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Diabetes mellitus is a growing problem across the world. In 2000 WHO announced approximately 171 million of world population has diabetes and it was estimated by 2030 this figure would rise to 366 million cases of diabetes patient, each year about 3.2 million of diabetes patients decease since of the complications, which mean six patients dies every one minute (1).
There are 2 types of diabetes: type 1 diabetes (T1D) and type 2 diabetes (T2D), type 1 diabetes identified to caused by complete insulin insufficiency and it can be treated by supplement of exogenous insulin. (NIDDM) non-insulin dependent diabetes also known type 2 diabetes, which is defined, by insulin absences and amplified insulin resistance (2).
T2D is more common than T1D, including 85-90% of diabetes mellitus cases with disease complications. Consequently T2D considered as the sixth primary reason of death worldwide.
2.0 Diabetes mellitus:
It is a complicated metabolic disorder (genetic disease) explained to be occurred by a resulting corrupt lifestyle and obesity, which includes a great number of the world population and it is estimated to be raised among the youthful individuals and children (6). This alteration in the distribution of this disease between populations is believed to be because of sedentary lifestyle, energy rich diet and worldwide industrialization which progressively more affecting all the world societies. T2D characterized by a defect in insulin resistance and the beta call dysfunction associated with dyslipidemia, hypertension, and obesity (7); both are associated to obesity (that isresponsible of the action which controls adipokines and that is organized by fat mass) and visceral fat (8).
2.1 Insulin resistance:
Insulin resistance basically is failure of the cells to operate insulin, which can be develop to hyperglycemia even in the presence of adequate quantity of insulin. Insulin resistance known to be not only plays responsibility in diabetes, although it play a role in different aspects such as the excess of additional metabolic abnormalities containing hypertension, dyslipidemia, and vasculopathy when all composed they described the insulin resistance or cardiovascular dysmetabolic syndrome. (3Insulin resistance can be found in most of T2D patients; but the occurrence of insulin resistance for prolonged time can finally lead to increase β- cell insulin secretion with hyperinsulinemia (9). Because as it known that hyperinsulinemia is enough to elevate the insulin resistance, in that case the glucose concentrations will be normal. In some individuals that are suspected to progress T2D the β-cell reaction goes down which causes insulin absence which progresses and finally T2D will take place. Insulin resistance does not cause diabetes but it is a compound causes which finally leads to diabetes, in overweight non-diabetic individuals, pancreatic tissue gives β cell authority to take an action and increase the biosynthesis and secretion of the insulin in case of insulin resistance (10).
2.2 Type 2 Diabetes complications:
As it has been known now, T2D has many complications, which leads to life threading and these complications correspond to the ability of T2D to stimulate a chronic inflammatory condition. This inflammatory condition is mostly a consequence of the elevated synthesis of inflammatory mediators via cells such as monocytes, macrophages and endothelial cells (8).
T2D is an inflammatory state characterized by increased levels of cytokines and the immune regulators like TNF-α, C-Reactive Protein (CRP) and IL-6.T2D inflammation involve in the pathogenesis of an atherosclerosis, which recognized universally a long with its inflammation involvement in coronary arteries in the progression of atherosclerosis. Also a T2D complication usually arises because of long exposure to hyperglycemia. Cardiovascular disease, neuropathy, nephropathy, and retinopathy classified to be most affecting complications. Diabetic patient are more likely to get those complications which can be developed because untreated conditions and that makes the body organs weak such as eyes, heart, and mostly kidney (7).
Atherosclerosis is a chronic inflammatory disease characterized by plaque growth inside the arterial intima. These atherosclerosis plaques are extremely cholesterol concentrations, essentially LDL. After some time the plaques grow and switch to large plaques, which will eventually make the arteries thin, and consequences to reduce oxygen level and sometimes to more risk condition and that is artery rupture (figure 2) (13).
Macrophages perform a huge part in the start and progression of atherosclerosis. One of the initial activities in atherosclerosis is macrophages enrolment in the artery wall. Intracellular buildup of cholesterol ends in the characteristic creation of foam cells, which stimulate the macrophages to produce growth factors, cytokines and other mediators that stimulate smooth muscle cell production and potentiate the inflammatory response causing arterial restoration (16,15).
3.1 Role of macrophages M1 and M2 phenotype in atherosclerosis:
M1 and M2 macrophages phenotype have been verified inside human atherosclerotic lesion. M2 macrophages are available at additional stable locations inside atherosclerotic plaques as using immunohistochemical analysis showed it. Macrophages known as heterogeneous cells that acclimatize and respond to much diversity of microinvironmental signals. They are plastic cells since they could change from an activated M1 (proinflammatory) macrophage state to M2 (anti-inflammatory). Th1 cytokines such as INF-γ, IL1-β and lipopolysaccharide (LPS), lead differentiation towards 'classic' pro-inflammatory M1 macrophage that can generate pro-inflammatory cytokines incorporating IL-6 and TNF-α, whereas Th2 cytokines such IL-13, IL-10 or IL-4 stimulate differentiation into 'alternative' M2 macrophages phenotype that produce anti-inflammatory mediators such as TGF-β, IL-11β and IL-10 receptor antagonist (15).
3.2 Atherosclerosis and T2D:
Atherosclerosis in T2D is responsible of 80% of T2D patient's death. Hence it is the major complication of diabetes macro vascular disease. Atherosclerosis is responsible for the elevated cardiovascular mortality and morbidity (15).
The hyperlipidemia and hyperglycemia that present in T2D leads to irreversible glycation of lipids and protein, which leads to chemical synthesis of clearly inflammatory metabolites, recognized as Advanced Glycosylated End-Products (AGEs)(16). Lipids and AGE protein are able to bind the surface receptor on the cells, which have been known as the receptor for advanced glycation end products or RAGE. AGEs could stimulate the synthesis and the release of proinflammatory cytokines and also activate the inflammatory pathways in a huge number of cell categories. Irreversible hyperglycemia consequence to cellular dysfunction. AGEs are long lasting, so will accumulate continually on proteins at a high rate in T2D. Due to this accumulation the atherosclerotic process will be enhanced through a variety of mechanisms (13).
4.0 Advance glycated end product (AGE):
AGEs are a heterogeneous group of product made by going throughout difficult sequence of no enzymatic glycation reaction between amino acid and carbohydrates (17).
In (T2D) patients AGEs can be boosted along with hyperglycemia, further linked factors may rise such as receptors of advance glycated end product (RAGE).
Numerous way routes can produce AGE (figure 3):
Chemically reversible glycated derivative-Schiff bases- is primarily formed, which will be converted after few weeks to Amadori derivative.
By transform glucose to biocarbonyl because of high levels of oxidative stress, further more biocarbonyl will bind with monoacid and form AGE.
Or glucose car directly form to AGE through another product, which called polyoles.
AGE creations will continuous growing outstanding to hyperglycemia
AGEs are divided in 2 categories:
AGE which crosslink with plasma lipid, plasma and tissue lipoprotein.
AGE, which do not crosslink with plasma lipid, plasma and tissue lipoprotein. It is operated their action by binding with certain receptor, which is named (RAGE), which will stimulate intercellular reaction and will raise oxidative stress and production of proinflammatory cytokines.
4.1 Receptor for Advance Glycation End Product (RAGE):
RAGE is a member of immunoglobulin superfamily; recently it has been it described in diabetic complications, such as macrophages, epithelial cells and monocytes. RAGE also known to be involved as a signal transduction receptor for a mloid β peptide, it also can be found in both normal and diabetic cells surface on the endothelial cell and macrophage, it can be stimulated by several types of ligands such as amphoterin, calgranulins and AGEs. However endothelial cell can be induced with AGEs transcription of tissue factor (TF) and the expression of mRNA and protein can be mediated by the p38 mitogen-activated protein kinase, which will stimulate the RAGE gene.
5.0 Role of Inflammation in Insulin Resistance, Obesity and Diabetes
Commonly it has been observed that insulin resistance linked with obesity by the secretion of a set of inflammatory mediators named as adipocytokinse which are produced by cells such as endothelial cells, monocytes and macrophages. These adipocytokinse involve the presented inflammatory mediators IL-6, TNF-α, resistin and adiponcetin. Elevated TNF-α in plasma is linked with human obese issues and the attendance of inflammatory mediators is recognized to have a large influence on glucose metabolism and insulin sensitivity ( figure 4)(42).
Tumor necrosis factor-alpha (TNF-α) is a pleiotropic inflammatory cytokine (18). TNF-α affects most of the body organ, and the cytokine acts a range of roles. There is a supported evidence, which claim that TNF-α plays a fundamental role in mediating insulin resistance consequently of obesity. In overweight individuals and many rodent models of obesity-diabetes syndromes, there is a noticeable raise in muscle and adipose TNF-α production, when it is compared to normal weight individuals. TNF-α levels can be decreased with an exercise which leads to weight loss or after being treated with insulin-sensitizing agent pioglitazone (23).
6.0 Peroxisomes proliferators- activated receptor:
Peroxisomes proliferators-activated receptor (PPARs) was discovered by Isseman and Green in 1990 (24). PPARs belong to the nuclear receptor superfamily which are triggered by fatty acids, eicosanoids, and numerous.
The PPARs of nuclear receptor mainly composed of three subtypes (PPARα, PPARγ, and PPAR δ/β) (figure5). It has been described PPARs play a serious role in the regulation of metabolic processes, like lipid redistribution and glucose.
The subtypes link to DNA as it needs heterodimers with the nuclear for 9-cis-retinoic acid (RXR α, RXR β or RXR γ). All three PPARs isoforms possess similar structural and functional features.
6.1 Peroxisome proliferator-activated receptor-alpha (PPAR-α)
The first PPAR was identified; is PPAR-α, is involved in the regulating of fatty acid homeostasis transport protein, lipid metabolism and glucose homeostasis by regulating the expression of proteins implicated in the transport and β-oxidation of FFAs (25). PPAR-α can found in different body organs such as liver, heart, skeletal muscle, and kidneys. Furthermore, It has plays a critical role in intracellular lipid metabolism Fibrates such as; fenofibrates or bezafibrate is generally used to treat hypertriglyceridemia patient. Several studies have examining the anti-inflammatory features of PPAR-α, by decreasing the expression of different numbers of cytokines and proteins found in monocyte, VSMC proliferation and inflammation, as a result of those PPAR- α agonists might, slow down atherosclerosis (26).
6.2 Peroxisome proliferator-activated receptor-BETA (PPAR-β)
PPAR-β can be found in common tissue of the body. PPAR-β is located in fatty acid, which controls the adipogenesis, skin biology, lipid metabolism, and energy homeostasis (27,28).
PPAR-β has also been recommended to module insulin resistance across the activation of consecutively activated macrophages, which inhabit inflammation in together adipose tissue and liver (29).
PPAR-β, agonist helped in decrease VCAM-1 and monocytes chemo attractant protein 1 (MCP-1) levels in endothelial cells, and reserved inflammatory gene levels in peritoneal macrophages (30). Therefore, PPAR-β, agonists may be significant nominee for the treatment of obesity, insulin resistance, and dyslipidemia (26)
6.3 Peroxisome proliferator-activated receptor-gamma(PPAR-γ)
PPAR-γ known to be nuclear hormone receptors, which require heterodimers with Retinoid X Receptor (RXR), and join to DR1 type structure, located in the promoter sites of targets genes (31). It plays as a key regulator of adipocyte differentiation in the adipogenesis activity. PPAR-γ controls the expression of gene involved in fatty acid usage and lipogenesis in addition to glucose transporter. Also it enhances apoptosis in matured adipocyte, which speed up adipogenesis and generate insignificant insulin-sensitive adipocyte (figure 6) (16).
PPAR-γ is one of the significant modulator of numerous forms of homeostasis. It can be located in macrophages, prostate, breast, colon, and adipose tissue. PPAR-γ have a significant role in glucose and adipogenesis (32), via binding ligands PPAR-γ is stimulated which leads to different types of modification such as 1) allosteric, 2) recruitment of co- activator, 3) assembly of a transcriptional complex and 4) regulated transcription of target gene (16).
Activation of PPAR-γ play critical roles to:
Maintain the expression of gene, which are involved in fatty acid consumption and lipogenesis moreover as glucose transports.
It stimulates apoptosis in matured adipocyte that results in stimulation of adipogenesis and in formation of small insulin sensitive adipocyte (16).
PPAY-γ known to control and adjust in many genes that are involved in insulin singling, it has been noticed activation of PPAR γ force the adipocytes to reduce the production of TNF-α that leads to progress insulin resistance (35). A recent study proposed macrophages, which are specific to PPAR-γ activation also showed to reduce insulin resistance in adipocytes through differentiation instead activated monocytes, which have anti-inflammatory phenotype. It was obvious that PPAR-γ gene expression is rising significantly in the time of macrophage activation and that leads to inhibit the NF-κB activity (figure 7) (36). PPAR-γ enhances M2 polarization of macrophages.
6.3.1 PPAR γ ligands:
220.127.116.11 Natural ligands
A number of polyunsaturated fatty acids and their metabolites have been recognized as PPAR-γ ligands (table1).
Nowadays, nitrolipids have been found, but more research should be done on their physiological function and role of PPAR-γ (16).
18.104.22.168 Synthetic ligands
It is a pharmacological mixtures used clinically as insulin sensitizers such as TZDs ''glitazones'', but TZDs for example Rosiglitazone have be found to have side effects and of the clinical trails showed weight gain, and cardiac hypertrophy which finally leads to death (33).
7.0 The pharmacological treatment of type 2 diabetes:
Thiazolidinediones (TZDs) or ''glitazones'':
Rosiglitazone goes under class of oral anti-diabetic agents called the thiazolidinedione's (TZDs), which appears to be perfectly suitable for T2D treatment. All agents of this group have a thiazolidine-2-4 dione shape as presented (figure 8). The numerous agents of this group vary in their side chain, which modify their pharmacologic and unexpected result profiles.
Rosiglitazone decreases insulin resistance by rising insulin-dependent glucose discarding in skeletal muscle cell and decreasing hepatic glucose production by the liver. In 2000 roglitazone was removed from the market, because it was found that it cause typical hepatoxicity, but the other types of glitazones, clinicians used pioglitazone.
Glitazones aims insulin resistance, which is the central of physiologic error in persons with T2D. Glitazones progress the glucose regulator, which means it advances insulin action in muscle, adipose, and hepatic tissue as well its performance as PPAR-γ agonists. There are a lot of benefits of glitazones such as; increase the non-oxidative glucose disposal, raise triglyceride synthesis, and develop free fatty acid metabolism (34).
There are new PPAR applicant drugs under trail for the metabolic syndrome treatment, PPAR (pan agonists and dual agonists) are new modules of dugs that aim various PPAR isoforms at once to create synergistic anti diabetic and cardioprotective outcomes. These drugs likely to progress insulin sensitivity and lower triglycerides, whereas decreasing the unwanted side effects of gaining weight and edema related to the management of TZDs and fibrates (47).
7.1 The non-pharmacological treatment of type 2 diabetes and atherosclerosis:
7.1.1 Dietary Fatty acids and health:
It is organic acids with a carboxyl acid group and a hydrogen chain with a number of carbon atoms. It has fit structural and physiological role via biological system. Epidemiological evidence proposed a diet that enriched with saturated fatty acid has been related with the progression of obesity, diabetes mellitus and cardiovascular disease (43).
Dietary fatty acids got the ability to activate PPARS and control gene expression in the metabolically primary tissues. Most of researches have been concentrated on how this dietary fatty acid could affect the immune system. Lately, CLA has been established useful effects on cancer, hyperlipidemia, obesity, diabetes and atherosclerosis.
7.1.2 Conjugated linoleic acid (CLA):
It belongs to group of fatty acids isomers that are linked to the fundamental fatty acid, linoleic acid (LA: 18:2, cis-9, cis-12) (see figure 9). Recently it has received a huge attention as therapeutic nutrient, CLA isomer has been indicated decrease obesity in animals models and reduce triglyceride buildup in adipocyte (41). CLA is available in meat, milk and different dairy products of ruminant animals that have more concentrated amount of CLA such as goats and sheep. The two main isomers of CLA found in food and commercial preparations are 9:11CLA isomer and 10:12 isomer of CLA. The effect of CLA isomers has been studied on health for many years, that because of their utilisation being linked with many different primary health benefits. For example, anti-carcinogenic, anti-atherosclerosis, anti-oxidative, anti-obesity activities, normalisation of the impaired glucose tolerance in both animals and human studies and also improving the immune system function (44).
CLA stimulates PPAR-γ activities, attenuates the pathway of NF-κB that directly can decrease the pro-inflammatory cytokines, which leads to reduce inflammation. This type of inflammation reduction can eventually control metabolic syndromes involving obesity, atherosclerosis and insulin resistance. CLA and its isomers have the ability to decrease RAGE expression and its related inflammation, suggest a possible function for this dietary lipid in replacing drugs such as the TZDs in treating T2D (45).
Exercise is a necessary element that helps in maintaining a healthy lifestyle. There is an increase interest to study the role of physical exercise in preventing and treating diseases related to T2D and atherosclerosis. Exercise is extensively considered to have important and varied benefits of reducing the risk of cardiovascular risk (46).
It has been established that in healthy but previously sedentary individuals, the Low-intensity exercise is competent of extensively affecting cholesterol levels and the HDL level in the serum and generating a significant raise in serum oxLDL resulting in enhancing the activation of PPARγ and consequent increases in gene expression in leukocytes, including its scavenge receptor CD36 for oxLDL. Nevertheless, pathway of macrophage CD36 can present a mechanism for lipid clearance, when joined to the RCT system. Exercise stimulates increases in the gene expression of the transcription factor LXRα, thus enhances leukocytes gene expression of two proteins concerned in RCT, ABCA1 and ABCG1 which are concerned in transport of reverse cholesterol (by which oxLDL gotten in via monocytes-macrophage is transferred from possible atherosclerosis locations to the liver to be disposal safely) (figure10)(46).
Exercise is able to reduce the expression of M1 markers through PPAR-γ mediated effects in the peripheral blood and promotes priming of the circulating monocytes for differentiation to the M2 phenotype through Th2-mediated stimulation of PPAR-γ and regulation of PGC-1α and PGC-1β signaling (figure 11). Consequently, activation of PPAR-γ during exercise could represent a potentially important anti-inflammatory, an insulin-sensitising and anti-atherogenic feature of low-intensity exercise (46).
They are two categories of prevention
Primary prevention: that is to take an action before getting diabetes., and that can be accomplished by having healthy diets and stay far from obesity by having usual physical activity such as (exercises)which may drop down or delay the diabetes complications.
Secondary prevention: that is post diabetes by doing routine checkup for glucose and lipids levels, which can help in suitable treatment.
In recent year, thousands of studies were done and published on diabetes prevention or help to just delay diabetes in most of the prediabetic individuals.
One of these studies that was done called Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM), everyday for 3 years 8mg of Rosiglitazone (an oral antidiabetes drug) and ramipril 15mg (angiotensin-converting enzyme inhibitor) were been given to 5269 patient from 191 different sites in 21 dissimilar counties. The mean of the age of those patients were 54.7 years and they all have something common and that was history of diabetes. The result showed, rosiglitazone reduce the development of T2D, but on the other hand, rampril drug didn't not succeed in stop or reduce the T2D (40).