Obesity and modern sedentary lifestyle are one of the main reasons lead to T2D disease by increased insulin resistance of the cell and raised plasma glucose levels. Overweight is an autonous danger factor for cardiovascular, hypertension and dyslipidemia and , thus, rise the danger of cardiovascular complications and cardiovascular dies in the illness with T2D.
Risk factors for the transformation form an insulin sensitive state to insulin resistance include obesity, diet, sedentary lifestyle and genetics.
Instead of the messing in hyperinsulinemia tends to do 1. Dyslipidemia 2. Decreases in vasodilatation mediated by nitric oxide 3. Increases in blood pressure, clotting factors, and coronary artery disease. Also diets with high saturated fat content and low fiber compassion could rise the risk of insulin resistance and also lead to the development of T2D.
Dietary fat intake
The kind and the quantity of dietary fat intake has been associated with insulin sensitivity. Monounsaturated or polyunsaturated fats started to get a beneficial effect on insulin level, whereas saturated fats and diets with much total fats have the effect to dropdown insulin sensitivity. It is hypothesized that fats affect the phospholipid of cell membranes in skeletal muscle and other tissues.
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Non-starch polysaccharides or dietary fiber have been shown to late on absorption of carbohydrates after a board and there by decrease the insulinemic response to other dietary carbohydrates. Associations with T2D were higher for
cereal than fruit and vegetable in the sources fiber (Abdelrahman, et al 2005)
Medium drinkers had the lowest risk for diabetes, although nondrinkers and heavy drinkers had the higher risk. The mechanisms by which alcohol may act to increase or decrease risk of diabetes are multifold. Several studies suggest that low-to-moderate amount of alcohol intake may decrease development of diabetes by increasing insulin sensitivity and slowing glucose uptake from a meal.
Excessive alcohol intake may contribute to excess energy intake and obesity, induction of pancreatitis, disturbance of carbohydrate and glucose metabolism and impairment of liver function.
Cigarette smoking may increase risk of diabetes in several ways. Smoking has been shown to cause elevations in blood glucose concentration and may increase insulin resistance. Current smokers also tend to have higher blood concentrations of glycosylated hemoglobin (HbA1c) than do nonsmokers . One recent population-based cross-sectional study showed an independent positive association between cigarette smoking and HbA1c concentration in men and women. In addition, although many studies have shown that smokers, on average, have lower BMI than nonsmokers, they also tend to have more central fat deposition which is associatedwith insulin resistance.
People who spent more time watching TV were more likely to smoke and drink alcohol and less likely to exercise.( Hu, et al 2003)
T2D inflammatory disease
Inflammation, which do an important function in lots of disease states, is linked with oxidative tension and promote expression of adhesion compund in the vasculature, out coming of the filtrated of neutrophils and monocytes/macrophages. The quantity of the produced from the pro-inflammatory cytokines and oxygen free radicals of the lived leukocytes could then in turn make tissue damage. Many lines of evidence propos that PPAR-g do anti-inflammatory strong effects by negatively regulating the expression of pro-inflammatory genes induced in response to macrophage activation and differentiation. PPAR-g is found in human and murine macrophages/monocytes and there is a connection between the form of monocyte/macrophage differentiation or activation and PPAR-g expression. In the mouse, PPAR-g is formed at low standard in non-activated macrophages, whereas much higher standards are expressed in activated peritoneal macrophages. In human peripheral blood monocytes, asimilar relationship between the form of differentiation and activation and PPAR-g expression has been characteried . Macrophages/monocytes activation with phorbol esters, oxidised LDL, macrophage colony-enhancing factor (MCEF), and granulocyte-macrophage CSF (GMCSF) induced an raised expression of PPAR-γ . The synthesis of the inflammatory cytokines interleukin(IL)-1h, IL-6 and tumour necrosis factor (TNF)-a in enhanced human peripheral blood monocytes is suppressed agonists by PPAR-g.
PPAR-g has effect in activated peritoneal macrophages, and that PPAR-g ligands do not allow the formation of iNOS, scavenger receptor A genes and gelatinase B , in portion by antagonising the transcription factors activities AP-1, STAT and NF-nB. Studies have showed that 12-PGJ2 was found to be a potent bloker of iNOS protein expression in stimulated macrophages, and it was proposed that this inhibition can be interpose via modulation of heme oxygenase-1 (HO-1).( Hontecillas R et al, 2010)
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PPAR-g macrophages expression is not only up-regulated by IL-4, however, that IL-4 also enhances the activation of PPAR-g via the production of endogenous PPAR-g ligands such as13-HODE, 12-HETE, 15d-PGJ2, and 15-HETE.
PPAR-g activation is enhances cycloxygenase (COX)-2 expression by preventing activation and translocation of NF-nB. In T cells, PPAR-g activation inhibits IL-2 production in a mechanism believed to involve transrepression of NFAT. (Abdelrahman et al, 2005)
Inflammation-induced C/EBP-y expression up-regulates transcription and protein expression of PPAR-g, which, in turn negatively modulates inflammation through suppression of C/EBP-y via STAT-3 signalling pathways. This negative feedback system may account for the anti-inflammatory action of PPAR-g ligands. PPAR-g is not only involved in down-regulation of pro-inflammatory cytokine expression, but also induces apoptosis. It has been reported that PPAR-g agonists induce apoptosis in
TNF-a/IFN-g-stimulated macrophages by interfering with the anti-apoptotic NF-nB signalling pathway.
6.1 Advance glycated end product (AGE):-
AGEs are a hetrogenous group of product formed by going through complex series of nonenzymatic glycation reaction between amino acid and carbohydrates (Vlassara et al, 1995).
In type 2 diabetes (T2D) patients AGEs can be raised, Furthermore of hyperglycemia, other bellowing factors may raise such as receptors of advance glycated end product (RAGE).
AGE can be funded by several way:-
1. Chemically reversible glycated derivative-Schiff bases- are pre-formed, which will be change after few weeks to Amadori derivative.
2. Transform glucose to biocarbonyl due to high levels of oxidative stress, further more biocarbonyl will bind with monoacid and form AGE.
3. Glucose car directly form to AGE through another product which called polyoles
AGE productions will continuous increasing due to hyperglycemia .AGEs are divided in 2 kind one which can crosslink with tissue lipoprotein, plasma lipid and plasma and the anther kind is can not crosslink. AGEs are start their working by binding with specific receptor which is called receptor advance glycated end product (RAGE) which activate the intercellular reaction and increase oxidative stress and production of proinflammatory cytokines .
Figure2:- Glycation and advanced glycation end product (AGE) formation.
6.2 Receptor for Advance Glycation End Product (RAGE):
It's one of immunoglobulin member, it has been detected in diabetic complication, such as monocytes, macrophages and endothelial cells, furthermore its play a key role in macrovascular and microvascular lesions (aorta and coronary arteries).
RAGE work as a signal transduction receptor for amloid β peptide, which is found in Alzheimer disease. It's composed of both an intracellular and extracellular domain.
RAGE may be found in both normal and diabetic cells surface on the endothelial cell and macrophage, it's can be activate by different types of liginds such as amphoterin, calgranulins and AGEs.
While incubation of cultured endothelial cell with AGEs Induced transcription of tissue factor (TF) mRNA and protein expression mediated by the p38 mitogen-activated protein kinase and consecutively the nuclear transcription factor NF- Ðšappa B, which will activate the RAGE gene.
TF is the main activator of the coagulation system and it's the number one association of diabetic vascular complication.
The anti-diabetic medicines used for the therapy of type 2 diabetic is thiazolidinedione ( TZD ) or glitazone. And it include ressiglitazone , pioglitazone , ciglitazone and troglitazone. Troglitazone was approved in January 1997 as glucose-lowering therapy in the treatment of patient with type 2 diabetes. Troglitazone was withdrawn from the market in March 2000 because of a serious hepatotoxicy in some patient. Rosigliazone and pioglitazone are available as PPAR-ϒ agonists, there are currently used alone or in combination with oral anti-diabetic agent for type2diabetes patients.( Yee MS et al, 2010)
TZD effect by stimulation PPAR-g through insulin-sensitising and hypoglycaemic. TZD-induced warning of PPAR-g results in change in the transcription of some genes used in glucose and lipid utilization and energy equal such as GLUT4 glucose transporter and fatty acid transporter protein.( Hsun, et al 2009)
Conjugated linoliec acid-CLA
CLA is the general name of set of group of fatty acids optioned naturally in foods, are alots in ruminant meats and milks and could be produced by animal. CLA is produced in vivo from Linoleic acid from rumen bacteria and animal-derived foods by heat processing. Processed cheese , cooked meat and dairy products are better dietary sources of fatty acids where its concentration range between 2.5 to 15mg/gm lipid.(Harrison, et al 1985)
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CLA known to be anti-diabetic, anti-carcinogenic, anti-atherosclerosis, anti-obesity and immune modulator. They might be relationship between weakness of insulin sensitivity and isomer-specific inflammation or oxidative tension after CLA is unexpored.CLA can also reactivate the immune system by increasing lymphocyte blastogenesis, lymphocyte cytotoxic activity, and macrophage killing ability and protecting from end-stage body wasting in autoimmune disease.(Hayek, et al 1999)
There is connection directly to raised insulin sensitivity, glucose tolerance, developed hyper-insulinemia and a few amount of circulating free fatty acid in the pre-diabetic Zucker fatty rat. Raised mixture of circulating glucose into adipocytes has also been connected to CLA.( Soonkyu Chung et al, 2005)
CLA involve functional similarities with ligands of PPARγ . For instance, PPARγ activation is linked with a rise down in colon and breast cancer and this receptor is important for adipogenesis and the anti-diabetic properties of TZDs ( Moya-Camarena et al, 1999).
8. Low-Intensity Exercise
Exercise has a wide range of benefits in terms of reducing cardiovascular risk. And so on, the level of oxidative stress in the body can be raised over a short time by raised the metabolic activity and the hypoxic condition associated by exercise. This oxidative form is linked with the raised outlet of cellular hydroperoxide, reactive oxygen species and free radical, and thus raised in the susceptibility of LDL to undergo oxidation. The oxidation of LDL stimulates the atherogenic steps by reasons of oxidized LDL (oxLDL) has been known as a strong chemoattractant triggering monocyte transfer into the subendothelial space. This improve the development of atherosclerosis because it can result in the massive accumulation of cholesterol that characteristic of macrophage foam cells. Synchronous with the movment of circulating monocytes onto the subendothelial space, a program of differentiation into macrophages take place that involves the actions of several nuclear transcription factors, including PPAR and liver X receptors (LXR), and the consequent up-regulation of PPAR response element (PPRE)- and LXR response element (LXRE)-bearing target genes oxidation make LDL unrecognizable to the LDL receptor and its promotes by manner; macrophage scavenger receptors such as CD36 are therefore thought to play a significant role in atheroselerotic foam cell development due to their ability to bind and internalize oxLDL.
There is evidence for antiatherosclerotic benefits of up-regulation of macrophage CD36 mRNA expression because stimulation of macroghage with CD36 ligands has been shown to reduce plasma cholesterol levels.
The ATP-binding casselte transporter A1 ( ABCA1) is plays a role in reverse cholesterol transport (RCT), in which oxLDL taken by macroghages is exported from the potential atherosclerotic site as a component of lipid-poor apolipoproteins. Similarly, ATP-binding cassette transporter G1 (ABCG1) is mediator of macrophage cholesterol effux, in this case to mature HDL but not to lipid-depleted apolipoproteins. Both ABCA1 and ABCG1 genes are LXRE-bearing target genes activated by nuclear receptor LXLα . Walking is a form of aerobic low-intensity exercise that have numerous health benefits. It is found a reduction in systolic blood pressure and percent age body fat after under taking two 45 min walk per week for 8 wk. Also it is found that it reduced mean LDL concentration.
I conclude that, the beneficial of CLA is proved to be anti-diabetic, anti-atherosclerosis and anti-obesity through its activation of PPAR-gamma which found to regulate the fat metabolism within the cell. On the other hand, low intensity exercise found to activate PPAR-gamma through the activation of metabolic activity and thus reducing cardiovascular risk and the level of oxidative stress in the body