Diabetes mellitus is a group of metabolic syndromes with a hallmark of hyperglycemia. Serious long-term complications from diabetes are a major cause of hospitalization and death. We recently discovered that grape pomace, the by-product from the waste of the wine and juice industries, had great potential to prevent diabetes. In this study, we examined the potential use of grape pomace in controlling high blood glucose in the form of Cabernet Franc Grape pomace aqueous extract (GPE). Both streptozotocin (STZ; 1 × 150 mg/kg)-treated mice and non-STZ treated mice were fed with high fat diet that was supplemented with 2.4 g/kg GPE for 12 weeks. GPE had no significant effect on the blood glucose levels in STZ-treated mice. However, GPE significantly reduced blood glucose levels by 16.1% (p < 0.05) in non-STZ treated mice following a 10-week HFD feeding period when compared with high fat diet controls. GPE reduction of hyperglycemia also promoted a significant reduction of GHbA1c accumulation. Circulating peptide hormones related to glucose homeostasis, including GLP-1, glucagon, DPP-4 and insulin, were drastically altered by GPE. Moreover, GPE attenuated the expressions of insulin, glucagon, and several gut hormones at the mRNA level. In addition, GPE significantly down regulated 5 biomarker genes for systematic inflammation. Taken together, our results highlight a role of GPE as a potential alternative approach to control diabetes epidemic.
Georgiev, V., Ananga, A. andTsolova, V. (2014) Recent Advances and Uses of Grape Flavonoids as Nutraceuticals. Nutrients, 6, 391-415. http://dx.doi.org/10.3390/nu6010391
Chacona, M.R., Ceperuelo-Mallafrea, V., Maymo-Masipa, E., Mateo-Sanzb, J., Arolac, L., Guitierreza, C., Fernandez-Reald, J., Ardevolc, A., Simona, I. and Vendrella, J. (2009) Grape-Seed Procyanidins Modulate Inflammation on Human Differentiated Adipocytes in Vitro. Cytokine, 47, 137-142. http://dx.doi.org/10.1016/j.cyto.2009.06.001
Bagchi, D., Bagchi, M., Stohs, S., Das, D., Ray, C., Kuszynski, S. and Joshi, H. (2000) Free Radicals and Grape Seed Proanthocyanidin Extract: Importance in Human Health and Disease Prevention. Toxicology, 148, 187-197. http://dx.doi.org/10.1016/s0300-483x(00)00210-9
Cantos, E., Espin, J. and Tomas-Barberan, F. (2002) Varietal Differences among the Polyphenol Profiles of Seven Table Grape Cultivars Studied by LC-DAD-MS-MS. Journal of Agricultural and Food Chemistry, 50, 5691-5696. http://dx.doi.org/10.1021/jf0204102
Tome-Carneiro, J., Gonzalvez, M., Larrosa, M., Garcia-Almagro, F., Aviles-Plaza, F., Parra, S., Yanez-Gascon, M., Ruiz-Ros, J., Garcia-Conesa, M., Tomas-Barberan, F. and Espin, J. (2012) Consumption of a Grape Extract Supplement Containing Resveratrol Decreases Oxidized LDL and ApoB in Patients Undergoing Primary Prevention of Cardiovascular Disease: A Triple-Blind, 6-Month Follow-Up, Placebo-Controlled, Randomized Trial. Molecular Nutrition & Food Research, 56, 810-821. http://dx.doi.org/10.1002/mnfr.201100673
Bertelli, A., Bertelli, A.A., Gozzini, A. andGiovannini, L. (1998) Plasma and Tissue Resveratrol Concentrations and Pharmacological Activity. Drugs under Experimental and Clinical Research, 24, 133-138.
Petrovski, G., Gurusamy, N. and Das, D. (2011) Resveratrol in Cardiovascular Health and Disease. Annals of the New York Academy of Sciences, 1215, 22-33. http://dx.doi.org/10.1111/j.1749-6632.2010.05843.x
Dell Agli, M., Galli, G., Vrhovsek, U., Mattivi, F. and Bosisio, E. (2005) In Vitro Inhibition of Human cGMP-Specific Phosphodiesterase-5 by Polyphenols from Red Grapes. Journal of Agricultural and Food Chemistry, 53, 1960-1965. http://dx.doi.org/10.1021/jf048497+
Olas, B., Wachowicz, B., Tomczak, A., Erler, J., Stochmal, A. andOleszek, W. (2008) Comparative Anti-Platelet and Antioxidant Properties of Polyphenol-Rich Extracts from: Berries of Aronia melanocarpa, Seeds of Grape and Bark of Yucca schidigera in Vitro. Platelets, 19, 70-77. http://dx.doi.org/10.1080/09537100701708506
Stumvoll, M., Goldstein, B. andHaeften, T. (2005) Type 2 Diabetes: Principles of Pathogenesis and Therapy. Lancet, 365, 1333-1346. http://dx.doi.org/10.1016/S0140-6736(05)61032-X
Aronoff, S., Berkowitz, K., Schreiner, B. and Want, L. (2004) Glucose Metabolism and Regulation: Beyond Insulin and Glucagon. Diabetes Spectrum, 17, 183-190. http://dx.doi.org/10.2337/diaspect.17.3.183
Zunz, E. and La Barre, J. (1929) Contributiona a l’etude des variations physiologiques de la secretion interne du pancreas: relations entre les secretions externe et interne du pancreas. Archives Internationales de Physiologie, 31, 162-179.
Arora, S. and Anubhuti (2006) Role of Neuropeptides in Appetite Regulation and Obesity—A Review. Neuropeptides, 40, 375-401. http://dx.doi.org/10.1016/j.npep.2006.07.001
Tsuda, T. (2012) Dietary Anthocyanin-Rich Plants: Biochemical Basis and Recent Progress in Health Benefits Studies. Molecular Nutrition & Food Research, 56, 159-170. http://dx.doi.org/10.1002/mnfr.201100526
Chuang, C. and McIntosh, M. (2011) Potential Mechanisms by which Polyphenol-Rich Grapes Prevent Obesity-Mediated Inflammation and Metabolic Diseases. Annual Review of Nutrition, 31, 155-176. http://dx.doi.org/10.1146/annurev-nutr-072610-145149
Chuang, C., Bumrungpert, A., Kennedy, A., Overman, A., West, T., Dawson, B. and McIntosh, M. (2012) Grape Powder Extract Attenuates Tumor Necrosis Factor α-Mediated Inflammation and Insulin Resistance in Primary Cultures of Human Adipocytes. The Journal of Nutritional Biochemistry, 22, 89-94. http://dx.doi.org/10.1016/j.jnutbio.2009.12.002
Al-Awwadi, N., Azay, J., Poucheret, P., Cassanas, G., Krosniak, M. and Auger, C. (2004) Antidiabetic Activity of Red Wine Polyphenolic Extract, Ethanol, or Both in Streptozotocin-Treated Rats. Journal of Agricultural and Food Chemistry, 52, 1008-1016. http://dx.doi.org/10.1021/jf030417z
Al-Awwadi, N., Bornet, A., Azay, J., Araiz, C., Delbosc, S., Cristol, J., Linck, N., Cros, G. and Teissedre, P. (2004) Red Wine Polyphenols Alone or in Association with Ethanol Prevent Hypertension, Cardiac Hypertrophy, and Production of Reactive Oxygen Species in the Insulinresistant Fructose-Fed Rat. Journal of Agricultural and Food Chemistry, 52, 5593-5597. http://dx.doi.org/10.1021/jf049295g
Hogan, S., Canning, C., Sun, S., Sun, X. and Zhou, K. (2010) Effects of Grape Pomace Antioxidant Extract on Oxidative Stress and Inflammation in Diet Induced Obese Mice. Journal of Agricultural and Food Chemistry, 58, 11250-11256. http://dx.doi.org/10.1021/jf102759e
Hogan, S., Canning, C., Sun, S., Sun, X., Kadouh, H. and Zhou, K. (2011) Dietary Supplementation of Grape Skin Extract Improves Glycemia and Inflammation in Diet-Induced Obese Mice Fed a Western High Fat Diet. Journal of Agricultural and Food Chemistry, 59, 3035-3041. http://dx.doi.org/10.1021/jf1042773
Parry, J., Li, H., Liu, J., Zhou, K., Zhang, L. and Ren, S. (2011) Antioxidant Activity, Antiproliferation of Colon Cancer Cells, and Chemical Composition of Grape Pomace. Food and Nutrition Sciences, 2, 530-540. http://dx.doi.org/10.4236/fns.2011.26076
Livak, K. and Schmittgen, T. (2001) Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-ΔΔCT Method. Methods, 25, 402-408. http://dx.doi.org/10.1006/meth.2001.1262
Kim, W. and Egan, J. (2008) The Role of Incretins in Glucose Homeostasis and Diabetes Treatment. Pharmacological Reviews, 60, 470-512. http://dx.doi.org/10.1124/pr.108.000604
El-Alfy, A., Ahmed, A. and Fatani, A. (2005) Protective Effect of Red Grape Seeds Proanthocyanidins against Induction of Diabetes by Alloxan in Rats. Pharmacological Reviews, 52, 264-270.
Kim, H., Bartley, G., Arvik, T., Lipson, R., Nah, S. and Seo, K. (2014) Dietary Supplementation of Chardonnay Grape Seed Flour Reduces Plasma Cholesterol Concentration, Hepatic Steatosis, and Abdominal Fat Content in High-Fat Diet-Induced Obese Hamsters. Journal of Agricultural and Food Chemistry, 62, 1919-1925. http://dx.doi.org/10.1021/jf404832s
Kim, H., Kim, D., Seo, K., Chon, J., Nah, S., Bartley, G., Arvik, T., Lipson, R. and Yokoyama, W. (2015) Modulation of the Intestinal Microbiota Is Associated with Lower Plasma Cholesterol and Weight Gain in Hamsters Fed Chardonnay Grape Seed Flour. Journal of Agricultural and Food Chemistry, 63, 1460-1467. http://dx.doi.org/10.1021/jf5026373
Pezzuto, J.M. (2008) Grapes and Human Health: A Perspective. Journal of Agricultural and Food Chemistry, 56, 6777-6784. http://dx.doi.org/10.1021/jf800898p
Seeram, N.P. (2008) Berry Fruits: Compositional Elements, Biochemical Activities, and the Impact of Their Intake on Human Health, Performance, and Disease. Journal of Agricultural and Food Chemistry, 56, 627- 629. http://dx.doi.org/10.1021/jf071988k
Laight, K., Rooprai, H., Shaw, K. and Cummings, M. (2009) Effects of Grape Seed Extract in Type 2 Diabetic Subjects at High Cardiovascular Risk: A Double Blind Randomized Placebo Controlled Trial Examining Metabolic Markers, Vascular Tone, Inflammation, Oxidative Stress and Insulin Sensitivity. Diabetic Medicine, 26, 526-531. http://dx.doi.org/10.1111/j.1464-5491.2009.02727.x
Yabe, D., Kuroe, A., Watanabe, K., Iwasaki, M., Hamasaki, A., Hamamoto, Y., Harada, N., Yamane, S., Lee, S., Murotani, K., Deacon, C., Holst, J., Hirano, T., Inagaki, N., Kurose, T. and Seino, Y. (2015) Early Phase Glucagon and Insulin Secretory Abnormalities, but Not Incretin Secretion, Are Similarly Responsible for Hyperglycemia after Ingestion of Nutrients. Journal of Diabetes and Its Complications, 29, 413-421. http://dx.doi.org/10.1016/j.jdiacomp.2014.12.010
Unger, R. and Cherrington, A. (2012) Glucagonocentric Restructuring of Diabetes: A Pathophysiologic and Therapeutic Makeover. Journal of Clinical Investigation, 122, 4-12. http://dx.doi.org/10.1172/JCI60016
Drucker, D. (2013) Incretin Action in the Pancreas: Potential Promise, Possible Perils, and Pathological Pitfalls. Diabetes, 62, 3316-3323. http://dx.doi.org/10.2337/db13-0822
Holst, J. (2007) The Physiology of Glucagon-Like Peptide 1. Physiological Reviews, 87, 1409-1439. http://dx.doi.org/10.1152/physrev.00034.2006
Seino, Y. and Yabe, D. (2013) GIP and GLP-1: Incretin Actions beyond Pancreas. Journal of Diabetes Investigation, 4, 108-130. http://dx.doi.org/10.1111/jdi.12065
Christensen, M., Calanna, S. and Sparre-Ulrich, A. (2014) Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes. Diabetes, 64, 72-78. http://dx.doi.org/10.2337/db14-0440
Christensen, M., Vedtofte, L. and Holst, J. (2011) Glucose-Dependent Insulinotropic Polypeptide: A Bifunctional Glucose-Dependent Regulator of Glucagon and Insulin Secretion in Humans. Diabetes, 60, 3103-3109. http://dx.doi.org/10.2337/db11-0979
Mentis, N., Vardarli, I. and Kothe, L. (2011) GIP Does Not Potentiate the Antidiabetic Effects of GLP-1 in Hyperglycemic Patients with Type 2 Diabetes. Diabetes, 60, 1270-1276. http://dx.doi.org/10.2337/db10-1332
Taminato, T., Seino, Y. and Goto, Y. (1977) Synthetic Gastric Inhibitory Polypeptide. Stimulatory Effect on Insulin and Glucagon Secretion in the Rat. Diabetes, 26, 480-484. http://dx.doi.org/10.2337/diab.26.5.480
McIntosh, C., Demuth, H., Pospisilik, J. and Pederson R. (2005) Dipeptidyl Peptidase IV Inhibitors: How Do They Work as New Antidiabetic Agents? Regulatory Peptides, 128, 159-165. http://dx.doi.org/10.1016/j.regpep.2004.06.001
Behme, M., Dupré, J. and McDonald, T. (2003) Glucagon-Like Peptide 1 Improved Glycemic Control in Type 1 Diabetes. BMC Endocrine Disorders, 3, 3. http://dx.doi.org/10.1186/1472-6823-3-3
Dupre, J., Behme, M., Hramiak, I., McFarlane, P., Williamson, M., Zabel, P. and McDonald, T. (1995) Glucagon-Like Peptide I Reduces Postprandial Glycemic Excursions in IDDM. Diabetes, 44, 626-630. http://dx.doi.org/10.2337/diab.44.6.626
González-Abuín, N., Martínez-Micaelo, N., Blay, M., Ardévol, A. and Pinent, M. (2014) Grape-Seed Procyanidins Prevent the Cafeteria-Diet-Induced Decrease of Glucagon-Like Peptide-1 Production. Journal of Agricultural and Food Chemistry, 62, 1066-1072. http://dx.doi.org/10.1021/jf405239p
González-Abuín, N., Martínez-Micaelo, N., Blay, M., Green, B., Pinent, M. and Ardévol, A. (2014) Grape-Seed Procyanidins Modulate Cellular Membrane Potential and Nutrient-Induced GLP-1 Secretion in STC-1 Cells. American Journal of Physiology-Cell Physiology, 306, C485-C492. http://dx.doi.org/10.1152/ajpcell.00355.2013
González-Abuín, N., Martínez-Micaelo, N., Blay, M., Pujadas, G., Garcia-Vallvé, S., Pinent, M. and Ardévol, A. (2012) Grape Seed-Derived Procyanidins Decrease Dipeptidyl-Peptidase 4 Activity and Expression. Journal of Agricultural and Food Chemistry, 60, 9055-9061. http://dx.doi.org/10.1021/jf3010349
Zhang, L., Hogan, S., Li, J., Sun, S., Canning, C. Zheng, S. and Zhou, K. (2011) Grape Skin Extract Inhibits Mammalian Intestinal α-Glucosidase Activity and Suppresses Postprandial Glycemic Response in Streptozocin-Treated Mice. Food Chemistry, 126, 466-471. http://dx.doi.org/10.1016/j.foodchem.2010.11.016
Baur, J., Pearson, K., Price, N., Jamieson, H., Lerin, C., Kalra, A., Prabhu, V., Allard, S. and Lopez-Lluch, G. (2004) Resveratrol Improves Health and Survival of Mice on a High-Calorie Diet. Nature, 444, 337-342. http://dx.doi.org/10.1038/nature05354
Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X. and Shi, X. (2007) SIRT1 Improves Insulin Sensitivity under Insulin Resistance Conditions by Repressing PTP1B. Cell Metabolism, 6, 307-319. http://dx.doi.org/10.1016/j.cmet.2007.08.014
Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C. and Daussin, F. (2006) Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1Alpha. Cell, 127, 1109-1122. http://dx.doi.org/10.1016/j.cell.2006.11.013
Hokayem, M., Blond, E., Vidal, H., Lambert, K., Meugnier, E., Feillet-Coudray, C., Coudray, C., Pesenti, S., Luyton, C., Lambert-Porcheron, S., Sauvinet, V., Fedou, C., Brun, J., Rieusset, J., Bisbal, C., Sultan, A., Mercier, J., Goudable, J., Dupuy, A., Cristol, J., Laville, M. and Avignon, A. (2013) Grape Polyphenols Prevent Fructose-Induced Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients. Diabetes Care, 36, 1454-1461. http://dx.doi.org/10.2337/dc12-1652
Perez-Jimenez, J. and Saura-Calixto, F. (2008) Grape Products and Cardiovascular Disease Risk Factors. Nutrition Research Reviews, 21, 158-173. http://dx.doi.org/10.1017/S0954422408125124
Vislocky, L. and Fernandez, M. (2010) Biomedical Effects of Grape Products. Nutrition Reviews, 68, 656-670. http://dx.doi.org/10.1111/j.1753-4887.2010.00335.x
Schini-Kerth, V., Auger, C., Kim, J., Etienne-Selloum, N. and Chataigneau, T. (2010) Nutritional Improvement of the Endothelial Control of Vascular Tone by Polyphenols: Role of NO and EDHF. Pflügers Archiv, 459, 853-862. http://dx.doi.org/10.1007/s00424-010-0806-4
Barona, J., Aristizabal, J., Blesso, C., Volek, J. and Fernandez, M. (2012) Grape Polyphenols Reduce Blood Pressure and Increase Flow-Mediated Vasodilation in Men with Metabolic Syndrome. Journal of Nutrition, 142, 1626-1632. http://dx.doi.org/10.3945/jn.112.162743
Lovejoy, J., Champagne, C., Smith, S., DeLany, J., Bray, G. and Lefvre, M. (2001) Relationship of Dietary Fat and Serum Cholesterol Ester and Phospholipid Fatty Acids to Markers of Insulin Resistance in Men and Women with a Range of Glucose Tolerance. Metabolism, 50, 86-92. http://dx.doi.org/10.1053/meta.2001.19440
Mayer-Davis, E., Monaco, J., Hoen, H., Carmichael, S., Vitolins, M. and Rewers, M. (1997) Dietary Fat and Insulin Sensitivity in a Triethnic Population: The Role of Obesity: The Insulin Resistance Atherosclerosis Study (IRAS). The American Journal of Clinical Nutrition, 65, 79-87.
Flanagan, A., Brown, J., Santiago, C., Aad, P. and Spicer, L. (2008) Spicer M.T. High-Fat Diets Promote Insulin Resistance through Cytokine Gene Expression in Growing Female Rats. The Journal of Nutritional Biochemistry, 19, 505-513. http://dx.doi.org/10.1016/j.jnutbio.2007.06.005
Tanaka, S., Hayashi, T., Toyoda, T., Hamada, T., Shimizu, Y., Hirata, M., Ebihara, K., Masuzaki, H., Hosoda, K., Fushiki, T. and Nakao, K. (2007) High-Fat Diet Impairs the Effects of a Single Bout of Endurance Exercise on Glucose Transport and Insulin Sensitivity in Rat Skeletal Muscle. Metabolism, 56, 1719-1728. http://dx.doi.org/10.1016/j.metabol.2007.07.017
Ahima, R. and Flier, J. (2000) Adipose Tissue as an Endocrine Organ. Trends in Endocrinology and Metabolism, 11, 327-332. http://dx.doi.org/10.1016/S1043-2760(00)00301-5
Trujillo, M. and Scherer, P. (2006) Adipose Tissue-Derived Factors: Impact on Health and Disease. Endocrine Reviews, 27, 762-778. http://dx.doi.org/10.1210/er.2006-0033
Barnes, K. and Miner, J. (2009) Role of Resistin in Insulin Sensitivity in Rodents and Humans. Current Protein & Peptide Science, 10, 96-107. http://dx.doi.org/10.2174/138920309787315239
Rangwalam, S., Richm, A., Rhoadesm, B., Shapirom, J., Obicim, S., Rossettim, L. and Lazarm, M. (2004) Abnormal Glucose Homeostasis Due to Chronic Hyperresistinemia. Diabetes, 53, 1937-1941. http://dx.doi.org/10.2337/diabetes.53.8.1937
Kim, K., Lee, K., Moon, Y. and Sul, H. (2001) A Cysteine-Rich Adipose Tissue-Specific Secretory Factor Inhibits Adipocyte Differentiation. The Journal of Biological Chemistry, 276, 11252 -11256. http://dx.doi.org/10.1074/jbc.C100028200
Ouchi, N., Parker, J., Lugus, J. and Walsh, K. (2011) Adipokines in Inflammation and Metabolic Disease. Nature Reviews Immunology, 11, 85-97. http://dx.doi.org/10.1038/nri2921
Hotamisligil, G., Arner, P., Caro, J., Atkinson, R. and Spiegelman, B. (1995) Increased Adipose Expression of Tumor Necrosis Factor-Alpha in Human Obesity and Insulin Resistance. Journal of Clinical Investigation, 95, 2409-2415. http://dx.doi.org/10.1172/JCI117936
Hotamisligil, G., Shargill, N. and Spiegelman, B. (1993) Adipose Expression of Tumor Necrosis Factor-Alpha: Direct Role in Obesity-Linked Insulin Resistance. Science, 259, 87-91. http://dx.doi.org/10.1126/science.7678183
Tomé-Carneiro, J., Gonzálvez, M., Larrosa, M., Yáñez-Gascón, M., García-Almagro, F., Ruiz-Ros, J., Tomás-Barberán, F., García-Conesa. M. and Espín. J. (2013) Grape Resveratrol Increases Serum Adiponectin and Downregulates Inflammatory Genes in Peripheral Blood Mononuclear Cells: A Triple-Blind, Placebo-Controlled, One-Year Clinical Trial in Patients with Stable Coronary Artery Disease. Cardiovascular Drugs and Therapy, 27, 37-48. http://dx.doi.org/10.1007/s10557-012-6427-8