2009 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.
Disturbances in insulin metabolism, especially insulin resistance, play a role in most pathogenic processes that promote the development of chronic diseases including hypertension and Alzheimer’s diseases. Central insulin resistance is thought to be a trigger to Alzheimer’s disease and type 2 diabetes mellitus which also share several molecular processes that underlie their respective degenerative developments. Previously studies by scientists in the Diet, Genomics, and Immunology Laboratory have shown that cinnamon polyphenols improve insulin function in vitro, in experimental animals, and in humans. In this reporting year studies involving rats fed a high fat/high fructose diet to induce insulin resistance were initiated and demonstrated that cinnamon prevents the negative effects of the diet-induced insulin resistance. Using a cell culture model, that cellular-based brain abnormalities were prevented and reversed by an extract of cinnamon containing several polyphenols, as well as isolated, purified, individual type A polyphenols that also improve insulin sensitivity. Green tea polyphenols were also effective.
Health benefits of fruits and vegetables are well documented; however, there is still little information regarding the potential beneficial effects of phenolic conjugates found in plants on hypertension. Unfortunately, studies of phenolic conjugates have been severely hindered because these compounds are not commercially available, which is often an important requirement to study specific effects of a compound. In this reporting year significant progress has been made in the identification, isolation, and/or syntheses of several phenolic conjugates including caffedymine-type and safflomide-type phenylpropenoid acid amides and chlorogenic acid found in coffee, cocoa, garlic, green onion, and others. In vitro culture systems were developed to test the effects of these phenolic conjugates on the cellular and molecular events critical to the initiation and/or progression of inflammation and hypertension.
Polyphenols extracted from cinnamon and from green tea, which can improve insulin function, were found to decrease cell swelling and reverse abnormal energy (mitochrondrial) function in brain cells in an in vitro system. Brain cells (C6 glial cells) were deprived of oxygen and glucose to mimic brain damage associated with brain swelling and strokes. When compared with control cells not deprived of oxygen or glucose, deprivation increased cell volume by 34%, indicating significant cell swelling. This increase was blocked by cinnamon and green tea polyphenols, as well as by insulin, but not by conventional antioxidants including vitamin E and resveratrol or by typical chemical blockers of oxidative/nitrosative stress. Mitochondrial dysfunction, a key component of injury due to the decreased blood flow seen in strokes---and which contributes to cell swelling---was also blocked by cinnamon and green tea polyphenols. These results showed that cinnamon and green tea polyphenols reduced brain cell swelling, as well as improved mitochondrial function, independent of changes in antioxidant capacity of the cell, and likely by improvements associated with insulin function in this cell system.
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Panickar, K.S., Polansky, M.M., Anderson, R.A. 2009. Green tea polyphenols attenuate glial swelling and mitochondrial dysfunction following oxygen-glucose deprivation in cultures. Nutritional Neuroscience.
Panickar, K.S., Polansky, M.M., Anderson, R.A. 2009. Cinnamon polyphenols attenuate cell swelling and mitochondrial dysfunction following oxygen-glucose deprivation in glial cells. Journal of Experimental Neurology. 216:420-429.