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© 2015 Michelle Hause Johnson © 2015 Michelle Hause Johnson ANTHOCYANINS AND PROANTHOCYANIDINS FROM BLUEBERRY AND BLACKBERRY FERMENTED BEVERAGES TO REDUCE INFLAMMATION AND TYPE-2 DIABETES: A COMPREHENSIVE IN VITRO AND IN VIVO EVALUATION BY MICHELLE HAUSE JOHNSON DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Nutritional Sciences in the Graduate College of the University of Illinois at Urbana-Champaign, 2015 Urbana, Illinois Doctoral Committee: Professor John Erdman, Jr., Chair Professor Elvira de Mejia, Director of Research Professor Gregory Freund Professor Jack Juvik Professor Mary Ann Lila, North Carolina State University ABSTRACT Type-2 diabetes is a serious metabolic disease that currently affects 9.3% of the U.S. population and is aggravated by diets low in fruit and vegetable intake leading to postprandial oxidative stress and inflammation [1, 2]. Berries are one of the richest dietary sources of polyphenolic compounds associated with decreased markers of chronic inflammation and decreased risk for type-2 diabetes [3,4], specifically anthocyanins [5] (ANC) and proanthocyanidins (PAC), polymerized forms of ANC and other phenolics [6]. Fermentation is a feasible way to increase phenolic content of berry juice products, and fermented products may be more bioactive than their unfermented counterparts, thus increasing the potential for health benefits [7]. Our long-term goal, as outlined in Chapter 1, was to fill the gap of knowledge in understanding the mechanisms by which dietary bioactives found in fermented berry beverages contribute to the management of type-2 diabetes using in vitro enzymatic kinetics, analytical assays, computational modeling, in vitro cell culture, and in vivo animal feeding trials. A review of the literature focusing on the role of berries to reduce diabetes is presented in Chapter 2. Our research focused on the evaluation and potential mechanisms of action of alcohol- free blueberry (Vaccinium corymbosum) and blackberry (Rubus spp.) fermented beverages and their bioactive ANC and PAC components to reduce inflammation and type-2 diabetes in vitro and in vivo through the aims introduced in Chapter 3. First we prepared blueberry and blackberry wines that were comparable to those commercially available (Chapter 4), and found that blueberries and their wine, especially when fermented at cold temperature, contain phenolic compounds that act as antioxidants and potential inhibitory factors of starch-cleaving enzymes that could be used to limit glucose absorption (Chapter 5). We then generated ANC- and PAC- enriched fractions and found that blueberry and blackberry ANC and PAC inhibited expression of proteins in the NF-κB-mediated pathway in macrophages, indicating potential to reduce chronic inflammation associated with hyperglycemia (Chapter 6). ANC were found to bind strongly within active pockets of dipeptidyl-peptidase IV (DPP-IV), an incretin-cleaving target of diabetes therapy, to effectively reduce its activity (IC50 = 4.0 μM) (Chapter 7). ANC were also able to reduce the inflammatory cross-talk between macrophages and adipocytes (Chapter 8). Further, ANC increased insulin secretion from pancreatic β-cells by 233 and 100 µIU insulin/mL directly and after epithelial transport, respectively, due to reduced DPP-IV expression and up- ii regulated insulin-receptor associated genes and proteins (Chapter 9). Lastly, in Chapter 10 we established the role of phenolic compounds in 30:70% blueberry-blackberry alcohol-free fermented beverage to reduce body weight (BW) gain (10.3 vs. 16.7 g), fat mass (18.0 vs. 31.3% BW), and fasting blood glucose (184 vs. 222 mg/dL), in diet-induced obese C57BL/6j mice consuming ANC beverage vs. water, (p < 0.05). There were some adverse effects noted at the highest dose, warranting future studies into the optimal dose of phenolic compounds extracted and concentrated from the alcohol-free fermented blueberry-blackberry beverage. These results, as summarized in Chapter 11, suggest that ANC in blueberry and blackberry fermented beverages are beneficial sources of antioxidants, decrease glucose absorption, and inhibit inflammation and DPP-IV, and therefore could be used in the management of type-2 diabetes. 1. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2014. Atlanta, GA: U.S. DHHS, Centers for Disease Control and Prevention, 2014. 2. Jennings A, Welch AA, Spector T, Macgregor A, Cassidy A. (2014) Intakes of anthocyanins and flavones are associated with biomarkers of insulin resistance and inflammation in women. J Nutr 144(2):202-8. 3. Ley SH, Hamdy O, Mohan V, Hu FB. (2014) Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet 383(9933):1999-2007. 4. van Dam RM, Naidoo N, Landberg R. (2013) Dietary flavonoids and the development of type 2 diabetes and cardiovascular diseases: review of recent findings. Curr Opin Lipidol 24(1):25-33. 5. Wu X, Beecher GR, Holden JM, Haytowitz DB, Gebhardt SE, Prior RL. (2006) Concentrations of anthocyanins in common foods in the United States and estimates of normal consumption. J Agric Food Chem. 54, 4069-4075. 6. Wedick NM, Pan A, Cassidy A, Rimm EB, Sampson L, Rosner B, Willett W, Hu FB, Sun Q, van Dam RM. (2012) Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. Am J Clin Nutr 95: 925-33. 7. Su MS, Chien PJ. (2007) Antioxidant activity, anthocyanins, and phenolics of rabbiteye blueberry (Vaccinium ashei) fluid products as affected by fermentation. Food Chem 104:182- 187. iii ACKNOWLEDGMENTS I would like to thank my doctoral advisor Dr. Elvira de Mejia for her support and motivation to complete the work described in this dissertation, for providing a laboratory experience that spans from food chemistry to disease mechanism, and for being an example of confidence and execution. I would also like to thank the members of my committee, Drs. Erdman, Freund, Juvik, and Lila for their time and contributions to my project, including Dr. William Artz for being on my committee for the first two years of my graduate studies. I would especially like to thank Dr. Lila for welcoming me into her lab at the Plants for Human Health Research Institute in Kannapolis, North Carolina to learn more about blueberries and to complete the phenolic extraction procedures. My research experience was supported by the lab team of all the current and former de Mejia lab members and visiting scholars, of whom I’d like to thank especially Vermont Dia and Jodee Johnson for training and support. I would also like to thank my collaborating visiting scholars Diego Garcia, for work with the adipocytes, and Junfeng Fan for work with the computational modeling. This work would not have been possible without the assistance of my undergraduate mentees in Food Science and Human Nutrition over the years (including Anita Lucius, Tessa Meyer, Mellisa Yu, Ally Meyer, Julia Amador, Valerie Munoz, Starr’Retiece Gibson, Luis M Real Hernandez, Lauren Hall, and Cheng Lu, among all the undergraduates working in our laboratory). Thanks to the Division of Nutritional Sciences for supporting my travel to scientific conferences and many opportunities for research funding and collaborating. I also want to thank Dr. Hartke, Dr. Johnson, Arena Jackson, and Ashley Brown in the DNS office for their excellent administrative assistance and support during my graduate studies. It has been a joy to be surrounded by all the graduate students in DNS for making my grad school experience a friendly and collaborative environment in which to learn and to conduct research. Finally, I want to thank my family for their unconditional support throughout my life and during grad school, particularly my mom and my sister for editing several of my papers and applications. None of my successes would have been possible without their love and encouragement. iv TABLE OF CONTENTS CHAPTER 1: OVERALL HYPOTHESES AND OBJECTIVES ............................................... 1 GENERAL INTRODUCTION ............................................................................... 2 CHAPTER 2: LITERATURE REVIEW: DIABETES AND BERRIES ...................................... 7 CHAPTER 3: OBJECTIVES ...................................................................................................... 46 CHAPTER 4: COMPARISON OF CHEMICAL COMPOSITION AND ANTIOXIDANT CAPACITY OF COMMERCIALLY AVAILABLE BLUEBERRY AND BLACKBERRY WINES IN ILLINOIS ........................................................................................................... 48 CHAPTER 5: CULTIVAR EVALUATION AND EFFECT OF FERMENTATION ON ANTIOXIDANT CAPACITY AND IN VITRO INHIBITION OF α-AMYLASE AND α- GLUCOSIDASE BY HIGHBUSH BLUEBERRY (Vaccinium corombosum) .................... 72 CHAPTER 6: ANTHOCYANINS AND PROANTHOCYANIDINS FROM BLUEBERRY- BLACKBERRY FERMENTED BEVERAGES INHIBIT MARKERS OF INFLAMMATION IN MACROPHAGES AND CARBOHYDRATE-UTILIZING ENZYMES IN VITRO ........................................................................................................... 97 CHAPTER 7: BERRY AND CITRUS PHENOLIC COMPOUNDS INHIBIT DIPEPTIDYL PEPTIDASE IV: IMPLICATIONS IN DIABETES MANAGEMENT ............................. 135 CHAPTER 8: ANTHOCYANINS FROM FERMENTED BERRY BEVERAGES INHIBIT INFLAMMATION-RELATED ADIPOSITY RESPONSE IN VITRO .............................. 164 CHAPTER 9: ANTHOCYANINS FROM FERMENTED BERRY BEVERAGES INCREASED INSULIN SECRETION FROM PANCREATIC Β-CELLS IN VITRO BEYOND THEIR
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