The diabetes was first time described by Asian Egyptian by all most 3000 years ago. The term was first coined by Araetus of Cappodocia in 81-133AD. Later on in the history Thomas Wills added the word mellitus (honey sweet) in 1675 after rediscovering the sweetness of blood and urine. Similarly 1776 Dobson first confirmed the presence of excess sugar in blood and urine coincides with the emergence of experimental diabetes. The biggest achievement in the history of diabetes was the role of liver in glycogenesis, and its relation with the excess production of glucose.
Diabetes is the major globally threatened metabolic disorder characterize by hyperglycemia resulting from defect in insulin secretion, insulin action or both affecting public health, the face is getting worst affecting working adults of developing countries. There are an estimated 246 million people with diabetes in the world, of whom about 80 % reside in developing countries. Although diabetes is often not recorded as the cause of death, globally, it is believed to be the fifth leading cause of death in 2000 after communicable diseases, cardiovascular disease, cancer and injury. Currently, there are 40 million people with diabetes in India estimated to rise to almost 70 million by 2025 (IDF, 2006). The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people > 65 years of age (Wild et al., 2004).
According to Wild et al. (2004) the ‘top’ three countries in terms of the number of T2DM individuals with diabetes are India (31.7 million in 2000; 79.4 million in 2030), China (20.8 million in 2000; 42.3 million in 2030); and the US (17.7 million in 2000; 30.3 million in 2030). Clearly, T2DM has become an epidemic in the 21st century where India leads the world with largest number of diabetic subjects (Singh, 2011). Until recent time T2DM was typically regarded as a metabolic disorder of middle age and elderly stage. Perhaps, this age group has higher risk to the younger adults. T2DM has been reported in children in number of developing countries including Japan, USA, India, Australia and UK (Bloomgarden, 2004).
Diabetes mellitus is a metabolic disorder characterized by resistance to the action of insulin, insufficient insulin secretion, or both. The clinical manifestation of DM is hyperglycaemia i.e., high glucose blood sugar (Davidson et al., 1995). It is further classified as
2.1.1 Type 1 diabetes Mellitus- IDDM (Insulin Dependent Diabetes Mellitus and Juvenile-onset Diabetes), it is characterize by inadequate or absolute absence of insulin. It is brought about as a result of organ specific autoimmune destruction of ??-cells of the pancreas by cytotoxic T-cells (Ahmed and Goldstein, 2006). It is one of the idiopathic disorders, where there is no evidence of immune-mediated ??-cells destruction and further characterized by inadequate insulin and progression of ??-cells loss. Destruction of ??-cells cells compromises the production of insulin and the function associated with it (Harris, 2000).
2.1.2 Type 2 diabetes mellitus-NIDDM (Non Insulin Dependent Diabetes Mellitus), is the most recent concerned, it is characterized by progressive deterioration of normal ??-cells function (Ahmed and Goldstein, 2006), it is managed by a combination of exercise, diet, oral hypoglycemic drugs and at times insulin injections (Bailey, 2000). In type 2, ??-cells become exhausted and eventually undergo apoptosis due to elevated glucose level with insufficient insulin in the blood that leads to over burden to ??-cells (Buttler et al., 2004). Whereas the marked symptoms of hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia.
2.1.3 Gestational diabetes mellitus (GDM) identifies woman who develop glucose intolerance during their last half of pregnancy. Hyperglycemia during last trimester of gestational period is associated with number of maternal, paternal adverse outcomes (Landon et al., 2011) and it also increase lifelong risk of glucose intolerance, obesity and metabolic syndrome to the offspring on the other hand mother will have higher risk of metabolic syndrome and diabetes in future (ADA, 2012). The range of prevalence of GDM is approximately 1% to 4% (ADA, 2012) all across the globe. Higher prevalence of GDM was recorded in African, Indian and Hispanic woman (Carolan et al., 2011; Makgoba et al., 2011). It has been estimated that woman diagnosed with GDM 70-90% of it achieve targeted glycemic goal with life style modification and nutritional therapy alone (Magon and Seshiah, 2011; Lee-Parritz, 2011).
2.1.4 Maturity onset diabetes of young (MODY) is associated with autosomal inheritance and is characterized by onset of hyperglycemia to an individual younger than 25 year. Studies have revealed that more than 80 % of patients presenting with DM suffer from T2DM (Mycek et al., 2000; Maiti et al., 2004; Ahmed and Goldstein, 2006). About 15-20 % of patients present with T1DM. It has also been reported, though uncommon, that 2-5 % of pregnant woman suffer from gestational diabetes (Urger and Foster, 1998; Maiti et al., 2004).
2.1.5 Latent autoimmune diabetes in adults (LADA): It is a disorder in which, despite the presence of islet antibodies at diagnosis of diabetes, the progression of autoimmune ??-cell failure is slow. Initially up to almost six month there is no need of insulin to regulate the glucose level after the diagnoses of diabetes. The frequency of individual affected by LADA is 10 % among the phenotypic of T2DM.
2.1.6 Other types of diabetes associated with pancreatic disease, hormonal disease, drug or chemical exposure, insulin receptor abnormality or certain genetic syndrome. In some of the conditions causes of hyperglycemia is known e.g., pancreatic disease. While as in rest of the cases an etiological relationship is associated with diabetes.
2.1.7 Risk Factor
Several factors contribute to accelerated diabetes epidemic in Asians, including the “normal-weight metabolically obese” phenotype; high prevalence of smoking and heavy alcohol use; high intake of refined carbohydrates and dramatically decreased physical activity levels.
Total prevalence of NIDDM increases with age, from 2.0 % at age 20-44 years to 18.7 % at age 65-74 years (Harris et al., 1987). About 50 % of NIDDM is undiagnosed. This percentage is similar across all age groups, for both male and female. The number of cases of DM increases with the increase in age.
18.104.22.168 Family history
Among the major risk factors family history leads to the prevalence of diabetes. Individual with family history is 50 % more susceptible to diabetes as compared to the individual with clear background (Abate and Chandila, 2001)
Poor nutrition in utero and in early life combined with over nutrition in later life may also play a role in Asia’s diabetes epidemic.
Obesity is one of the major risk factor for T2DM. It is a precursor for T2DM followed by insulin resistance (Frayn et al., 1996). Studies have shown that this relationship is different in different type of obesity and T2DM (Boden, 1997). Hypothesis that relate obesity with DM, leads to change in the profile of the hormone level secreted by adipose tissue (adipokines). In the state of obesity adipose tissues secreted more adipokines that causes insulin resistance and fewer that promote insulin sensitivity.
Cigarette smoking is a well documented risk factor in diabetes. Although diabetes and coronary heart disease also share a close relationship that leads to insulin resistance.
Alcohol consumption by diabetes can worsen the blood glucose level. Conversely long term alcohol consumption in none adequately nourished diabetes can lead to dangerous low blood sugar level. Heavy drinking causes accumulation of certain harmful acids in the blood that lead to adverse effects (Ben et al., 1991).
22.214.171.124 Insulin resistance
In the condition of insulin resistance the muscle, fat, and adipose tissue do not respond properly to insulin and thus cannot easily absorbed blood glucose from the circulating blood. As a result the blood stream needs more level of insulin to keep up the normal level of helping glucose entry into the cell.
As the world is developing the development, urbanization and industrialization throughout, prevalence of diabetes has increased dramatically in the past few decades (IDF, 2000). The developing world will suffer the more affecting relatively the younger age group undergoing epidemiological transition from communicable to chronic diseases. The factors contributing to these predicted rises include increased prevalence of obesity, decreased physical activity, changes in dietary habits, increased exposure to environmental triggers and increased virulence of viruses.
Relationship between diabetes and stress it little complex. Stress may have a role in the onset of diabetes, metabolic disorder and in quality of life. Particularly stress can affects especially in some stress reactive individuals. Physiological effects neuro endocrine system induces stress and can affect directly glucose level.
T1DM recognizes two major subtypes: 1A (autoimmune) and 1B (idiopathic). Among both the subunit 1A subtype is determined genetically a chronic immune mediated disorder that leads to lose of pancreatic insulin-secreting ??-cells. The classic views regarding pathogenesis of T1DM are genetically predisposed individuals, non genetic factor likely, environmental factors that may trigger an autoimmune process that lead to ??-cell destruction (Adrian vlad and Romulus timar, 2011).
Gepts et al. (1965) first identified the inflammatory markers infiltrates in pancreatic islets, which are the hallmark of DM. Recent evidence suggested that the initiation of T1DM requires both CD4+ and CD8+ T cells that auto react with that auto react with T cells differentiate into effectors ??-cell antigens on local antigen presenting cells (APcs) that leads to the initiation of CD4+ T cells which are insulin reactive and CD8+ plays major role as ?? cell killers. T cells have the capability to directly kill ?? cells via cell to cell contact, through a cytotoxic process, on the other hand they can also influence their destruction through other factors, that involves the release of grazyme B, pro-inflammatory cytokines, possible signaling through pathways of programmed cell death. Another bunch of immune cell types including B cells, natural killer T cells, NK cell, ‘?T and macrophages have been implicated in T1DM progression. T2DM is characterized by obesity, impaired insulin dysfunction and increased endogenous glucose output.
2.1.9Morphology of DM and its long term complications
In most of the cases they are likely to be found in arteries (atherosclerosis), basement membrane of small vessels (microangiopathy), nephrone (diabetic nephropathy), retina (retinopathy), nerves (neuropathy) and also some other tissues shown in (Figure 2.1). These changes are prominently in both types of diabetes.
Lot many changes are commonly related with T1DM and T2DM. Reduction in the number and size of islets of langerhan, leukocytic infiltration of the islets, beta cell degranulation, and degenerated cells appeared with nuclear pyknosis, fragmentation, and others showed cytoplasmic vacuolation. Apart from these changes islet cell hormone are known to act differently in cases with DM as compared to the healthy individual. Few of them play important role in the regulation of digestive and metabolic functions and in turn they lead to dysregulation of exocrine pancreatic function (Henderson, 1969).
Figure 2.1: Diabetic complication
126.96.36.199 Vascular system
Myocardial infraction caused by atherosclerosis of coronary arteries and it is the most common cause of death in cases with diabetes. Severe atherosclerosis is accelerated by change in the size of aorta and large and medium sized arteries. Similarly large renal arteries are also subjected to severe atherosclerosis and the most severe damaging effect is seen on the kidneys (Clare-salzler, 2003).
188.8.131.52 Diabetic microangiopathy
Electron microscopy revealed vigorous endothelial proliferation accompanied by thickening and reduplication of basal lamina in each instance. Fegerberg described thickening of neural endoneural blood vessels with accumulation of periodic acid shiffs (PAS).
184.108.40.206 Diabetic nephropathy
It is one of the major causes of end stage renal disease affecting worldwide. It is clinically defined as progressively increasing proteinuria that is accompanied by increasing blood pressure and impairment of glomerular filtration. While the characteristic feature of diabetic nephropathy are nodular glomerulosclerosis, tubule interstitial fibrosis and atrophy, hyaline atherosclerosis and arterial sclerosis (Alsaad, 2007).
220.127.116.11 Diabetic ocular complications
Epidemiological studies suggest a positive relation between prevalence of retinopathy and hypertension. Increased blood pressure, through an effect on blood flow, has been hypothesized to damage the retinal capillary endothelial cells, resulting in development and progression of retinopathy. Lession in the retina take two forms pre-proliferative diabetic retinopathy (moderate and severe non-proliferative diabetic retinopathy) lead to the increased sign of development of ischemia followed by arterial thinning and occlusion or more frequently venous beading and looping, and intra retinal microvascular abnormalities. Advanced proliferative disease is characterized by fibrovascular proliferation and contraction that can lead to continued vitreous haemorrhage and retinal detachment (Negi et al., 2003).
18.104.22.168 Diabetic Neuropathy
Diabetic neuropathies are the family nerve disorder caused by diabetes. The major complications of neuropathy are diffused neuropathy of the distal symmetric sensorimotor type. Individual suffer from mixed sensorimotor defect and may experience pain, paresthesia, hyperethesia, dysesthesia, proprioreactive defects, loss of sensation, and muscle weakness and atrophy (Brown and Asbury, 1984). Neuropathy affects predominantly the large nerve fibers lead to motor and prioreceptive dysfunction.
People with diabetes can develop many type of foot problems. Even ordinary problem left unnoticed could turn into a serious problem. These problems are usually caused when there is nerve damage also called as neuropathy. This can cause pain, numbness, tingling and weakness in the foot. Poor blood flow is also one of the major causes of foot injury.
22.214.171.124 Nonketotic hyperosmolar syndrome (NKHS)
Metabolic complications most frequently occurring in T2DM which is characterized by extreme dehydration, hyperglycemia, hyperosmolar plasma and change in the consciousness. NKHS is diagnosed by uncontrolled hyperglycemia, plasma hyperosmolality and absence of significant ketosis. If left untreated leads to coma, seizures and death.
126.96.36.199 Acute diabetic ketoacidosis
Diabetic ketoacidosis is a complex metabolic disorder characterized by hyperglycemia, acidosis and ketonaemia. The consequences that lead to this
metabolic state is absolute or relative insulin deficiency that is accompanied by an increase in regulatory hormones like glucagon, cortisol, growth hormones and epinephrine. This hormonal imbalance enhances hepatic gluconeogenesis and glycogenolysis resulting in severe hyperglycemia that triggers lipolysis which leads to the accumulation of ketone bodies and subsequent metabolic acidosis.
2.2 SIGN AND SYMPTOMS
Polydipsia, polyuria, polyphagia, fatigue, weight loss, blurred vision, slow healing, genital itching, dizziness, nausea are the symptoms that are similar in both type of diabetes but they vary in their intensity. Occurrences of symptoms are much more rapid in T1DM. Long term types 1 diabetes complications are microvascular and macrovascular like as coronary artery, heart and peripheral vascular disease.
Uncontrolled hyperglycemia in both T1DM and T2DM lead to the development of both acute and long term complications (Weiss and Sumpio, 2006). Acute complications of DM include ketoacidocis (T1DM) or nonketotic hyperosmolar coma (T2DM). Long term complications include cardiovascular diseases, hypertension, chronic renal failure, retinal damage, nerve damage, erectile dysfunction and macrovascular damage which may cause poor healing of wounds particularly of the feet and can lead to gangrene which may require amputation (WHO, 1999).
Chronically elevated blood glucose levels lead to increase production of mitochondrial ROS, which activate a number of metabolic pathways whose end products contribute to the development of long term complication of diabetes (Weiss and Sumpio, 2006). These metabolic pathways activated by hyperglycemia-induced ROS include: the polyol pathway, formation of AGEs, hexosamine pathway and the protein kinase C (PKC) pathway.
2.3 CAUSE OF DIABETES
2.3.1 Glucose metabolism and homeostasis
For every day to day activity like sitting, walking, and running or even for sleeping we require energy that depends on particular time and on the level of activity in which we are engaged. To fulfill our day to day requirements we require food. Ultimately, the fuel we burn in our cells to give energy for life is glucose, which is derived from our diet. Glucose levels in the blood are controlled within reasonably close limits by a complicated interaction of hormones. Glucose homeostasis is a complicated interaction of metabolic pathways, regulated by a complex web of hormones acting on a number of different tissues and cells. These processes coordinate together in order to maintain an optimal glucose level. Other hormones responsible to maintain the optimal glucose level are insulin, glucagon and adrenaline in which insulin is secreted from pancreatic beta cells into the portal circulation with a brisk increase in response to a rise in blood glucose (after meals). A glucose sensor has been identified in the portal vein which modulates insulin secretion via neural mechanisms. Insulin lowers blood glucose by suppressing hepatic glucose production and stimulating peripheral glucose uptake in skeletal muscle and fat, mediated by the glucose transporter, GLUT 4 (Frier, 2002) (Figure 2.2). Adipocytes and the liver synthesize triglyceride from non-esterified fatty acids (NEFAs) and glycerol. Insulin stimulates lipogenesis and inhibits lipolysis, so preventing fat catabolism (Davidson, 1986). Lipolysis, mediated by triglyceride lipase, is stimulated by catecholamines and liberates NEFAs which can be oxidised by many tissues. Their partial oxidation in the liver provides energy to drive gluconeogenesis and also produces ketone bodies (acetoacetate, which can be reduced to 3-hydroxybutyrate ordecarboxylated to acetone) which are generated in hepatocyte mitochondria.
Figure 2.2: A schematic representation of mechanism involved in the maintainence of glucose homeostasis (Frier, 2002)
Ketone bodies are organic acids which, when formed in small amounts, are oxidised and utilized as metabolic fuel (WHO, 1980). However, the rate of utilization of ketone bodies by peripheral tissues is limited, and when the rate of production by the liver exceeds their removal shown in (Figure 2.3). It is well established fact that glucagon induces hyperglycaemia in animals and man through its action on liver glycogenolysis (Sutherland, 1950) and gluconeogenesis (Exton and Park 1966). Adrenaline has similar metabolic effects on the liver (Sutherland, 1950; Exton and Park, 1966) and it is often thought that both hormones play a physiological role as glycogenolytic agents in blood glucose homeostasis. Ketogenesis is regulated by the supply of NEFAs reaching the liver and is therefore enhanced by insulin deficiency and release of the counter- regulatory hormones that stimulate lipolysis. It is well established fact that glucagon induces hyperglycemia in animals and man through its action on liver glycogenolysis (Sutherland, 1950) and gluconeogenesis (Exton and Park 1966). Adrenaline has similar metabolic effects on the liver (Sutherland, 1950; Exton and Park, 1966) and it is often thought that both hormones play a physiological role as glycogenolytic agents in blood glucose homeostasis. Several authors, however, have reported that when adrenaline was infused directly in the portal vein its effects on blood glucose and hepatic glycogenolysis were much less pronounced than when the hormone was administered into the systemic circulation (Sherlock et al., 1993). Moreover, Sokal and Rohlf, (1995) demonstrated both in vitro and in vivo that, in contrast to glucagon, doses of adrenaline within the physiological range had only small and transient effects on liver glycogen and phosphorylase activity (Sokal and Rohlf, 1995). They thus concluded that glucagon is the only agent promoting glycogenolysis in the liver in physiological conditions and suggested that the effect of moderate doses of
Figure 2.3: Ketone body synthesis in liver and its use in peripheral tissues (lipincott’s biochemistry)
Figure 2.4: Mechanism of diabetic ketoacidosis
adrenaline might be indirect, possibly mediated through stimulation of glucagon secretion.
Tissue damage and pathophysiological complications is due to decreased uptake of glucose into muscle and adipose tissue that leads to chronic extracellular hyperglycemia resulting in, heart disease, atherosclerosis, cataract formation, peripheral nerve damage, retinopathy and others (Brownlee and Cerami, 1981). Increased oxidative stress has been proposed to be one of the major causes of the hyperglycemia-induced trigger of diabetic complications. Hyperglycemia in an organism stimulates ROS formation from a variety of sources. These sources include oxidative phosphorylation, glucose auto oxidation, NAD(P)H oxidase, lipooxygenase, cytochrome P450 monooxygenases, and nitric oxide synthase (NOS).
2.3.2 A brief overview of insulin signaling
Insulin metabolic action result from its rapid interaction with the insulin receptor (IR) found at the target tissue (liver, muscle and adipose tissue). Insulin binds to the alpha-subunit of IR composed of two extra-cellular ??-subunits and two transmembrane ??-subunits linked by ‘s-s- bonds and activate the intrinsic tyrosine kinase activity of the beta-subunit of the receptor. Activated IR results in the subsequent phosphorylation of intracellular substrates including insulin receptor substrates (IRSs) such as IRS-1 and 2, phosphatidylinositol (PI) 3-kinase, and protein kinase B (PKB) shown in (Figure 2.5). Under normal condition insulin action leads to increased glycogen synthesis, glucose transport, and lipogenesis, and decreased gluconeogenesis, glycogenolysis and lipolysis shown in (Figure 2.5) (Postic, 2004).
Figure 2.5: Insulin signaling mechanism. (Saltiel and Kahn, 2001)
2.3.3 Diabetes and Reactive oxygen species
Oxidative stress is defined in general as excess formation and/or insufficient removal of highly reactive molecules such as ROS and reactive nitrogen species (RNS) (Turko et al., 2004). ROS include free radicals such as superoxide (O2′-), hydroxyl (OH’), peroxyl (RO2′), hydroperoxyl (‘HRO2-) as well as non radical species such as hydrogen peroxide (H2O2) and hydrochlorous acid (HOCl) (Evans et al, 2002). RNS include free radicals like nitric oxide (NO’) and nitrogen dioxide (NO2′-), as well as nonradicals such as peroxynitrite (ONOO), nitrous oxide (HNO2) and alkyl peroxynitrates (RONOO) (Turko et al., 2004) of these reactive molecules, O2′-, NO’ and ONOO- are the most widely studied species and play important roles in the diabetic-cardiovascular complications. ROS can stimulate oxidation of LDL, and ox-LDL, which is not recognized by the LDL receptor, can be taken up by scavenger receptors in macrophages leading to foam cell formation and atherosclerotic plaques (Boullier et al., 2001). As well as O2′-, can activate several damaging pathways in diabetes including accelerated formation of AGEs, polyol pathway, hexosamine pathway and PKC, all of which have been proven to be involved in micro and macrovascula complications. O2′- and H2O2 stimulate stress-related signaling mechanisms such as NF-??B, p38-MAPK and STAT-JAK resulting in VSMC migration and proliferation. In endothelial cells, H2O2 mediates apoptosis and pathological angiogenesis (Taniyama and Griendling, 2003). Furthermore, O2′-, immediately reacts with NO’ generating cytotoxic ONOO- and this reaction itself has several consequences. First, ONOO alters function of biomolecules by protein nitration as well as causing lipid peroxidation (Evans et al, 2002). For example, potassium channels, which regulate the vasorelaxation response, are inhibited by nitration (Liu and Gutterman, 2002). As recently reviewed by Turko et al., (2004) increased levels of nitrotyrosine are associated with apoptosis of myocytes, endothelial cells and fibroblasts in diabetes (Evans et al, 2002). Second, ONOO causes single-strand DNA breakage which in turn activates nuclear enzyme poly (ADP-ribose) polymerase (PARP) (Soriano et al., 2001). Third, it decreases NO’ bioavailability causing impaired relaxation and inhibition of the antiproliferative effects of NO’. Furthermore, ONOO oxidizes tetra hydrobiopterin (BH4), an important cofactor for NOS, and causes uncoupling of NOS, which produces O2′-, instead of NO’ (Maritim et al., 2003). ROS-induced peroxidation of membrane lipids alters the structure and the fluidity of biological membranes which ultimately affects function (Maritim et al., 2003). There are multiple sources of oxidative stress in diabetes including non enzymatic, enzymatic and mitochondrial pathways that initiate oxidative stress and related vascular complications in diabetes.
Non enzymatic sources of oxidative stress originate from the oxidative biochemistry of glucose. Hyperglycemia can directly cause increased ROS generation. Glucose can undergo autoxidation and generate OH’ radicals (Turko et al., 2004). In addition, glucose reacts with proteins in a nonenzymatic manner leading to the development of amadori products followed by formation of AGEs. ROS is generated at multiple steps during this process. In hyperglycemia, there is enhanced metabolism of glucose through the polyol (sorbitol) pathway, which also results in enhanced production of O2- shown in (Figure 2.6).
Enzymatic sources of augmented generation of reactive species in diabetes include NOS, NAD(P)H oxidase and xanthine oxidase (Guzik et al., 2002). All isoforms of NOS require five cofactors/prosthetic groups such as flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, BH4
Figure 2.6: Augmentation of ROS by various pathways under diabetic condition (Kaneto et al., 2010)
and Ca2+-calmodulin. If NOS lacks its substrate L-arginine or one of its cofactors, NOS may produce O2′-, instead of NO’ and this is referred to as the uncoupled state of NOS. Guzik et al., (2000) investigated O2′-, levels in vascular specimens from diabetic patients and probed sources of O2′-, using inhibitors of NOS, NAD(P)H oxidase, xanthine oxidase and mitochondrial electron transport chain. This study demonstrated that there is enhanced production of O2′-, in diabetes and this is predominantly mediated by NAD(P)H oxidase. There is plausible evidence that PKC, which is stimulate in diabetes via multiple mechanisms, i.e. polyol pathway and Ang II, activates NAD(P)H oxidase (Amiri et al., 2002).
The mitochondrial respiratory chain is another source of non enzymatic generation of reactive species. During the oxidative phosphorylation process, electrons are transferred from electron carriers NADH and FADH2, through four complexes in the inner mitochondrial membrane, to oxygen, generating ATP in the process (Green and Brand, 2004). Under normal conditions, O2′-, is immediately eliminated by natural defense mechanisms. A recent study demonstrated that hyperglycemia-induced generation of O2′-, at the mitochondrial level is the initial trigger of vicious cycle of oxidative stress in diabetes (Nishikawa et al., 2000). When endothelial cells are exposed to hyperglycemia at the levels relevant to clinical diabetes, there is increased generation of ROS and especially O2′- , which precedes the activation of four key pathways that are involved in the development of diabetic complications. Nishikawa and colleagues elegantly demonstrated that generation of excess pyruvate via accelerated glycolysis under hyperglycemic conditions floods the mitochondria and causes O2′-, generation at the level of complex II in the respiratory chain. What is more important is that blockade of O2′-, radicals by three different approaches using either a small molecule uncoupler of
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