2006 Annual Report 1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? Why does it matter? This project is part of the National Program 107 in Human Nutrition that relates to components of the research in “Relationship between Diet, Genetics, Lifestyle, and the Prevention of Obesity and Disease,” and “Nutrient Requirements.” Diabetes is one of the leading causes of lost productivity and death, but the real causes of diabetes are not fully understood. For the majority of people, the most important factors in controlling diabetes are the foods and nutrients consumed. Additional research is urgently needed to define foods and nutrients that play key roles in chronic diseases. One essential nutrient that has been shown to alter the risk factors associated with type 2 diabetes and cardiovascular diseases is chromium. Dietary intake of chromium is an important human health concern, since total intake of chromium is suboptimal and diets with high amounts of simple sugars, which are common in most Westernized diets, facilitate chromium loss. There are also other insulin-potentiating compounds found in plants that may improve insulin activity and prevent or alleviate glucose intolerance and diabetes. The objectives of the research are:. 1)Elucidate the role of chromium in the onset of impaired glucose metabolism using a stress induced rat model for chromium deficiency;. 2)Elucidate methods to assess chromium status and to determine its roles in human nutrition;. 3)Elucidate the role and mechanistic effects of insulin potentiating polyphenols from cinnamon on intracellular signals that regulate glucose uptake and oxidative stress; and. 4)Define the safety and antioxidant effects of chromium, cinnamon, and other naturally occurring, insulin-potentiating factors. The impact of the research will provide safe and effective food components that can improve insulin activity and reduce chronic disease in the U.S. population. 2.List by year the currently approved milestones (indicators of research progress) Milestone 1 (1–5 years) – Determine the role of chromium in the onset of impaired glucose metabolism in a stress-induced rat model: Year 1 - Ascertain deficiency using dexamethasone. Year 2 - Raise chromium deficient rats for stress-induced model, optimize conditions, and evaluate deficiency. Year 3 - Initiate immune and physiological studies. Year 4 - Analyse data and prepare for publication. Year 5 - Complete additional analysis for chromium deficiency and transfer technology. Milestone 2 (1–5 years) – Assess methodology for chromium status and elucidate its functions in human nutrition: Year 1 - Verify collections and conditions, check for chromium contamination, and perfect analytical measurements. Years 2 and 3 - Verify tissues and conditions and conduct chromium measurements in urine and plasma. Year 4 - Measure red blood cell chromium levels and analyze data. Year 5 - Collate data and finalize manuscripts along with technology transfer. Milestone 3 (1–5 years) – Define the mechanism of insulin-potentiating polyphenols from cinnamon on intracellular signals that regulate insulin-induced glucose uptake and oxidative stress. Year 1 - Initiate animal and tissue culture studies, and evaluate oxidative stress. Years 2 and 3 - Conduct feeding studies of cinnamon and isolated polyphenols from cinnamon in a rat model. Year 4 - Evaluate intracellular signaling pathways using polymerase chain reaction and protein detection technology. Year 5 - Analyze data and interpret mechanistic studies for publication and technology transfer. 4a.List the single most significant research accomplishment during FY 2006. Cinnamon improves factors associated with cardiovascular diseases in people with type 2 diabetes: This project is part of the National Program 107 in Human Nutrition that relates to components of the research in “Relationship between Diet, Genetics, Lifestyle, and the Prevention of Obesity and Disease”, and “Nutrient Requirements.” Hypertension is one of the leading risk factors of cardiovascular diseases. Factors that improve insulin often also improve hypertension. It has been shown that cinnamon improves cholesterol, triglycerides, and related factors associated with cardiovascular diseases in people with type 2-diabetes. The purpose of the present study was to examine the effects of dietary cinnamon on blood pressure in a strain of rats with increased sensitivity to eating sugar. Addition of cinnamon to the diets of rats consuming added sugar reduced the sugar-induced blood pressure to virtually the same level as those not consuming sugar. The addition of cinnamon to the diet also decreased the blood pressure of rats not consuming sugar suggesting that cinnamon reduces more than just sugar-induced blood pressure elevations, but perhaps a component(s) of basal metabolism as well. This study was completed in conjunction with scientists from Georgetown University Medical School, and a study entitled, “Whole cinnamon and aqueous extracts ameliorate sucrose-induced blood pressure elevations in spontaneously hypertensive rats”, was published in the journal of the American College of Nutrition 25(2):144-150, 2006. Cinnamon is used for flavor and taste in food preparation, but cinnamon may have additional roles in the control of hypertension. It may be possible to aid in controlling hypertension by not only limiting the amounts of dietary substances that have negative effects but also the addition of beneficial ones, such as cinnamon, that have positive effects on hypertension. This work will be of importance to the scientific and medical communities, but also to the millions of people who take drugs to control hypertension. 4b.List other significant research accomplishment(s), if any. B. Other significant accomplishment: Chromium deficiency may represent a risk factor for cardiovascular diseases: This project is part of the National Program 107 in Human Nutrition that relates to components of the research in “Relationship between Diet, Genetics, Lifestyle, and the Prevention of Obesity and Disease”, and “Nutrient Requirements.” The incidence of type 2 diabetes, one of the leading causes of morbidity and mortality, is increasing at an alarming rate. Experimental and clinical studies demonstrate that chromium supplementation often improves the signs and symptoms of diabetes including elevated blood sugar, fats, and insulin. Because these factors have potential roles in the development of atherosclerosis, chromium deficiency may represent a risk factor for cardiovascular diseases. In conjunction with scientists from Ljubljana University Medical Center, Ljubljana, Slovenia, changes in heart function, similar to those that are measured during a routine electrocardiogram, were measured to determine if the heart function of people with diabetes improved when chromium intake improved. It was demonstrated that cardiac interval pulse prolongation, which has been shown to be a powerful predictor of total mortality, cardiac death, and future stroke in patients with type 2 mellitus, improved when chromium intake improved. This work will be of importance to the medical community involved in diabetes and cardiovascular diseases, but also the lay public for improved health. 4c.List significant activities that support special target populations. C. Significant activities that support special target populations: People with glucose intolerance or diabetes can be a target of improved nutrition to help prevent and/or control diabetes; minority populations in the U.S. where economic and social factors limit appropriate food choices are especially vulnerable. There is also a need for preventative strategies in developing countries where people may not have access to or cannot afford therapy including drugs. Chromium intake of people from Tunisia displayed large seasonal variations which may be related to specific ethnic foods; and increased intake of chromium was associated with reduced risk factors of diabetes and cardiovascular disease. The seasonal variation in chromium was not observed in subjects from the U.S. Other work with people with diabetes demonstrate that small dietary changes, such as adding roughly one half teaspoon of cinnamon per day to the diet, can lead to significant decreases in risk factors associated with diabetes and cardiovascular diseases. 5.Describe the major accomplishments to date and their predicted or actual impact. Type 2 diabetes and cardiovascular diseases are major contributors to poor health status of the U.S. population and a major drain on the health care system. Simple and inexpensive adjustments to diet that improve insulin function and lead to reductions in cardiac pathologies would have significant impact on the broad spectrum of the population where health care opportunities are limited. The research in this project has demonstrated that the risk factors associated with type-2 diabetes and cardiovascular diseases can be alleviated by compounds that improve insulin function, including chromium and other insulin-potentiating factors found in foods, herbs, and spices. Modern diets that are high in fats, sugars, and other refined components are also low in chromium and other potentiators of insulin action. In addition, consumption of these foods increases chromium losses and this, coupled with a low intake of foods high in factors that improve insulin function, may lead increased risk factors of diabetes and cardiovascular diseases, including elevated blood sugars and fats. These factors have significant negative effects on health and are likely related to the large recent increases in the incidence of type 2 diabetes mellitus and obesity. Collaborative studies with scientists under a joint Israel-U.S. proposal entitled, "Spices, Medicinal Plants and Yeasts as Dietary Sources for Antioxidant, Lipid Lowering and Hypoglycemic Materials," addressed the need to find biologically active compounds in foods that can improve efficient glucose utilization. The early work in the project led to a joint human study project entitled "Chromium and Insulin Action" that is funded by the National Institutes of Health. These studies are designed to determine the mode of action of chromium and methods to determine chromium status in humans. Earlier studies in animal models to examine chromium deficiency and to elucidate its mode of action will be expanded during the life of the current project. Last year the work was expanded with an additional Cooperative Research and Development Agreement partner to characterize natural polyphenols that function in insulin potentiation and also function as antioxidants. A group of scientists from Iowa State University that is proficient in natural product synthesis was enlisted to synthesize polyphenols for testing as insulin potentiators and antioxidants to understand the function of naturally occurring polyphenols. Safety and efficacy of polyphenols found in cinnamon is being monitored in cell culture, animal, and human studies to ascertain natural products that decrease risk factors associated diabetes and cardiovascular diseases. The impact of the work will provide important information on the nutritional needs of the diverse U.S. population, and on trace element nutrition to determine requirements, bioavailability, and health consequences of suboptimal nutrient intakes. Several collaborative studies have been prepared and submitted to document the products of the research including. 1)the effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome;. 2)the effects chromium status on rats subjected to thermic stress; and. 3)the absence of DNA damage in cultured cells exposed to chromium. 6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? The benefits of the work have already been transferred to the general population in that millions of people are improving their chromium intake due in part to the published studies. A patent entitled “Chromium Histidine Complexes as Nutrient Supplements” was issued February 10, 2004, and two companies have been granted licenses. In addition, a reimbursable agreement has been initiated with Pennington Biomedical Research Center and funded through the National Institutes of Health for project 1235-51520-037-04R, entitled “Chromium as adjuvant therapy for type 2 diabetes and impaired glucose tolerance.” This project is a double-blind placebo controlled randomized study to determine the mode of action of chromium in people with type 2 diabetes. The form of Cr will be Cr picolinate at 1,000 µg of Cr per day for 24 weeks with 56 subjects in the Cr group and an equal number in the placebo group. The cinnamon studies have led to two cooperative research agreements, including a multiyear project, with funding for two human studies to substantiate observations made from the research. The multiyear cooperative research and development agreement with Polyphenol Technologies Corporation is project 1235-51520-037-05T, entitled “Polyphenol Complexes Similar to Those Found in Cinnamon as Nutrient Supplements and Food Additives.” The research, to date, has shown that aqueous extracts of the most commonly consumed spice, cinnamon, improve the action of insulin and help to control risk factors associated with diabetes including, glucose, insulin, cholesterol, triglycerides and related variables. The other project with Integrity Neutraceuticals International is 1235-51520-037-06T, entitled” Insulin Enhancing Products from Cinnamon.” Water-soluble polyphenolic polymers have been isolated and characterized from cinnamon that increase insulin-dependent in vitro glucose metabolism roughly 20-fold and also function as antioxidants. Since these compounds improve the action of insulin and therefore control blood sugar, it is postulated that adding these compounds to foods high in sugar will lead to decreased negative effects associated with eating high sugar foods. Cooperative research with scientists at the Joseph Fourier University has been established to expand the scope of the work towards development of useable products under project 1235-51520-037-03N, entitled “Naturally occurring insulin enhancing factors.” The research has already demonstrated the beneficial effects of chromium, cinnamon and tea extracts as they relate to oxidative stress and insulin action. In addition, this project will evaluate the nutritional chromium status of European elderly, and the safety of different forms of chromium in cell culture systems. 7.List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below). A summary of the cinnamon research has been added to the Beltsville Area Website http://www.ars.usda.gov/is/pr/2004/040419.htm. Cinnamon articles have been the subject of numerous newspaper and magazine articles; an internet search will produce hundreds of articles in the lay press that are related to research completed in this project. Review Publications Preuss, H.G., Echard, B., Polansky, M.M., Anderson, R.A. 2006. Whole cinnamon and aqueous extracts ameliorate sucrose-induced blood pressure elevations in spontaneously hypertensive rats. Journal of the American College of Nutrition. 25(2):144-150. Anderson, R.A., Sandre, C., Bryden, N.A., Agay, D., Chancerelle, Y., Polansky, M.M., Roussel, A.M. 2006. Burn-induced alterations of chromium and the glucose/insulin system in rats. Burns. 32(1):46-51. Anderson, R.A. 2006. Chromium: Roles in the Regulation of Lean Body Mass and Body Weight. In: Encyclopedia of Dietary Supplements, 1st Edition, Coates, P., Blackman, M., Cragg, G., Levine, M., Moss, J., White, J., Eds,; Marcel Dekker, Inc., New York, NY. Anderson, R.A. 2005. Chromium: recent studies regarding nutritional roles and safety. Nutrition Today. 40(4):189-195. Vrtovec, M., Vrtovec, B., Briski, A., Kocijancic, A., Anderson, R.A., and Radovanevic, B. 2005. Chromium supplementation shortens QTc interval duration in patients with type 2 diabetes. American Heart Journal. 149(4): 632-639. Lampke, S.M., Pavlovich, J., Polansky, M.M., Anderson, R.A., Graves, D.J. 2006. Activation of insulin-like activity of proanthocyanidins from cinnamon. Journal of Federation of American Societies for Experimental Biology. 20:A939. Diaz, M., Watkins, B., Li, Y., Campbell, W., Anderson, R.A. 2006. Chromium picolinate and conjugated linoleic acid: effects on diet and exercise-induced changes in metabolic and cardiovascular health indexes in overweight women (abstract). Journal of Federation of American Societies for Experimental Biology. 20:A592. Cao, H., Polansky, M.M., Anderson, R.A. 2007. Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin recepter, and glucose transporter 4 in mouse 3T3-L1 adipocytes. Archives Of Biochemistry and Biophysics. 459:214-222. Khan, A., Qadir, S., Kattak, K., Anderson, R.A. 2006. Cloves improve glucose, cholesterol, and triglycerides of people with type 2 diabetes mellitus [abstract]. Journal of Federation of American Societies Experimental Biology. 20(5):A990:640.3. Anderson, R.A., Cefalu, W. 2006. Chromium. In: Coates, P., Blackman, M., Cragg, G., Levine, M., Moss, J, White, J., editors. Encyclopedia of Dietary Supplements, First Ed., pp175-189. Online Updates. New York, NY, Marcel Dekker, Inc. Available: http://www.dekker.com/sdek/abstract~db=enc~content=a713623441.