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History suggests that diabetes and cardiovascular diseases were present in ancient civilizations. Physicians in Ancient Egypt described the diabetes-like syndrome nearly 3,500 years ago in Ebers papyrus, found in a grave in Thebes region in the south of Egypt in 1862 (Ahmed, 2002). Sushrant, an Indian physician, described diabetes as polyuric wastage diseases in literature from the 5th-6th century AD (Ahmed, 2002). The term "diabetes" was first coined by Arataeus the Cappodocian (approximately 81-133AD), meaning "a siphon". Thomas Willis (Britain) in 1675 added another word "mellitus" meaning "honey-like sweet" (Ahmed, 2002). The Persian physician, Ibn Sina (980-1037), known as Avicenna in Western Europe, described some of the clinical features and complications of diabetes such as peripheral neuropathy, gangrene and erectile dysfunction (Iskeandar, 1986).
Diabetes can be described as dysfunction of the pancreatic ¢-cell hormone, insulin. The most common form of diabetes involves the development of insulin resistance where insulin loses its effectiveness to increase glucose uptake into cells, especially in skeletal muscle and liver. This form of diabetes, known as type 2 diabetes, often occurs in patients with hypertension and obesity; this clustering of symptoms is now known as the metabolic syndrome (Huang, 2009), formerly as syndrome X (Reaven, 1988). The clinical definition of the metabolic syndrome was first reported by Alberti & Zimmer (1998) with the essential requirements being insulin resistance together with any two of the following four criteria: obesity, dyslipidaemia, hypertension and microalbuminuria (Alberti and Zimmer 1998). Diagnostic criteria were refined in 1999 by the European Group for the Study of Insulin Resistance (EGIR), in 2001 by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) updated in 2005 by American Heart Association and the National Heart Lung and Blood Institute and in 2005 by the International Diabetes Foundation (IDF) (Alberti et al., 2006). All the definitions required increased plasma glucose concentrations together with hypertension, dyslipidaemia and central obesity. These symptoms do not fully define the syndrome as the socioeconomic background, life style, family history, age, sex and environmental factors are rarely considered.
According to the American Heart Association report, metabolic syndrome and cardiovascular disease are the leading causes of morbidity and mortality of patients in USA and also in the developed world (Bleich et al., 2008; Lloyd-Jones et al., 2010). The number of patients is also increasing in developing countries such as India, China, Latin America and Eastern Europe (Hossain et al., 2007, Mishra and Khurana, 2008). Major well-known risk factors of cardiovascular disease include a family history of premature coronary disease, hypertension, elevated concentrations of low-density lipoprotein cholesterol (LDL-C), hyperlipidaemia, smoking and type-2 diabetes. Clinical characteristics of cardiovascular disease include myocardial infarction, coronary artery disease, stroke, peripheral artery disease and congestive heart failure. The Framingham Heart Study revealed that hypertension, diabetes and left ventricular remodelling lead to the development of congestive heart failure (Armstrong 2000). The Framingham Heart Study also found that a 5% increase in weight increases the chance of hypertension by 30% over a four-year period of time. An increased sympathetic activity, impaired renin-angiotensin system, retention of fluid volume, peripheral vasoconstriction, dyslipidaemia, increased blood viscosity due to the increased haematocrit and fibrinogen may increase pressure overload on heart in obesity (Schunkert, 2002). Recently, inflammatory signalling mechanisms and an overproduction of reactive oxygen species have been well documented in cardiovascular disorder and diabetes (du Toit et al., 2005; Rodford et al., 2008; Renna et al., 2009; Yamaguchi et al., 2009).
1.2 Oxidative stress
Oxidative stress can be defined as the cellular damage caused by excess formation of highly reactive molecules such as reactive oxygen species (ROS) and reactive nitrogen species or an insufficient removal of ROS due to the lack of antioxidative enzymes including superoxide dismutase, catalase and preoxidase or both (Turko et al., 2003; Johansen et al., 2005). ROS include free radicals such as superoxide (â€¢O2-), hydroxyl (â€¢OH) as well as nonradical species such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) etc. (Evans et al., 2002; Johansen et al., 2005). The mitochondrial respiratory chain and NADPH oxidase family are the most important sources of ROS in non-phagocytic cells including pancreatic islets (Yu et al., 2008; Nishikawa et al., 2000; Uchizono et al., 2006; Dworakowski et al., 2006, Paravicini and Touyz, 2008). The tissue damage caused by ROS in diabetes includes lipid peroxidation, inactivation of proteins and protein glycation as intermediate mechanisms (Wolffe et al., 1991) which may cause complications including retinopathy, nephropathy and coronary heart disease (Makimattila et al., 1999; Inoguchi et al., 2003).
1.3 Cardiac remodelling and hypertrophy
Cardiac remodelling is usually an adaptive process that occurs in response to long-term changes in haemodynamic conditions such as volume overload or increased sheer stress, but it may subsequently contribute to the pathophysiology of vascular diseases and circulatory disorders. Thus cardiac remodelling can be defined as a process of structural changes in one or more cardiac chambers, in particular the ventricles. Cardiac remodelling is best described as molecular, cellular, interstitial and genomic changes that are manifested clinically as alterations in size, shape and function of the heart following cardiac injury (Feuerstein and Weck, 1999). Epidemiological studies suggest that left ventricular remodelling is common in patients with metabolic syndrome (Patel et al., 2009). Important mediators include haemodynamic load, wall stress, neurohormonal activation (sympathetic system, renin-angiotensin system, aldosterone and endothelin), cytokines, oxidative stress and ischaemia.
1.4 Obesity, diabetes and cardiovascular remodelling
Obesity is considered as an independent risk factor for developing cardiovascular disorder and various degrees of cardiac remodelling (Avelar et al., 2007, Abel et al., 2008). These changes include hypertrophy of the heart, left ventricular weight gain, interstitial fibrosis and collagen deposition, epicardial fat accumulation and infiltration of lipid in myocardium (Avelar et al., 2007, Abel et al., 2008). High carbohydrate, high fat feeding caused obesity, left ventricular hypertrophy and remodelling in Wistar rats (Panchal et al., 2010).
Insulin itself is another regulator of cardiac myocyte growth and energy metabolism. Clinical studies have found that hypertensive patients with high plasma insulin concentrations have an increased incidence of left ventricular hypertrophy, suggesting that insulin may trigger pathological cardiac growth when the heart is subjected to chronic pressure overload (Shigematsu et al., 2005; Rutter et al., 2003; Stiefel et al., 2004).
Glucose auto-oxidation increases the ROS generation through mitochondrial electron transport chain during production of ATP. Accelerated flux of glucose through glycolysis and feeding of pyruvate to the tricarboxylic acid cycle overloads mitochondria, causing excessive generation of free radicals at the level of complex II (succinate:ubiquinone oxidoreductase), one of the four inner membrane-associated complexes central to oxidative phosphorylation (Nishikawa et al., 2000). Cross-talk between mitochondrial electron transport chain ROS production and NAD(P)H oxidase system has been reported recently (Ceriello, 2003). The activation of protein kinase C together with increased de novo synthesis of NAD(P)H oxidase contributes to produce more superoxide anions (Hink et al., 2001).
Systemic hypertension induces chronic left ventricular pressure overload and is a recognised contributor to heart failure. Several studies also suggest that the cause of hypertension itself may contribute to left ventricular hypertrophy in obese individuals as the increase of BMI increases the chance of hypertension (De Simone et al., 1994; Avelar et al., 2007). High dietary fat intake increases the expression of AT1B and ETA receptors (Neilsen et al., 2004; Zhang et al., 2005). Plasma concentrations of angiotensin II and endothelin 1 (physiological vasoconstrictor agents) were increased in both obese patients and animal models (Barton et al., 2000; Neilsen et al., 2004; Zhang et al., 2005). Mouse models deficient in ROS-forming enzymes have lower blood pressures compared with wild-type counterparts and angiotensin II infusion in these mice failed to induce hypertension (Bendall et al., 2002; Li and Shah 2003). Angiotensin II also stimulated ROS generation by activating the NADPH oxidase in endothelial system. PLD, PLA, PKC, c-Src, PI3 K, RhoA, and Rac 1, 2 proteins are believed to be involved in up-regulating signalling cascade for AT1 signalling to NAD(P)H oxidase (Seshiah et al., 2002; Touyz et al., 2003).
Significance of the study
The use of natural products in treating diseases and illness has been recognized since ancient times. Public and scientific interest in the use of natural products is considerable with the assumption that they have notably less toxicity compared to synthetic drug medication to combat human diseases such as cardiovascular disease, cancer and inflammatory diseases. Diabetes and cardiovascular diseases are becoming epidemic non-communicable diseases around the world. This is creating a burden on the health sector of both developed and developing world and slows down the growth of economies of these countries. This economic burden includes the productivity lost and increasing cost for the management and treatment of the diseases condition. The International Diabetes Federation Diabetes Atlas (4th edition, 2009 report) notes that global healthcare expenditure to treat and prevent diabetes is International Dollars (ID) 418 billion in 2010 and is predicted to rise to 561 billion ID in 2030 (Economic impacts of diabetes, Diabetes atlas, 2009).
Australia is one of the most developed countries where life expectancy is the second highest in the world after Japan (about 81.4 years) with cardiovascular diseases remaining the major cause of death (Australian Institute of Health and Welfare, 2008). Diabetes, obesity and cardiovascular diseases have been increasing in recent years, doubling between 1988 and 2002. With an ageing and increasingly obese population, the financial burden of treating type II diabetes could quadruple by 2051 unless more is done to prevent or delay the disease and its complications (Davis et al., 2006). The Australian Diabetes, obesity and life style study (AUSDIAB) predicted the changes in glucose indices, health behaviour and incidence of diabetes in 5 year follow-up experiments among 5842 participants (Barr et al., 2007). This study suggested that a large number of Australians suffer mortality due to cardiovascular diseases associated with abnormal glucose metabolism every year. The projects reported in this thesis will determine the structural and functional changes in the cardiovascular system as well as in the liver and pancreas, as well as metabolic changes due to oxidative stress and metabolic syndrome and then determine the potential beneficial roles of phenolic acids and natural antioxidants using an appropriate rat model