2011 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 are involved in most pathogenic processes that promote the development of chronic diseases including obesity, hypertension, diabetes, cardiovascular diseases, cancer, and Alzheimer’s disease. One of the key components in controlling these diseases is to control the declines in insulin sensitivity associated with eating unhealthy diets, including those high in refined sugars and fat. In FY2011 we demonstrated in an animal model that cinnamon prevents the onset of insulin resistance resulting from eating a diet high in a refined sugar, fructose. We also demonstrated that extracts of cinnamon regulate the expression of multiple genes controlling insulin function in fat cells.
The health benefits of fruits, vegetables, and plants are widely recognized and their major phytochemicals are relatively well-documented. However, there is still little information regarding the potential beneficial effects of phenolic conjugates such as caffedymine-type phenylpropenoic acid amides and safflomide-type phenylpropenoic acid amides on inflammation, obesity, and hypertension. In FY2011 safflomide and analogues from plant sources (e.g., coffee, coco, garlic, green onion, spices, and herbs) were investigated and found to have significant anti-oxidant, anti-inflammatory, and serotonergic activities. These compounds are involved in quenching reactive oxygen species, inhibiting COX enzymes and NO synthase, and modulating serotonin receptor-related effects associated with chronic diseases conditions such as inflammation, obesity, and hypertension. In addition, we investigated the effects of secoisolariciresinol diglucoside lignan found in flaxseed on obesity and blood pressure, and initiated an animal study to determine the effects of safflomide and analogues on inflammation, obesity, and hypertension.
Cinnamon added to the diet of rats fed a diet high in fat and fructose prevented the decline in insulin function and onset of the risk factors associated with the metabolic syndrome. The metabolic syndrome is often an early stage of type 2 diabetes in which insulin becomes inefficient followed by higher levels of insulin production by the pancreas that ultimately leads to diminution of pancreatic function and type 2 diabetes. The high fat/high fructose diet also induced a reduction in pancreatic weight that was prevented by the addition of cinnamon to the diet. There was an abnormal accumulation of fat in rats consuming the high fat/high fructose diet that was alleviated by cinnamon. An extract of cinnamon was also shown to regulate genes critical to the uptake of glucose and the function of insulin in isolated fat cells. In summary, these results indicate that components of cinnamon may be important in the prevention of insulin resistance and possibly unhealthy body fat distribution. This is important in the preservation of proper insulin function and the prevention and alleviation of risk factors of the metabolic syndrome, type 2 diabetes, and related diseases including hypertension, cardiovascular diseases, some forms of cancer and Alzheimer’s disease.
Cao, H., Graves, C.J., Anderson, R.A. 2010. Cinnamon extract regulates glucose transporter and insulin-signaling gene expression in mouse adipocytes. Phytomedicine. 17(3):1027-1032.
Cao, H., Anderson, R.A. 2011. Cinnamon polyphenol extract regulates tristetraprolin and related gene expression in mouse adipocytes. Journal of Agricultural Food & Chemistry. 59(6):2739-2744.
Park, J.B. 2011. Identification and quantification of a major anti-oxidant and anti-inflammatory phenolic compound found in basil, lemon, thyme, mint, oregano, rosemary, sage, and thyme. International Journal of Food Sciences and Nutrition. 62(6):577-584.
Couturier, K., Batandier, C., Awada, M., Hininger, I., Canini, F., Anderson, R.A., Leverve, X., Roussel, A. 2010. Cinnamon improves insulin sensitivity and alters body composition in an animal model of the metabolic syndrome. Archives Of Biochemistry and Biophysics. 501(1):158-61.
Puch, F., Benaraba, R., Hazane, F., Valenti, K., Osman, M., Laporte, F., Favier, A., Anderson, R.A., Roussel, A., Hininger, I. 2010. Chromium III histidinate exposure modulates antioxidant gene expression in HaCaT human keratinocytes exposed to oxidative stress. Biological Trace Element Research. (137):23-39.
Panickar, K.S., Anderson, R.A. 2011. Mechanisms underlying the protective effects of myricetin and quercetin following oxygen/glucose deprivation-induced cell swelling and the reduction in glutamate uptake in glial cells. Journal of Neuroscience. 183:1-14.
Park, J.B. 2011. Protective effects of veskamide, enferamide, becatamide, and oretamide on H2O2-induced apoptosis of PC-12 cells. Phytomedicine. 18(10):843-847.