2012 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. This year we continued our studies demonstrating that insulin resistance leads to changes in insulin signaling in the brain and also changes in behavior of rats. The detrimental effects on insulin function in the brain were also associated with negative effects on parameters related to Alzheimer’s disease including amyloid precursor protein and tau (proteins thought to cause Alzheimer’s disease). Rats fed a water extract of cinnamon enriched in polyphenols that improve insulin sensitivity were more active and curious in a Y maze test than rats fed the control and high fat/high fructose diets. The high fat/high fructose fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding cinnamon.
Dietary polyphenols exert protective effects on injury to the brain associated with strokes. Swelling of brain cells was significantly blocked by a type-A polyphenol trimer isolated from cinnamon but not by the major non-polyphenol fractions of cinnamon including cinnamaldehyde (a major component in cinnamon that gives the cinnamon taste and smell), and coumarin. Increased free radical production, a contributing factor in cell swelling following brain injury, was also significantly reduced by the type-A compound. Effects of the type-A polymer are likely mediated through their action on the mitochondria, the energy producing component of cells.
The health benefits of fruits, vegetables, and plant-derived materials are well documented; however, there is still little information regarding the potential beneficial effects of phenolic conjugates found in plants on inflammation and hypertension. Unfortunately, these phenolic conjugates are not commercially available and must be synthesized in order to study their effects. This year, the effects of 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 investigated on cyclooxygenase and related enzymes involved in inflammation. Pharmaceutical compounds like aspirin and ibuprofen exert their anti-inflammatory effects through inhibition of cyclooxygenase. Thus, in vitro culture systems were used to determine the potential effects of synthesized phenolic conjugates on catalase, peroxidase, cyclooxygenase and others enzymes critically associated with the initiation and/or progression of inflammation and hypertension.
A component of cinnamon may prevent or alleviate damage associated with strokes based on in vitro studies. A protective role of a purified dietary cinnamon polyphenol, cinnamtannin D1, was demonstrated in a cell culture model of ischemia/stroke. A major feature of cerebral ischemia or lack of blood flow is the swelling of cells that are responsible for the development of brain edema. Our results suggested that swelling of brain cells, when deprived of oxygen and glucose, can be significantly prevented by a biochemically isolated dietary cinnamon polyphenol. Our data also suggested that cinnamon polyphenols exert protective effects through improved function of mitochondria by reducing free radical mediated damage and by regulating intracellular calcium.
Natural products may alleviate inflammation and hypertension based on in vitro studies. Specific phenolic conjugates (N-caffeoyltyramine, N-feruloyltyramine, and other phenylpropenoic acid amides) found in coffee, cocoa, tea, garlic, green onion, spices, and herbs were isolated and/or synthesized and tested for effects on cyclooxygenase and related enzymes involved in inflammation and hypertension. Several of these phenolic conjugates inhibited cyclooxygenase and related enzymes in vitro and animal studies to evaluate changes in inflammation and hypertension have been planned.
Cinnamon increases liver glycogen, a storage form of energy, in animal studies. Cinnamon and water extracts of cinnamon improved insulin sensitivity in vitro and in animal and human studies. Given the relationship between the glucose/insulin system and glycogen metabolism, the objective of this study was to determine the effects of cinnamon on glycogen synthesis, related gene expression and protein levels in the muscle and liver using an animal model of insulin resistance, the high fat/high fructose diet fed rat. The high fat/high fructose diet caused a significant decline in insulin function that was reversed by cinnamon. Cinnamon added to the high fat/high fructose diet led to highly significant improvements in insulin function and increased in glycogen levels. Liver and muscle glycogen are the major storage forms of energy. Cinnamon also counteracted the decrease in insulin signalling proteins induced by the high fat/high fructose diet. In summary, these data suggest that cinnamon improves insulin sensitivity and enhances liver glycogen via regulating insulin signalling and glycogen synthesis.
Panickar, K.S., Polansky, M.M., Graves, D.J., Urban Jr, J.F., Anderson, R.A. 2012. A procyanidin type A trimer from cinnamon extract attenuates glial cell swelling and the reduction in glutamate uptake following ischemic injury in vitro. Neuroscience. 202:87-98.
Couturier, K., Qin, B., Batandier, C., Awada, M., Hininger, I., Canini, F., Leverve, X., Roussel, A., Anderson, R.A. 2011. Cinnamon increases liver glycogen in an animal model of insulin resistance. Metabolism. 60(11):1590-7.
Panickar, K.S., Anderson, R.A. 2011. Effect of polyphenols on oxidative stress and mitochondrial dysfunction in neuronal death, brain edema, and cell swelling in cerebral ischemia. International Journal of Molecular Sciences. 12:8181-8207.
Park, J.B., Wang, T.T. 2012. Safflomide increases the expression of adiponectin in vitro and in vivo: Implication for hypoadiponectemia, visceral obesity, and insulin resistance. Journal of Agricultural and Food Chemistry. 25(60):4048-52.
Park, J.B., Velasquez, M.T. 2012. Effects of secoisolariciresinol diglucoside lignan-enriched flaxseed powder on body weight, visceral fat, lipid profile, adipokines, and blood pressure in rats fed a high-fructose and high-fat diet. Fitoterapia. 83(5):941-6.
Panickar, K.S., Anderson, R.A. 2011. Dietary polyphenols exert neuroprotective effects by attenuating neuronal and astrocytic damage in cerebral ischemia. In: Farooqui, A.A., Farooqui, T., 1st Edition. New York, NY: Nova. p135-155.
Qin, B., Anderson, R.A., Kuzuya, T., Kitaura, Y., Shinomura, Y. 2012. Mechanisms responsible for hepatic very low density lipoprotein-apoB100 overproduction in Otsuka Long-Evans Tokushima fatty rats. Atherosclerosis. 222:407-416.