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Liver plays an important role in glucose metabolism. It is the organ that absorb and stores glucose. When there is excess amount of glucose in the blood, the liver will convert that into glycogen or fatty acid (Germann, 2005).Such action is linked to the concentration of insulin in the blood.
Insulin is a peptide hormone that is produced and secreted by beta cells of the islets of Langerhans in the pancreas. Its main action is to promote the uptake of glucose in tissues and the synthesis of glycogen and fatty acid from glucose. It also inhibits the breakdown of protein, triglyceride and glycogen. When there is a decrease production or resistance on insulin, this will result in the abnormality in glucose metabolism and will cause hyperglycaemia. This will then progress into diabetes.
According to the World Health Organization, there are more than 220 million people have diabetes in the worldwide and about 5% of the global deaths are caused by diabetes(WHO, 2010).
Diabetes is a chronic disease that will result in hyperglycaemia, this occurs when there is a deficiency and/or resistant of insulin. The reference range of blood glucose level is 3.5-8.0mmol/L. Blood glucose level is regulated by the body and will rarely go out of the range even during fasting, exercising or having a meal. Having a blood glucose level higher than the range means the individual has diabetes. Diabetes mellitus can be classified into 3 major types which is type 1, type2 and gestational diabetes. It is a disease that is difficult to cure, but can be monitored and managed.
Type 1 diabetes:
Type 1 diabetes also known as insulin dependent diabetes mellitus is a form of diabetes that usually onset during childhood but can happen in any age, but the peak incidence is about the time of puberty. It is caused by the reduced insulin production due to the loss of insulin- producing beta cells in the islet of Langerhans. Usually the cause of the reduced beta cells is the presences of autoantibody that is directed against the pancreatic islet result in a T-cell mediated attack. The reduced amount of insulin, type 1 diabetes patient will have4 elevated blood glucose level result due to the excess glucose is not being metabolise or stored.
Type 2 diabetes:
Type 2 diabetes also known as non-insulin dependent diabetes mellitus is a common form of diabetes across all population. Studies show that genetics can be a risk factor of type 2 diabetes, but in 55% of diabetes cases in the U.S. was found to be associated with the high fat diet lifestyle, which the chronic obesity lead to insulin resistance.
This type of diabetes happens on pregnant women who does not have diabetes before but have developed a high blood glucose level. Gestational diabetes have similar symptoms as type 2 diabetes.
Signs and Symptoms of diabetes:
Diabetic patients will have common signs of polyuria and polydipsia which means they will have frequent urination and more thirsty. They might also show signs of increased hunger. Type 1 diabetes patients might also develop a significant weight loss and fatigue. Patients that have blood glucose level higher then 10mmol/L might have glucosuria where the glucose level has exceeded the renal threshold and the glucose in the urine has not completely reabsorbed in the proximal renal tubule. The high glucose level in the urine causes the increase of the osmotic pressure where the water is pull into the urine, this result in the increase in urine volume which is the reason of the polyuria. The fluid loss into the urine will causes the body to dehydrate which will causes polydipsia.
Diabetes is a disease that is associated with different kind of complications; this includes diabetic comas, muscle infraction, nephropathy, neuropathy, retinopathy and cardiovascular disease.
Diabetic ketoacidosis and hyperglycaemic hyperosmolar state are complications that can lead to a coma and is potentially life-threatening. It is due to the relative or absolute deficient on insulin causes the level of glucagon, catecholamines and cortisol to elevate which in terms will stimulate glycogenolysis which will increase the level of blood glucose as the glycogen in the liver is being broken down. The hyperglycemic state will cause osmotic diuresis, excess water is loss in the urine due to the high level of glucose in the urine, which will pull the water from to the urine, so as other electrolytes such as sodium and potassium. Osmotic diuresis will then result in dehydration.
The deficiency of insulin will also promotes the gluconeogenesis, where the protein stored is broken down into glucose and also the fatty acid in adipose tissue is also released. Such process will result acetoacetate and β-hydroxybutyrate which is known as ketone bodies, they can be use as energy for the brain when the glucose level is too low. The consequence of using ketone bodies as energy is that it is acidic, which will lower the blood pH and cause acidosis.
When the complication proceeds without treatment, it will then progress into a coma as the result of hyperglycemia and dehydration.
Diabetic patients have an increased risk of having cardiovascular disease. More than 50% of diabetic patients develop macrovascular complications .Atherosclerosis is believed to cause virtually 80% of the deaths for diabetic patients (Aronson, 2002).Dyslipidemia, hypertension and hyperglycaemia are risk factors for cardiovascular disease in diabetic patients (Vedel, 2003).
Atherosclerosis is caused by the build up of fatty materials in artery walls, this will causes the formation of plaque which will harden over time and narrow the blood vessel. When this plaque suddenly ruptures, the clot formation will be triggered result in a clot within the blood vessel, blocking the blood from flowing causes infarction of the organ. When this happens in coronary artery, this will cause myocardial infarction. Studies that have conducted in the last decades have started to appreciate more on the role of inflammation on atherosclerosis (Libby 2002).
Inflammation in Atherosclerosis:
Normal endothelial cells usually do not support the binding of leukocytes on the surface. A diet that is atherogenic will initiate the expression of surface selective adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) that is capable of binding with different kind of leukocytes including monocytes and T-lymphocytes (Libby 2002). After the adhesion, the leukocytes will starts to penetrate the intima of the vessel and research suggested that the monocyte chemoattrant protein-1 (MCP-1) might be responsible for the migration of the monocytes.
Diabetes and tissue damage
One of the characteristics of diabetes is the elevated blood glucose, causes hyperglycaemia. Body tissues in diabetics are having a hyperglycaemic environment. Most cells in the body have the capability to reduce the uptake of glucose when they are exposed to a hyperglycaemic environment, but some cells, such as capillary endothelial cells, mesangial cells and Schwann cells does not carry out this process as efficient as other cells, result in high cellular glucose level (Brownlee, 2004).
Within the cell, aldose reductase is usually function to reduce toxic aldehydes into inactive alcohol. High intracellular glucose level causes the aldose reductase to reduce the glucose into sorbitol, such process will consumes NADPH as an cofactor in which it is also an essential cofactor for the regeneration of an intracellular antioxidant, reduced glutathione. The reduced amount of reduced glutathione makes the cell more susceptible to intracellular oxidative stress.
Diabetes and Endothelial Dysfunction:
There are different possible metabolic pathways that can potentially involve or cause endothelial dysfunction.
High concentration of glucose will causes the increases of intracellular diacylglycerol (DAG) level; this will then ultimately lead to the activation of protein kinase C (PKC). PKC activation increases the gene expression of nitric oxide synthase (NOS III) and will increase the production of superoxide (Hink, 2001). Other metabolic pathways that are potentially involved in endothelial dysfunction includes polyol pathway and AGE formation.
(Endothelial Dysfunction in Diabetes)
Advanced Glycation End products (AGEs):
Through nonenzymatic glycation and oxidation, protein and lipids can form Advanced Glycation End products (AGEs). Condition such as diabetes, inflammation, renal failure and aging will cause the accumulation of AGEs in the body (Ramasamy, 2005).
AGE was first described as a group of compounds that is characterized by their yellow-brown fluorescent colour and their ability to form amino acid cross-links, but AGEs is now a term used to describe a much broader range of compounds that result from the Maillard Reaction (Bierhaus, A., 1998).
In healthy individual, AGE will be produced in a slow constant rate (Peppa, 2003), but studies have shown that diabetes will lead to the increase formation of AGEs within the body (reference).
Formation of AGEs starts from the formation of a Schiff base from the non-enzymatic between reducing sugars and proteins, lipids or nucleic acids, in which it will then be rearranged and form Amadori products. Glycated Haemoglobin (HbA1c) is one of the widely used measurements for monitoring diabetic patient, and is one of the examples of the glycation process. At the stage of Schiff base and Amadori products, it is reversible.
Through dehydration, successive β-eliminations and condensation reactions will then yield the final AGEs, which is irreversibly cross-linked.
Examples of AGEs included FFI, AFPG, pentosdine, pyrraline and CML.
(Bierhaus, A., 1998)
Studies have shown that type 2 diabetes patients have an elevated level of serum AGEs (Kilhovd, 1998).
AGEs can damage blood vessel wall through two mechanisms which can be receptor-dependant and non-receptor dependant.
Blood vessel wall contains collagen which have a relatively longer half-life and can be able to undergone non-enzymatic glycation causes the formation of AGEs. This will then affect its ability on forming a normal network-like structure which will then alter its function on the vessel. AGEs is also able to promote the cross-linking of proteins which can alter the structure and function of protein, this will lead to the trapping of low-density lipoprotein (LDL) in the arterial wall which can cause atherosclerosis (Lindsey, 2010). AGEs is a ligand of RAGE, the binding of AGEs to RAGE will activate the intracellular action of NF-κB, causes the inflammation of the vessel wall.
Receptor of Advanced Glycation End products:
The Receptors of Advanced Glycation End products (RAGE) are first describe as receptor for AGEs, but studies have now shown that RAGE is a multi-ligand receptor of the immunoglobulin superfamily (Ramasamy, 2005).
RAGE is a protein that contains 403 amino acids. (Basta, 2004). The extracellular region of the RAGE is composed of three immunoglobulin-like domains. There are one V-type and two C-type domains which is called C1 and C2. The V and C1 is thought to be linked together to form one integrated unit (VC1) with a cytoplasmic tail of 43 amino acid long. C2 is linked to the VC1 by a flexible linker which is fully independent (Bierhaus, 2009). The V-type domain is used for ligand binding but the cytoplasmic tail is critical for the intracellular signalling function. (Bierhaus, 2005).
RAGE gene is localized on chromosome 6 somewhere near the HLA locus which is also the area near where the MHC III complex gene is coded (Bierhaus, 2005).
Amyloid-beta peptide (a substance that accumulate in Alzheimer's disease), β-sheet fibrils, s100/calgranulins, amyloid A (a subdtances that accumulate in systemic amyloidosis), amphoterin and MAC-1 are also ligands known that can bind with RAGE (Bierhaus, 2005).
Other than these ligands, RAGE is also used as an endothelial adhesion receptor for leucocytes intergrins for the promotion of recruitment leucocytes during inflammation and when having an immune response (Jandeleit-Dahm, 2008). RAGE is also found to be able to interact with surface molecules of bacteria (Chapman, 2002) and prions (Sasaki, 2002). Due to its ability on binding with bacteria and prions, some scientists think RAGE should be considered to be pattern recognition receptors (PRR) (Liliensiek, 2004).
Receptors that binds with AGEs were thought to be involved in AGE disposal and cell regenerative, therefore were called scavenger receptors (Bierhaus, 2005), but after the RAGE have been successfully cloned and studied, scientists found that RAGE does not accelerate the clearance or degradation of AGEs, instead, the AGEs-RAGE interaction induce the post-receptor signalling. This includes the activation of p21ras, MAP kinases and the NF-κB pathway (Bucciarelli, 2002).
Animal models show that overexpression of RAGE have increases the vascular injuries in diabetes associated enhanced atherosclerosis model. This confirmed that RAGE contributes at least in part of the development of macro- and microvascular complications in diabetic patients (Bierhaus, 2009).
Nuclear Factor kappa-light chain-enhancer of activated B cells (NF-κB) is a protein complex that acts as a proinflammatory transcription factor (Bierhaus, 2005). There are 5 proteins in the NF-κB family, they are NF-κB1, NF-κB2, RelA, RelB and c-Rel. Studies have shown that v-Rel is also belongs to the NF-κB family (Gilmore, 2006).
NF-κB can be refers to the superfamily where Rel and NF-κB is the subfamilies included across species, but it can also refers to the subfamily which includes p100, p105 and Relish or even the specific p50-Rel A hetetodimer, the protein that is known as the major NF-κB dimmer (Gilmore, 2006).
The NF-κB is closely regulated by the IκB proteins which is an inhibitor of the NF-κB transcription factors. There are different IκB proteins which are IκB, IκBβ, IκB and IκB. When the NF-κB is activated the IκBwill be phosphorylated and degraded rapidly, this action will cause the release of the NF-κB hetrodimer p50/p65 into the nucleus of the cell.
The released NF-κB will then binds to the DNA sequence and the transcription of the target gene will starts, these includes cytokines, adhesion molecules, prothromobotic and vasoconstrictive gene products (Bierhaus, 2005) RAGE mediated NF-κB activation will uniquely overwhelm the endogenous auto regulatory feedback inhibition loops due to its prolonged time course (Bierhaus, 2001). As the expression of RAGE is induced by NF-κB, the continuous activation of RAGE will form a postive feedback loop which will enhance the cellular inflammation response causes chronic inflammation (Jandeleit-Dahm, 2008).
RAGE-dependent NF-κB activation is result from the degradation of the inhibitory IκB protein, this will then followed by the synthesis of new NF-κBp65 when there is new IκBβ being synthesized. This is called De novo synthesis of NF- κBp65 which will result in an excess amount of transcriptionally active NF- κBp65 where the amount of IκB is not sufficient to retain it in the cytoplasm. As NF-κB induce RAGE expression, the sustain activation of NF-κB will upregulate RAGE, maintain and amplification of the signal. RAGE expression is usually low under physiological conditions. Inflammation can induce RAGE as its transcription is controlled by different proinflammatory transcription factors such as SP-1, AP-1, NF-IL6 and NF-κB (Bierhaus, 2005).
Many pharmacological studies have been done on the intervention of the AGE/RAGE axis in order lower the risk of atherosclerosis. This is done by the inhibition of AGE accumulation by either inhibiting the AGE formation or breaking the cross-links.
Conjugated Linoleic Acids (CLA):
In 1979, Scientists investigated the effect of cooking time and temperature on the mutagen formation in pan-fried hamburger, but have discovered that there is mutagenic inhibitory activity on both cooked and uncooked ground beef (Pariza, 1979)
The molecular formula of CLA is C18H32O2 with the molecular of 280.44548.The is two double bonds in the CLAs and they are both conjugated. CLA is both trans and cis fatty acid.
Conjugated Linoleic Acids (CLA) are polyunsaturated fatty acid (PUFA), some of the isomers can be found naturally in animal products such as meat and diary products especially from ruminant (Chin, 1992). Studies have shown that CLA have anti-atherosclerosis and anti-diabetic effects in animal models (Whigham, 2000), CLA are also known to have anti-obesity effect (Blankson, 2000), therefore it is widely used as a weight loss supplement, but the data from human studies is not consistent with the animal models. CLA supplements are also being sold as a panacea that is able to reduce or eliminate cancer, prevent heart disease (Whigham, 2000). It usually contains 2 isomers (c9t11 and t10c12) in equal percentage. A lot of studies were conducted using both c9t11 and t10c12, but a report showed that the t10c12 CLA isomer have caused insulin resistance in abdominally obese men. The t10c12 supplementation increase the oxidative stress and inflammatory biomarkers in obese men, this might be clinical important on cardiovascular disease (Riserus, 2002), this indicates that individual isomers might have different effect on health.
C.M. Reynolds, H.M. Roche, Conjugated linoleic acid and inflammatory cell signalling, Prostaglandins Leukotrienes Essent. Fatty Acids (2010), doi:10.1016/j.plefa.2010.02.021
Dietary Source of CLA:
Dairy products and meat from grass fed animals contains CLA, this include milk, beef and mutton. Studies have been conducted on the diet of the cow and found that when the cow is fed with lionleic or linolenic acid rich diet, the CLA content in the milk shown to be increased (Dhiman, 2000). Eggs is also one of the dietary source that contains CLA, in fact studies shown that the CLA in eggs did not undergone significant change after the storage of 6 months or fried for 40 seconds, the studies concluded that there might be some components within the egg yolk that protect the CLA from degradation (Lin, 2004). Vegetable rarely contains CLA, but the common button mushroom (Agaricus bisporus) that is cultured in 0.4% of safflower oil is suitable for the production of c9t11 CLA (Jang, 2004)