. Review of nut phytochemicals, fat-soluble bioactives, antioxidant components and health effects. Br J Nutr 2015; 113: S68-S78
- 66 Slavin JL, Lloyd B. Health benefits of fruits and vegetables. Adv Nutr 2012; 3: 506-516
- 67 Gordon MH. Significance of dietary antioxidants for health. Int J Mol Sci 2012; 13: 173-179
- 68 Galal AM, Walker LA, Khan IA. Induction of GST and related events by dietary phytochemicals: sources, chemistry, and possible contribution to chemoprevention. Curr Top Med Chem 2015; 14: 2802-2821
- 69 Shankar S, Kumar D, Srivastava RK. Epigenetic modifications by dietary phytochemicals: implications for personalized nutrition. Pharmacol Ther 2013; 138: 1-17
- 70 Johnson IT, Belshaw NJ. The effect of diet on the intestinal epigenome. Epigenomics 2014; 6: 239-251
- 71 Li CC, Cropley JE, Cowley MJ, Preiss T, Martin DI, Suter CM. A sustained dietary change increases epigenetic variation in isogenic mice. PLoS Genet 2011; 7: e1001380
- 72 Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity 2014; 40: 833-842
- 73 Riccardi G, Rivellese AA. Dietary treatment of the metabolic syndrome – the optimal diet. Br J Nutr 2000; 83: S143-S148
- 74 Stanhope KL. Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit Rev Clin Lab Sci 2016; 53: 52-67
- 75 Cabrera Escobar MA, Veerman JL, Tollman SM, Bertram MY, Hofman KJ. Evidence that a tax on sugar sweetened beverages reduces the obesity rate: a meta-analysis. BMC Public Health 2013; 13: 1072
- 76 Ruel G, Shi Z, Zhen S, Zuo H, Kröger E, Sirois C, Lévesque JF, Taylor AW. Association between nutrition and the evolution of multimorbidity: the importance of fruits and vegetables and whole grain products. Clin Nutr 2014; 33: 513-520
- 77 Alonso-Castro AJ, Domínguez F, Zapata-Morales JR, Carranza-Álvarez C. Plants used in the traditional medicine of Mesoamerica (Mexico and Central America) and the Caribbean for the treatment of obesity. J Ethnopharmacol 2015; 175: 335-345
- 78 Etkin NL. Multidisciplinary perspectives in the interpretation of plants used in indigenous medicine and diet. In: Etkin NL, editor Plants in indigenous medicine and diet: biobehavioral approaches. Bedford Hills, NY: Redgrave Press; 1986: 1-29
- 79 Salas-Salvadó J, Guasch-Ferré M, Bulló M, Sabaté J. Nuts in the prevention and treatment of metabolic syndrome. Am J Clin Nutr 2014; 100: 399S-407S
- 80 Heber D. Herbal preparations for obesity: are they useful?. Prim Care 2003; 30: 441-463
- 81 Cercato LM, White PA, Nampo FK, Santos MR, Camargo EA. A systematic review of medicinal plants used for weight loss in Brazil: Is there potential for obesity treatment?. J Ethnopharmacol 2015; 176: 286-296
- 82 Ezuruike UF, Prieto JM. The use of plants in the traditional management of diabetes in Nigeria: pharmacological and toxicological considerations. J Ethnopharmacol 2014; 155: 857-924
- 83 J Afolayan A, O Sunmonu T. In vivo studies on antidiabetic plants used in South African herbal medicine. J Clin Biochem Nutr 2010; 47: 98-106
- 84 Jouad H, Haloui M, Rhiouani H, El Hilaly J, Eddouks M. Ethnobotanical survey of medicinal plants used for the treatment of diabetes, cardiac and renal diseases in the North centre region of Morocco (Fez-Boulemane). J Ethnopharmacol 2001; 77: 175-182
- 85 Ríos JL, Francini F, Schinella GR. Natural products for the treatment of type 2 diabetes mellitus. Planta Med 2015; 81: 975-994
- 86 Parikh NH, Parikh PK, Kothari C. Indigenous plant medicines for health care: treatment of diabetes mellitus and hyperlipidemia. Chin J Nat Med 2014; 12: 335-344
- 87 Rastogi S, Pandey MM, Rawat AK. Traditional herbs: a remedy for cardiovascular disorders. Phytomedicine DOI: 10.1016/j.phymed.2015.10.012. advance online publication 10 November 2015
- 88 Efferth T, Kaina B. Toxicities by herbal medicines with emphasis to traditional Chinese medicine. Curr Drug Metab 2011; 12: 989-996
- 89 Dutra RC, Campos MM, Santos AR, Calixto JB. Medicinal plants in Brazil: Pharmacological studies, drug discovery, challenges and perspectives. Pharmacol Res DOI: 10.1016/j.phrs.2016.01.021. advance online publication 23 January 2016
- 90 Hadjzadeh MA, Rajaei Z, Moradi R, Ghorbani A. Effects of hydroalcoholic extract of watercress (Nasturtium officinale) leaves on serum glucose and lipid levels in diabetic rats. Indian J Physiol Pharmacol 2015; 59: 223-230
- 91 Dudzińska D, Boncler M, Watala C. The cardioprotective power of leaves. Arch Med Sci 2015; 11: 819-839
- 92 Zhou Z, Li D, Zhou H, Lin X, Li C, Tang M, Feng Z, Li M. Plants and their bioactive compounds with the potential to enhance mechanisms of inherited cardiac regeneration. Planta Med 2015; 81: 637-647
- 93 Chen S, Zhu Y, Liu Z, Gao Z, Li B, Zhang D, Zhang Z, Jiang X, Liu Z, Meng L, Yang Y, Shi B. Grape seed proanthocyanidin extract ameliorates diabetic bladder dysfunction via the activation of the Nrf2 pathway. PLoS One 2015; 10: e0126457
- 94 Vujicic M, Nikolic I, Kontogianni VG, Saksida T, Charisiadis P, Orescanin-Dusic Z, Blagojevic D, Stosic-Grujicic S, Tzakos AG, Stojanovic I. Methanolic extract of Origanum vulgare ameliorates type 1 diabetes through antioxidant, anti-inflammatory and anti-apoptotic activity. Br J Nutr 2015; 113: 770-782
- 95 Leiherer A, Mündlein A, Drexel H. Phytochemicals and their impact on adipose tissue inflammation and diabetes. Vascul Pharmacol 2013; 58: 3-20
- 96 Grant SJ, Bensoussan A, Chang D, Kiat H, Klupp NL, Liu JP, Li X. Chinese herbal medicines for people with impaired glucose tolerance or impaired fasting blood glucose. Cochrane Database Syst Rev 2009; (4) CD006690
- 97 Lind J. A Treatise of Scurvy in three Parts. Edinburgh: Kincaid & Donaldson; 1753
- 98 Spedding S. Vitamins are more Funky than Casimir thought. Australas Med J 2013; 6: 104-106
- 99 Semba RD. The discovery of the vitamins. Int J Vitam Nutr Res 2012; 82: 310-315
- 100 Carpenter KJ. The Nobel Prize and the discovery of vitamins. Available at. http://www.nobelprize.org/nobel_prizes/themes/medicine/carpenter/ Accessed March 10, 2016
- 101 Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A 2008; 105: 9099-9104
- 102 Gertsch J. Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action?. Commun Integr Biol 2008; 1: 26-28
- 103 Sharma C, Al Kaabi J, Nurulain SM, Goyal SN, Kamal MA, Ojha S. Polypharmacological properties and therapeutic potential of β-caryophyllene: a dietary phytocannabinoid of pharmaceutical promise. Curr Pharm Des [in press]
- 104 Jacobs Jr DR, Steffen LM. Nutrients, foods, and dietary patterns as exposures in research: a framework for food synergy. Am J Clin Nutr 2003; 78: 508S-513S
- 105 Ulrich-Merzenich G, Zeitler H, Vetter H, Kraft K. Synergy research: vitamins and secondary plant components in the maintenance of the redox-homeostasis and in cell signaling. Phytomedicine 2009; 16: 2-16
- 106 Zhang A, Sun H, Wang X. Potentiating therapeutic effects by enhancing synergism based on active constituents from traditional medicine. Phytother Res 2014; 28: 526-533
- 107 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
- 108 Jenkins DJ, Kendall CW, Augustin LS, Franceschi S, Hamidi M, Marchie A, Jenkins AL, Axelsen M. Glycemic index: overview of implications in health and disease. Am J Clin Nutr 2002; 76: 266S-273S
- 109 Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Weinberger A, Ben-Yacov O, Lador D, Avnit-Sagi T, Lotan-Pompan M, Suez J, Mahdi JA, Matot E, Malka G, Kosower N, Rein M, Zilberman-Schapira G, Dohnalová L, Pevsner-Fischer M, Bikovsky R, Halpern Z, Elinav E, Segal E. Personalized nutrition by prediction of glycemic responses. Cell 2015; 163: 1079-1094
- 110 Montelius C, Gustafsson K, Weström B, Albertsson PÅ, Emek SC, Rayner M, Erlanson-Albertsson C. Chloroplast thylakoids reduce glucose uptake and decrease intestinal macromolecular permeability. Br J Nutr 2011; 106: 836-844
- 111 Montelius C, Szwiec K, Kardas M, Lozinska L, Erlanson-Albertsson C, Pierzynowski S, Rehfeld JF, Weström B. Dietary thylakoids suppress blood glucose and modulate appetite-regulating hormones in pigs exposed to oral glucose tolerance test. Clin Nutr 2014; 33: 1122-1126
- 112 Montelius C, Erlandsson D, Vitija E, Stenblom EL, Egecioglu E, Erlanson-Albertsson C. Body weight loss, reduced urge for palatable food and increased release of GLP-1 through daily supplementation with green-plant membranes for three months in overweight women. Appetite 2014; 81: 295-304
- 113 Bligh HF, Godsland IF, Frost G, Hunter KJ, Murray P, MacAulay K, Hyliands D, Talbot DC, Casey J, Mulder TP, Berry MJ. Plant-rich mixed meals based on Palaeolithic diet principles have a dramatic impact on incretin, peptide YY and satiety response, but show little effect on glucose and insulin homeostasis: an acute-effects randomised study. Br J Nutr 2015; 113: 574-584
- 114 Kim KS, Jang HJ. Medicinal plants qua glucagon-like peptide-1 secretagogue via intestinal nutrient sensors. Evid Based Complement Alternat Med 2015; 2015: 171742
- 115 Freeman H, Cox RD. Type-2 diabetes: a cocktail of genetic discovery. Hum Mol Genet 2006; 15: R202-R209
- 116 Kopp W. The atherogenic potential of dietary carbohydrate. Prev Med 2006; 42: 336-342
- 117 Vinayagam R, Jayachandran M, Xu B. Antidiabetic effects of simple phenolic acids: a comprehensive review. Phytother Res 2016; 30: 184-199
- 118 Elekofehinti OO. Saponins: Anti-diabetic principles from medicinal plants – A review. Pathophysiology 2015; 22: 95-103
- 119 Guo H, Ling W. The update of anthocyanins on obesity and type 2 diabetes: experimental evidence and clinical perspectives. Rev Endocr Metab Disord 2015; 16: 1-13
- 120 Pathak M. Diabetes mellitus type 2 and functional foods of plant origin. Recent Pat Biotechnol 2014; 8: 160-164
- 121 Singhal P, Kaushik G, Mathur P. Antidiabetic potential of commonly consumed legumes: a review. Crit Rev Food Sci Nutr 2014; 54: 655-672
- 122 Heinrich M, Nebel S, Leonti M, Rivera D, Obón C. ‘Local Food-Nutraceuticals’: bridging the gap between local knowledge and global needs. Forum Nutr 2006; 59: 1-17
- 123 Egner PA, Stansbury KH, Snyder EP, Rogers ME, Hintz PA, Kensler TW. Identification and characterization of chlorin e(4) ethyl ester in sera of individuals participating in the chlorophyllin chemoprevention trial. Chem Res Toxicol 2000; 13: 900-906
- 124 Serpeloni JM, Batista BL, Angeli JP, Barcelos GR, Bianchi Mde L, Barbosa Jr. F, Antunes LM. Antigenotoxic properties of chlorophyll b against cisplatin-induced DNA damage and its relationship with distribution of platinum and magnesium in vivo . J Toxicol Environ Health A 2013; 76: 345-353
- 125 Subramoniam A, Asha VV, Nair SA, Sasidharan SP, Sureshkumar PK, Rajendran KN, Karunagaran D, Ramalingam K. Chlorophyll revisited: anti-inflammatory activities of chlorophyll a and inhibition of expression of TNF-α gene by the same. Inflammation 2012; 35: 959-966
- 126 Higdon J. Chlorophyll and Chlorophyllin. Available at. http://lpi.oregonstate.edu/book/export/html/456 Accessed March 7, 2016
- 127 McCarty MF. The chlorophyll metabolite phytanic acid is a natural rexinoid – potential for treatment and prevention of diabetes. Med Hypotheses 2001; 56: 217-219
- 128 Heim M, Johnson J, Boess F, Bendik I, Weber P, Hunziker W, Fluhmann B. Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes. FASEB J 2002; 16: 718-720
- 129 Schlüter A, Barberá MJ, Iglesias R, Giralt M, Villarroya F. Phytanic acid, a novel activator of uncoupling protein-1 gene transcription and brown adipocyte differentiation. Biochem J 2002; 362: 61-69
- 130 Schlüter A, Giralt M, Iglesias R, Villarroya F. Phytanic acid, but not pristanic acid, mediates the positive effects of phytol derivatives on brown adipocyte differentiation. FEBS Lett 2002; 517: 83-86
- 131 Baxter JH. Absorption of chlorophyll phytol in normal man and in patients with Refsumʼs disease. J Lipid Res 1968; 9: 636-641
- 132 Hellgren LI. Phytanic acid – an overlooked bioactive fatty acid in dairy fat?. Ann N Y Acad Sci 2010; 1190: 42-49
- 133 Moser AB, Hey J, Dranchak PK, Karaman MW, Zhao J, Cox LA, Ryder OA, Hacia JG. Diverse captive non-human primates with phytanic acid-deficient diets rich in plant products have substantial phytanic acid levels in their red blood cells. Lipids Health Dis 2013; 12: 10
- 134 Watkins PA, Moser AB, Toomer CB, Steinberg SJ, Moser HW, Karaman MW, Ramaswamy K, Siegmund KD, Lee DR, Ely JJ, Ryder OA, Hacia JG. Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions. BMC Physiol 2010; 10: 19
- 135 Baxter JH, Steinberg D. Absorption of phytol from dietary chlorophyll in the rat. J Lipid Res 1967; 8: 615-620
- 136 Silva RO, Sousa FB, Damasceno SR, Carvalho NS, Silva VG, Oliveira FR, Sousa DP, Aragão KS, Barbosa AL, Freitas RM, Medeiros JV. Phytol, a diterpene alcohol, inhibits the inflammatory response by reducing cytokine production and oxidative stress. Fundam Clin Pharmacol 2014; 28: 455-464
- 137 De Moraes J, de Oliveira RN, Costa JP, Junior AL, de Sousa DP, Freitas RM, Allegretti SM, Pinto PL. Phytol, a diterpene alcohol from chlorophyll, as a drug against neglected tropical disease Schistosomiasis mansoni. PLoS Negl Trop Dis 2014; 8: e2617
- 138 Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”?. Am J Hum Genet 1962; 14: 353-362
- 139 Turner BL, Thompson AL. Beyond the Paleolithic prescription: incorporating diversity and flexibility in the study of human diet evolution. Nutr Rev 2013; 71: 501-510
- 140 Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, OʼKeefe JH, Brand-Miller J. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 2005; 81: 341-354
- 141 Guldbrand H, Lindström T, Dizdar B, Bunjaku B, Östgren CJ, Nystrom FH, Bachrach-Lindström M. Randomization to a low-carbohydrate diet advice improves health related quality of life compared with a low-fat diet at similar weight-loss in Type 2 diabetes mellitus. Diabetes Res Clin Pract 2014; 106: 221-227