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The Rapidly Increasing Prevalence of Diabetes Mellitus Worldwide Is One of The Most Serious and Challenging Health Problems in The 21st Century
The Rapidly Increasing Prevalence of Diabetes Mellitus Worldwide Is One of The Most Serious and Challenging Health Problems in The 21st Century
Prevalence of Diabetes
The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century. Over the past 30 yr, the status of diabetes has changed from being considered as a mild disorder of the elderly to one of the major causes of morbidity and mortality affecting the youth and middle aged people. According to recent estimates, approximately 285 million people worldwide (6.6%) in the 2079 year age group will have diabetes in 2010 and by 2030, 438 million people (7.8%) of the adult population, is expected to have diabetes [International Diabetes Federation, 2009].The largest increases will take place in the regions dominated by developing economies. The global increase in the prevalence of diabetes is due to population growth, aging, urbanisation and an increase of obesity and physical inactivity. The primary determinants of the epidemic are the rapid epidemiological transition associated with changes in dietary patterns and decreased physical activity. Unlike in the West, where older populations are most affected, the burden of diabetes in Asian countries is disproportionately high in young to middle-aged adults [Chan et al., 2009; Ramachandran et al., 2010]. Roughly 80% of people with diabetes are in developing countries, of which India and China share the larger contribution [Ramachandran et al., 2010]. It is estimated that the total number of people with diabetes in 2010 to be around 50.8 million in India, rising to 87.0 million by 2030 [International Diabetes Foundation, 2009].
production via regulation of inducible NO synthase (iNOS) [Stephens et al., 1999; Eizirik et al., 1996]. IFN- also enhances IL-1 production by APC which is also toxic to -cells [Papaccio et al., 2005]. Proinflammatory cytokines, TNF-, IFN-, and IL-1, can also upregulate Fas expression on -cells, facilitating cell recognition, and also stimulate Nitric oxide and reactive oxygen species (ROS) production, exacerbating cell death [McKenzie et al., 2006; Wachlin et al.,2003; Kwon et al., 1999; Kim et al., 2005]. Similar to T1DM, T2DM is also characterised by progressive loss of -cells through multiple pathways. These mechanisms include increased circulating cell nutrients [Maedler et al.,2001; Roehrich et al., 2003], endoplasmic reticulum (ER) stress [Harding & Ron, 2002], signalling factors from adipocytes [Zhao et al., 2006] and more recently, infiltration of immune cells. Plasma free fatty acid (FFA) levels are permanently increased in obesity, which causes insulin resistance and diminishes glucose uptake, resulting in transient postprandial hyperglycemic excursions. Elevated glucose causes oxidative stress due to increased production of mitochondrial ROS [Brownlee, 2001], nonenzymatic glycation of proteins [Brownlee & Cerami, 1981; Brownlee, 2000], and glucose autoxidation [Wolff & Dean, 1987; Wolff et al., 1991].The toxic effect of FFA is manifested as oxidative stress via formation of ceramide, increased nitric oxide production, mitochondrial uncoupling [Wojtczak & Schonfeld, 1993; Carlsson et al., 1999] and -oxidation [Yamagishi et al., 2001; Rao & Reddy, 2001], leading to activation of the apoptotic mitochondrial pathway [Maedler et al., 2003; Shimabukuro et al., 1998].This mild hyperglycemia could act on the -cells even before diabetes manifests itself or at the very early stages of the disease. Therefore both nutrients, FFAs and glucose, may interfere with -cell turnover and function influencing the onset and course of diabetes. ER is stressed by disturbances in cellular redox regulation, glucose deprivation, high fat diet and protein misfolding [Yoshida, 2007; Kim et al., 2008] that cause apoptosis of the -cells. Adipocyte secreted factors are leptin, TNF, IL-6 and IL-1 receptor antagonist (IL-1 Ra) [Fried et al., 1998; Hotamisligil et al., 1993; Meier et al., 2002; Zhang et al., 1994], whose expression are upregulated in obesity and have been causally linked to insulin resistance. Increase serum levels of IL-1, IL-6, and TNF- is also contributed by macrophages and endothelium in Type 2 diabetics patients [Pickup & Crook, 1998]. These cytokines may act on the pancreatic islets and impair -cell secretory function.
Insulin regulates gene expression through MAP Kinase pathway. Insulin initiates a signal that travels a branched pathway from the plasma membrane receptor to insulin-sensitive enzymes in the cytosol and to the nucleus, where it stimulates the transcription of specific gene. The Insulin receptor INS-R is a receptor enzyme with tyrosine kinase activity. Insulin signalling pathway begins when binding of insulin to INS-R activates its Tyrosine kinase activity and each subunit phosphorylates three critical tyrosine residues near the carboxyl terminus of the other subunit in the () 2 dimer. The kinase catalyzes the phosphorylation of tyrosine residue on other protein such as IRS-1. Phosphotyrosine residues of IRS-1 binds to the SH2 (Src homology-2) domain of the protein Grb2, which act as an adaptor protein to bring together IRS-1 and Sos protein. Sos bound to Grb2 catalyzes GDP-GTP exchange on Ras (a small G protein), which in turn activates a MAPK cascade that ends with the phosphorylation of target proteins in the cytosol and nucleus. The result is specific metabolic changes and altered gene expression. The enzyme PI-3K (Phosphoinositide 3 kinase), activated by interaction with IRS-1, converts the membrane lipid PIP2 (Phosphatidylinositide 4,5-bisphosphate) to PIP3 (Phosphatidylinositide 3,4,5triphosphate), which becomes the point of nucleation for proteins in a second and third branch of insulin signalling [Lehninger 5th Edition, 2008 A].
N-acetylglucosamine. Specific O-linked N-acetylglucosamine (O-GlcNAc) transferases use this for posttranslational modification of specific serine and threonine residues on cytoplasmic and nuclear proteins by O-GlcNAc.
mitochondrial isoform of the enzyme SOD degrades this oxygen free radical to hydrogen peroxide, Figure 1: Production of ROS by the mitochondrial electron transport chain. which is then converted to H2O and O2 by other enzymes. In primary arterial endothelial cells in culture, intracellular hyperglycemia increases the voltage across the mitochondrial membrane above the critical threshold necessary to increase superoxide formation [Korshunov, 1997] and, subsequently, increases production of ROS. It has been also demonstrated that dynamic changes in mitochondrial morphology are associated with high glucose-induced overproduction of ROS. Inhibition of mitochondrial fission prevented periodic fluctuation of ROS production during high glucose exposure [Yu et al., 2006]. Neither hyperglycemia nor increased fatty acid oxidation in vascular endothelium increases ROS nor activates any of the pathways when either the voltage gradient across the mitochondrial membrane is collapsed by uncoupling protein 1 (UCP-1) or when the superoxide produced is degraded by manganese super oxide dismutase (MnSOD) [Du et al., 2001]. Although it thus appears that the mitochondria are required for the initiation of hyperglycemia-induced superoxide production, much evidence indicates that this, in turn, can activate a number of other superoxide production pathways that may amplify the original damaging effect of hyperglycemia. These include redox changes, NADPH oxidases, and uncoupled endothelial nitric oxide synthase (eNOS). Diabetes in animals and patients, and hyperglycemia in cells, all decrease the activity of the key glycolytic enzyme Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in cell types that develop intracellular hyperglycemia. Hyperglycemia-induced superoxide inhibits GAPDH activity in vivo by modifying the enzyme with polymers of ADP-
ribose [Du et al., 2003]. Inhibition of GAPDH activity by hyperglycemia does not occur when mitochondrial overproduction of superoxide is prevented by either UCP-1 or MnSOD [Nascimento et al., 2006]. When GAPDH activity is inhibited, the levels of all the glycolytic intermediates those are upstream of GAPDH increase. This then increases the flux into the 5 pathways described earlier. Along with UCP-1 or MnSOD, both modification of GAPDH by poly (ADP-ribose) and reduction of its activity by hyperglycemia were prevented by a specific inhibitor of poly (ADP-ribose) polymerase (PARP), the enzyme that makes these polymers of ADP-ribose. Normally, PARP resides in the nucleus in an inactive form, waiting for DNA damage to activate it. When increased intracellular glucose generates increased ROS in the mitochondria, free radicals induce DNA strand breaks, thereby activating PARP. Once activated, PARP splits the NAD molecule into its 2 component parts: nicotinic acid and ADP-ribose. PARP then proceeds to make polymers of ADP-ribose, which accumulate on GAPDH and other nuclear proteins.
Glutathione disulde is recycled back to glutathione by glutathione reductase, using the cofactor NADPH generated by glucose 6-phosphate dehydrogenase. There is not total agreement about the effects of diabetes on the activities of these enzymes. However, glutathione peroxidase activity is seen to be elevated in liver [Rauscher et al., 2001; Rauscher et al., 2001; Rauscher et al., 2000; Rauscher et al., 2000; Aragno et al., 1999; Sanders et al., 2001], kidney [Rauscher et al., 2001; Rauscher et al., 2001; Rauscher et al., 2000; Aragno et al., 1999; Kedziora-Kornatowska et al., 2000], aorta [Kocak et al., 2000], pancreas [Jang et al., 2000], blood [Mohan & Das, 1998; El-Khatib et al., 2001; Kedziora-Kornatowska iet al., 1998], and red blood cells [Sailaja et al., 2000], whereas decreased activity was seen in heart [Kaul et al., 1995; Kaul et al., 1996] and retina [Obrosova et al., 2000].
Glutathione level
Reduced glutathione is a major intracellular redox buffer that may approach concentrations up to 10 mM. Glutathione functions as a direct free-radical scavenger, as a co-substrate for glutathione peroxidase activity, and as a cofactor for many enzymes, and forms conjugate in endo- and xenobiotic reactions. Glutathione concentration is found to be decreased in the liver [Ewis & Abdel-Rahman, 1995], kidney [Ha & Lee, 2000], pancreas, plasma, red blood cells, nerve, and pre-cataractous lens of chemically induced diabetic animals. However, there is also some contradictory evidence of increased glutathione concentration in diabetic rat kidney and lens.
Vitamins
Vitamins A, C, and E are diet-derived and detoxify free radicals directly. They also interact in recycling processes to generate reduced forms of the vitamins. -Tocopherol is reconstituted when ascorbic acid recycles the tocopherol radical; dihydroascorbic acid, which is generated, is recycled by glutathione. These vitamins also foster toxicity by producing prooxidants under some conditions. Vitamin E, a component of the total peroxyl radical-trapping antioxidant system, reacts directly with peroxyl and superoxide radicals and singlet oxygen and protects membranes from lipid per-oxidation. The deciency of vitamin E is concurrent with increased peroxides and aldehydes in many tissues. There have been conicting reports about vitamin E levels in diabetic animals and human subjects. Plasma and /or tissue levels of vitamin E are reported to be unaltered, increased, or decreased by diabetes.
into several fragments, which are encapsulated within the forming apoptotic bodies. In the plasma membrane, cell junctions are disintegrated, whereby the plasma membrane becomes active and convoluted, eventually blebbing. The cells Breaks up in a florid manner leading to the falling away of several membrane spheres containing the packaged cellular contents identified as apoptotic bodies of various size [Kerr et al., 1994]. Since the apoptotic bodies are surrounded by an intact plasma membrane, apoptosis is usually occurs without leakage of cell content and usually without inflammation. This form of physiological cell death is morphologically quite different from oncosis, in which the cell swell and disintegrates in an unordered manner, eventually leading to the destruction of cellular organelles and finally rupture of the plasma membrane and leakage of the cell content, which signs necrosis. Apoptosis process requires two very important proteins to occur, without which it is impossible. They are Bcl-2 family protein and Caspase. The Bcl-2 proteins are again subdivided into anti-apoptotic members, Bcl-2 and Bcl-XL, and pro-apoptotic members, Bax, Bak, Bad, Bim, Bid, and Bik. Bcl-2 is the first discovered proto-oncogene and its oncogene characteristics are due to its ability to prevent apoptosis (rather than stimulate proliferation). It was reported to act in an antioxidant manner. The anti-apoptotic protein, Bcl-2 and Bcl-XL contains a C-terminal membrane anchor and the four Bcl-2 homology (BH1-BH2) domains. The pro-apoptotic members, Bax and Bak lack some of the four BH domains and Bad, Bik, Bid, and Bim contains only the BH3 domain. The relative levels of pro- and anti-apoptotic proteins determine a cells susceptibility to apoptosis [Korsmeyer, 1995]. There are fourteen mammalian caspases identified to date [Strasser et al., 2000]. Caspase is so named because it contain a key cysteine residue in the catalytic site and selectively cleave proteins at sites just C-terminal to aspartate residues. They are synthesized as pro-enzymes, which usually undergo proteolysis and activation by other caspases in a cascade [Earnshaw et al., 1999]. Caspases can be grouped into subclasses in various ways. Functionally, we can distinguish three classes of caspases; (i) the initiator caspases that are characterized by long prodomains (> 90 amino acids) containing either death effector domain (DED) domains (caspase-8 and caspase-10) or a caspase recruitment domain (CARD) (caspase2 and caspase-9); (ii) the executioner or effector caspases containing short prodomains (caspase-3, caspase-6 and caspase-7) and (iii) the remaining caspases which main role lies in cytokine maturation rather than apoptosis [Grutter, 2000]. Apoptosis can be triggered by a wide variety of cellular stresses, including DNA damage, radiation, ionizing radiation, heat shock and oxidative stress, as well as by extracellular stimuli acting through cell-surface receptors. Nevertheless, most cells undergoing apoptosis exhibit a similar series of changes, suggesting that these signals converge to engage a common pathway leading to cell death. The regulatory mechanisms that trigger apoptosis involve some of the same proteins that regulate the cell cycle. The signal for suicide often comes from outside, through a surface receptor. Tumor necrosis factor (TNF), produced by cells of the immune system, interacts with cells through specific TNF receptors. These receptors have TNFbinding sites on the outer face of the plasma membrane and a "death domain" (-80 amino acid residues) that carries the self-destruct signal through the membrane to cytosolic proteins such as TRADD (TNF receptor-associated death domain). Another receptor, Fas, has a similar death domain that allows it to interact with the cytosolic protein FADD (flas-associated death domain), which activates the cytosolic protease caspase 8. When caspase 8, an "initiator" caspase, is Figure 2: Extrinsic pathway of apoptosis mediated
activated by an apoptotic signal carried through FADD, it further self-activates by cleaving its own proenzyrne form. Mitochondria are one target of active caspase 8. The protease causes the release of certain proteins contained between the inner and outer mitochondrial membranes:cytochrome c and several effector caspases. Cytochrome c binds to the proenzyrne form of the effector enzyme caspase 9 and stimulates its proteolytic activation. The activated caspase 9 in turn catalyzes wholesale destruction of cellular proteins-a major cause of apoptotic cell death. This pathway of apoptosis is known as extrinsic or receptor mediated pathway (Figure 2) [Lehninger 5th Edition 2008, B].
Another pathway (also called intrinsic or Bcl-2 regulated) involved in the activation of apoptosis is carried out through mitochondria under oxidative stress and treatment with cytotoxic drugs. Mitochondria play a critical role in triggering
apoptosis. When a stressor gives the signal for cell death, one early consequence is an increase in the permeability of the outer mitochondrial membrane, allowing cytochrome c to escape from the intermembrane space into the cytosol (Figure 3)
The increased permeability is due to the opening of the permeability transition pore complex (PTPC), a multisubunit protein in the outer membrane; its opening and closing are affected by several proteins that stimulate or suppress apoptosis. When released into the cytosol,
cytochrome c interacts with monomers of the protein Apaf-l (apoptosis protease activating factor-l), causing the formation of an apoptosome composed of seven Apaf-l and seven cytochrome c molecules.The
apoptosome provides the platform on which the protease procaspase-9 is activated to caspase-9, and activated caspase-9 initiates a cascade of proteolytic activations, with one caspase activating a second, and it in turn activating a third, and so forth [Lehninger 5th Edition 2008, C] Figure 3: Intrinsic pathway of apoptosis Endoplasmic reticulum (ER), a highly dynamic organelle with a central role in lipid and protein biosynthesis, also plays important role in apoptosis. The translation of proteins is performed by ribosomes on the cytosolic surface of the ER [Adesnik et al., 1976], and the unfolded polypeptide chains are translocated into the ER lumen, where they are often Nglycosylated and folded into secondary and tertiary structures that are stabilized by disulfide bonds [Kornfeld & Kornfeld, 1985]. The unique oxidizing environment of the ER and the numerous protein chaperones present in the organelle are crucial for the proper folding of proteins and protein complexes [Gething & Sambrook, 1992] The ER is exquisitely sensitive to alterations in homeostasis, and proteins formed in the ER may fail to attain correct conformation due to: 1) lack of chaperones or cellular energy to promote chaperone-protein interactions; 2) Ca2 depletion; 3) disruption of redox state; 4) protein mutations that hamper adequate folding; and 5) reduction of disulfide bonds. Accumulation of misfolded proteins that aggregate in the ER lumen causes ER stress and activation of a signal response termed the unfolded protein response (UPR) [Patil & Walter, 2001; Marciniak & Ron, 2006; Zhang & Kaufman, 2006; Ron & Walter, 2007]. The aim of the UPR is to alleviate ER stress, restore ER homeostasis, and prevent cell death. To achieve these goals, the UPR induces several coordinated responses, including: 1) a decrease in the arrival of new proteins into the ER, thus preventing additional protein misfolding and overloading of the organelle; 2) an increase in the amount of ER chaperones, thus augmenting the folding capacity of the ER to deal with misfolded proteins; 3) an increase in the extrusion of irreversibly misfolded proteins from the ER and subsequently degradation of these proteins in the proteasome; and 4) in case the steps described above fail, apoptosis is triggered. In case the UPR fails to solve ER stress, the apoptosis pathway will be activated.
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peroxides and an enhancement of erythrocyte Cu, Zn-SOD activity, this effect resulting from a free radical scavenging activity independent of glycemic control [Jennings & Belch, 2000]. In recent years there has been an increased interest in areas related to newer developments in the prevention of disease especially those involving natural compounds with antioxidant activities. These antioxidants neutralize free radicals or their activities. Such compounds, especially derived from natural sources and capable of minimizing oxidative damage in situ, have potential uses to control human diseases. These compounds, capable of interacting with DNA, cellular membranes and other biomolecules have potential protective properties against deleterious free radicals [Sies, 1996; Packer & Ong, 1998; Surh, 2003]. Chlorophyllin (CHL) is a water-soluble analogue of chlorophyll, the ubiquitous photosynthetic green pigment present in food materials of plant origin as well as in nutritional supplements such as extracts from Spirulina and Chlorella vulgaris. Chlorophyll has been credited with several beneficial properties. Chlorophyllin, has proved to be better than the parent compound as evident from studies employing model systems [Negishi, 1997; Dashwood et al, 1998]. It possesses highly potent antioxidant activity [Sato et al, 1984; Sato et al, 1985; Kamat et al, 2000; Kumar et al, 2001]. It has been used, without apparent toxic side effects, to treat a number of human ailments. Chlorophyllin is a potent antioxidant against oxidative stress induced by radiation, photosensitization and peroxynitrite as measured by inhibition of lipid peroxidation, protein oxidation, DNA damage and restoration of endogenous antioxidants [Kamat et al, 2000; Kumar et al, 2001]. It is therefore considered apropriate to investigate protective effects of CHL agaist oxidative damage under different forms of oxidative stress such as hyperglycemia induced oxidative stress. To summarize, Free radicals have been implicated in the etiology of large number of major diseases. They can adversely alter many crucial biological molecules leading to loss of form and function. Such undesirable changes in the body can lead to diseased conditions. Antioxidants can protect against the damage induced by free radicals acting at various levels. Dietary and other components of plants form major sources of antioxidants. The relation between free radicals, antioxidants and functioning of various organs and organ systems is highly complex and the discovery of redox signaling is a milestone in this crucial relationship. Recent research centers around various strategies to protect crucial tissues and organs against oxidative damage induced by free radicals. Many novel approaches are made and significant findings have come to light in the last few years. Coordinated research involving biomedical scientists, nutritionists and physicians can make significant difference to human health in the coming decades. Research on free radicals and antioxidants involving these is one such effort in the right direction.
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A literature review submitted to the Department of Biochemistry for the partial fulfilment of the pre Ph.D course work (2012)