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Type two diabetes also known as non-insulin-dependent diabetes mellitus is a heterogeneous, complex, costly disease with serious etiologic effects (1). It affects about 8 percent of adult in the United States. Many drugs are available to treat T2D but does not usually maintain normal glycaemia or treat its devastating complication. In many cases there is a fail of early diagnosis until complication are appear and the available treatment methods are insufficient for treatment of T2D , prevention is preferable(8). There are three combination factor are associated in T2D these are, insulin resistance , progressive of beta cell deterioration which cause in impaired insulin secretion and release, increase hepatic glucose production as the result of enhance glycogenolysis and gluconeogenesis (1). The primary cause are of T2D is unknown, but there are many factor that are associated with development of T2D such as obesity due to increase demand of fast food, luck of exercise due to sedentary lifestyle, genetic and environmental factors(7).
2. Insulin resistance and type two diabetes (T2D)
Insulin resistance is defined as a failure to respond to normal concentration of circulating insulin. The most characteristic feature of insulin resistance is defect or decrease ability of insulin to act on peripheral tissues such as adipose tissue, skeletal muscle, liver and pancreatic Î² -cell defects as well as failure of insulin to inhibited glucose output of the liver. Insulin resistance in skeletal muscle and liver is considering the basic defects in the pathogenesis of T2D (2).
Fig. 1. The T2D pathway adapted from http://savvyhealthfitness.com/get-healthy/diabetes/type-
3. PPARÎ³ and Thiazolineodiones (TZDs) or Glitazones
Peroxisome proliferation-activated receptor (PPAR) is a family of ligand-activated transcription factors, that have three subfamily, knows as Î± , Î² , and Î³ . PPARÎ³ subfamily plays important role in regulating glucose and lipid metabolism and it is concerned in many associated metabolic diseases for examples T2D hyperlipidemia and atherosclerosis. Therefore it has been target for many therapeutic applications (10).
There are many drugs that have been developed to treat T2D. Thiazolineodiones (TZD) are new class of drugs for treatment of type 2 diabetes. These medicines bind to peroxisome proliferators activated receptor gamma in adipocytes to promote adipogenesis and fatty acid uptake. This cause reduction of fatty acid concentration in the circulation and the availability in liver and muscle and consequence the drugs improve the patient sensitivity to insulin (4). Even though the beneficial of antidiabetic drugs available to treat T2D, these drugs have many side effect and some of them have been reported to be associated with cardiac failure and death, such as TZD as it was reported in Nissen at al (2007).
Fig. 2. Mechanism of thiazolidiones adapted from ( Greenfied J at al 2004)
4. The role of non-pharmaceutical methods in prevention and treating of T2D.
Many observation shows that insulin can be induced by high fat and sugar diet which cause decrease of the ability of insulin to activate GLUT4 in the muscles. Hyper glycaemia in this case can be overcome successfully by physical exercise to over expression the GLUT4 in the muscles. Moreover, obesity or increase of body mass by overdiet is linked to decrease of peripheral cell sensitivity to insulin and deficiency in cellular glucose transportation. However this can be overcome by reduce of the body mass or weight (3). Since T2D is caused by overweight, sedentary lifestyle it can theoretically be reversible by modifying lifestyle (8). For example, The Diabetes Prevention Program Research Group (DPPRG) conducted a large group randomly selected adult who at high risk for developing T2D. The participants were assigned to three groups, standard lifestyle recommendation plus metaformin (glucophage) drugs, standard lifestyle recommendation plus placebo, and intensive program of lifestyle modification. The standard lifestyle recommendation was provided as written information about health lifestyle such diet and increase their physical activity. Intensive lifestyle intervention was to follow low-fat diet and engage in physical activity of moderate intensity for at least 150 minutes per week. The average follow-up was 2.8 years and it was fund that the incidence of diabetes was 11.0, 7.8, and 4.8 causes per 100 people in the placebo, metaformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence of diabetes by 85 percent as compared with the other groups who taking antihyperglycemic agent (placebo and metaformin ) . From this research we can conclude that, healthy diet and exercise can prevent and reduce the incidence of diabetes in persons at high risk and it is more effective then treatment with drugs (8).
Generally physical activities such as exercise are known to increase, directly and indirectly, in muscles uptake of glucose and insulin sensitivity, also it play important role in the treatment of metabolic disorder such as T2Dand atheroclersis . Despite the beneficial of the exercise the effect of exercise is different from one person to another, and can be affected by many conditions such as environment and genetic background (5). For instance, many studies shows that oxidation of LDL enhance the atherogenic process. According to Butcher et al. (2008) an exercise cause increase in metabolic activity and hypoxia and subsequent increase the level of oxidative stress in the body over short period these cause elevated production of cellular hydroperoxides which cause increases the oxidation of the LDL. Oxidized LDL (oxLDL) acts as chemoattractant triggering the emigrations of monocyte to the subendothelial space and cause the development of atherosclerosis. However, the differentiation of monocytes into macrophages process involves many transcription factors, they are; peroxisome proliferator-activated receptors (PPAR), liver X receptors (LXR), the consequent up-regulation of PPAR response element (PPRE)- and LXR response elemet (LXRE)- bearing target genes. For example, the process of binding of PPARÎ³ (one of the PPAR isoform) to PPRE within the promoter of the gene encoding CD36 (a lipid scavenger receptor) can be activated by oxLDL isoform , this upregulation cause enhance oxLDL uptake. Moreover, as it has been stated in Butcher et al." oxidation renders LDL unrecognizable to the LDL receptor and encourages its uptake by scavenger receptor on macrophages in an unregulated manner" (6). CD36 is expressed in many cell types; such as microvascular endothelial cells, skeletal muscle, as well as macrophages or monocytes. Moreover, many studies reveals that macrophage CD36 mRNA up-regulation expression phenomena is beneficial and can be used as therapeutic target to reduce plasma cholesterol level because stimulation of macrophage with CD36 ligands by acting as antiatherosclerotic agents (6). This approach can be achieved, since migrated oxLDL into atherosclerotic site can be exported in the form of lipid-poor apolipoproteins by reverse cholesterol transport (RCT). This mechanism is done by ATP-binding cassette transporter A1 (ABCA1) protein with the associated of ATP- binding cassette transporter G1 (ABCG1) as a mediator of macrophage cholesterol efflux (6). In the base of this finding, many studies was done and one of these recent study was done with thirty-four inactive adult participated based on aerobic low-intensity exercise program , serum lipoprotein concentration was collected and shows a significant decrease in total cholesterol compared with the unexercised ( control) group and significant increase in HDL after the exercise program. Furthermore, there was a significant increase in serum oxidized LDL concentration in the exercise group before and after exercise. A significant increase in leucocytes mRNA expression for CD36 (the oxLDL scavenger receptor) was noted also there was significantly upregulated of ABCA1 and ABCG1 after 8 weeks (6). The author argues that 'this change will stimulate RCT and promote clearance of proatherogenic lipid from the vascular' (6). Similar study was done to see how low- intensity exercise increase expression of circulating monocytes and show how the differentiated in to an anti-inflammatory M2 macrophagetype, the result shows that low intensity exercise cause up regulation of M2 markers, PGC-1Î± and PGC-1Î² and down regulation of M1 marker (9).
In addition to exercise there are many traditional herbs and traditional medicine with anti-hyperglycaemic affect have been reported such as resveratrol (RSV) one of the plant derived compounds existing in grapes, peanuts and many other plants which can reduce the effect of calorie constraint(11).