Location: Diet, Genomics and Immunology Laboratory2010 Annual Report
1a. Objectives (from AD-416)
This project is based on the premise that many chronic diseases, including type 2 diabetes, cardiovascular diseases (CVD), and Alzheimer’s disease (AD), are strongly influenced by insulin resistance. The hypothesis is that diets that lead to improved insulin sensitivity will decrease risk factors to prevent and alleviate these diseases. We propose to evaluate the following objectives: Objective 1: To determine the role of insulin-potentiating, antioxidant polyphenols on improved brain insulin signaling, cognitive function, and antioxidant status in rats fed a high fat, high fructose diet to induce insulin resistance and obesity. Objective 2: To examine the mechanisms by which antioxidant polyphenols (from cinnamon, tea, coffee, and chocolate) protect neural cells from varying levels of glucose and beta-amyloid toxicity. Objective 3: To determine the roles of these polyphenols on the renin-angiotensin system in the heart and related organs via determining their potential effects on potential mediators such as inflammatory cytokines, nitric oxide synthase, NF-kB, ACE, PPARs, serotonin receptors, and adrenoceptors.
1b. Approach (from AD-416)
The epidemic of insulin resistance associated with obesity, metabolic syndrome, type 2 diabetes, and cardiovascular diseases (CVD) is sweeping both developed and emerging countries. Insulin resistance has been implicated in the pathogenesis of Alzheimer’s disease (AD) and the term “type 3 diabetes” has been used to describe AD. Moreover, obesity has been recognized as an important risk factor for AD. Diets high in fat and (or) fructose contribute prominently to insulin resistance. We have recently shown in animal and human studies that cinnamon polyphenols, and related compounds, not only improve insulin function but also act as antioxidant and anti-inflammatory compounds to counteract the negative effects of insulin resistance and obesity. This proposal is designed to test the hypothesis that insulin-potentiating polyphenols from cinnamon, coffee, tea, and chocolate will alleviate insulin resistance and related diseases including CVD and AD. Insulin resistance and related pathologies will be induced by feeding rats diets high in fat and fructose. The effects of insulin potentiating polyphenols on insulin resistance, brain insulin signaling, AD-like neuropathology, cognitive function, antioxidant status, hypertension, and the renin-angiotensin system will be evaluated. Cell culture studies will also be used to elucidate the mechanisms of actions of polyphenols and related compounds derived from natural products. Verification of our hypothesis will support the use of natural products containing insulin-potentiating polyphenols, and related compounds, as important nutritional components for the prevention or decreasing risk of chronic diseases including diabetes, CVD, and AD.
3. Progress Report
Disturbances in insulin metabolism are involved in most pathogenic processes that promote the development of chronic diseases including obesity, hypertension, diabetes, cardiovascular diseases, cancer, and Alzheimer’s disease. This year, we demonstrated that components of cinnamon may be important in the prevention and/or alleviation of Alzheimer’s disease by preventing and reversing the formation of brain isolated tau filaments which are thought to be important in the development of Alzheimer’s disease. In cell and animal models, cinnamon components were shown to prevent the formation of new blood vessels needed for the growth of new cells related to cancer and obesity. In a rodent model, water extracts of cinnamon and green tea were also shown to be beneficial in the regulation of the formation of lipoproteins involved in cardiovascular disease and inflammation. Health benefits of fruits, vegetables, and plants are well documented in epidemiological studies; however, there is still little information regarding the potential beneficial effects of phenolic conjugates typically found in these foods (e.g., caffedymine-type phenylpropenoic acid amides and safflomide-type phenylpropenoic acid amides) on inflammation and hypertension. Unfortunately, these phenolic conjugates are not commercially available, and studies of their activity and mechanism of action have been hindered severely. This year, several phenolic conjugates (including caffedymine-type and safflomide-type phenylpropenoid acid amides, rosmarinic acid, and chlorogenic acid) found in coffee, cocoa, garlic, green onion, spices, and herbs were isolated or synthesized to investigate their action on cyclooxygenase (COX), lipoxygenase (LOX), and related enzymes in animal models to determine their effects on these important enzyme systems which are involved with initiation or progression of inflammation. In vitro culture systems were also utilized to determine potential effects of these phenolic conjugates on radical quenching, catalase, peroxidase, COX, LOX, and others enzymes that are, critically associated with the initiation and/or progression of inflammation and hypertension. Specific phenolic conjugates (N-caffeoyltyramine, N-feruloyltyramine, and other phenylpropenoic acid amides) found in coffee, cocoa, tea, garlic, green onion, spices, and herbs can affect human chronic diseases such as inflammation and hypertension. We identified and/or isolated many of the previously defined compounds and determined their potential effects, using a rodent model, on inflammation and hypertension processes, including COX and related enzymes. The results of these studies indicated that the amides found in plants are able to inhibit COX, LOX, and related enzymes that are critically associated in the inflammatory processes related to hypertension.
Peterson, D.W., George, R.C., Scaramozzino, F., Lapointe, N.E., Anderson, R.A., Graves, D.J., Lew, J. 2009. Cinnamon extract inhibits tau aggregation associated with Alzheimer’s Disease in vitro. Journal of Alzheimer's Disease. 17(3):585-597.