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Indian Journal of Medical Sciences, Vol. 61, No. 5, May, 2007, pp. 292-306 Practitioners section Atherosclerosis in diabetes mellitus: Role of inflammation Maiti Rituparna, Agrawal NeerajK Department of Pharmacology, Prathima Institute of Medical Sciences, Karimnagar, Andhra Pradesh Code Number: ms07047 Abstract Inflammation plays a central role in the pathophysiology of atherosclerosis, starting from initiation, through progression, and ultimately the thrombotic complications of atherosclerosis. Diabetes mellitus is a major risk factor for atherosclerosis. Hyperglycemia-induced endothelial dysfunctions, along with hypercoagulable potential of diabetes mellitus, accelerate the process of atherothrombotic complications. Therefore, clinically feasible markers to monitor subtle systemic inflammatory burden and specific add-on therapy for the same constitute need of the present day. The understanding of the concept of inflammation in diabetes-accelerated atherosclerosis can be used practically to predict future cardiovascular risk by evaluating inflammatory biomarkers and to design clinical trials making inflammation as a therapeutic target.Keywords: Atherosclerosis, cardiovascular risk, diabetes mellitus, inflammation, inflammatory biomarkers Atherosclerosis was considered formerly as the outcome of dyslipidemia, but the emerging knowledge of vascular biology and basic sciences has proved that the inflammatory mechanisms couple with dyslipidemia to form atheroma. Over the past decade, a prominent role of inflammation has been appreciated in the pathogenesis of atherosclerosis. The recent evidences suggest atherosclerosis as a dynamic and progressive disease arising from the combination of endothelial dysfunction and inflammation. The markers of inflammation and endothelial activation have become useful in measuring a patient′s risk of developing atherosclerosis as well as in providing new targets for treatment. The metabolic syndrome (METs), a cluster of metabolic abnormalities with insulin resistance as a major characteristic, is a major risk factor for atherosclerosis. (The state of insulin resistance is not universally accepted as a component in the diagnosis of the metabolic syndrome). The major adverse consequence of METs is cardiovascular diseases. Insulin resistance, most important of the abnormalities of METs, also predisposes to the development of type 2 diabetes mellitus. Diabetes is associated with accelerated atherosclerosis and consequently with an increased risk of myocardial infarction, stroke and limb amputation. Triggers for inflammation in atherogenesis The concept of inflammation occupies the central position in the pathophysiology of atherosclerosis, but we are still lacking in the knowledge of the inciting factors. Oxidized low-density lipoprotein (ox LDL) and other biologically active moieties localize in the lipid core of the atheroma, and these modified lipids induce the expression of adhesion molecules, chemokines, pro-inflammatory cytokines in macrophages and endothelium. Apart from LDL, β-VLDL (very low density lipoprotein) and IDL (intermediate density lipoprotein) particles also can undergo oxidative modification and may themselves activate inflammatory function of vascular endothelial cells. Abdominal fat (subcutaneous and intraperitoneal fat depot) is the source of high level of free fatty acids, which stimulate synthesis of triglyceride-rich lipoprotein VLDL in liver, resulting in an augmentation of exchange from high-density lipoprotein (HDL) to VLDL by cholesteryl ester transfer protein. There is a growing list of adipokines involved in inflammation (TNF-α, IL-β, IL-6, IL-8, IL-10, TGF-β, nerve growth factor) and the acute-phase response (PAI-1, Haptoglobin, Serum Amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines have led to the view that the obese are characterized by a state of chronic low-grade inflammation and that this links causally to insulin resistance and the metabolic syndrome. It is however unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalized or local state of inflammation. Hypertension is one of the classical risk factors for atherosclerosis. Angiotensin II, in addition to its vasoconstrictor properties, can induce intimal inflammation by eliciting production of superoxide anion, increasing the expression of pro-inflammatory cytokines by endothelial cells and smooth muscle cells. Diabetes is a very important risk factor for atherosclerosis. Large prospective clinical studies have already shown a strong relation between atherogenesis and hyperglycemia and insulin resistance. [1] Endothelial dysfunction leading to atherosclerosis Endothelial dysfunction is a state of imbalance between relative contribution of endothelium-derived relaxing and contracting factors. The key endothelium-derived relaxing factor is nitric oxide (NO), which plays a pivotal role in the regulation of vascular tone and vasomotor function. Impaired vascular homeostasis in coronary arteries with established atherosclerosis leads to reduced myocardial perfusion and myocardial ischemia. Apart from its vasodilatory effect, NO also protects vessels from injury, inflammation and thrombosis. NO inhibits leukocyte adhesion to endothelium, reduces platelet aggregability and vascular smooth muscle proliferation. The endogenous defenses of the vascular endothelium break down in response to the traditional cardiovascular risk factors like hypertension, hypercholesterolemia and diabetes mellitus. [2] In ordinary conditions, endothelium is resistant to leukocyte adhesion, but hypercholesterolemia promotes leukocyte adhesion to endothelium. Oxidized LDL reduces intracellular concentration of NO and causes endothelium activation. [3] Angiotensin II has an important role in endothelial dysfunction. It opposes NO action; increases production of reactive oxygen species (ROS); increases expression of pro-inflammatory cytokines like IL-6, monocyte chemoattractant protein-1 (MCP-1); and also up-regulates vascular adhesion molecule-1 (VCAM-1). [4],[5] These endothelial changes coupled with elevated acute phase protein (CRP) levels set the stage for initiation and progression of atherogenesis by promoting inflammation within the vessel wall. [6] Initiation of inflammation The inflammatory activation of endothelial cells causes increased expression of selectin, VCAM-1, intercellular adhesion molecule-1 (ICAM-1). [7],[8] Different pro-inflammatory cytokines (IL-1β, TNF-α), acute phase protein, ox LDL, CD40/CD40 ligand interactions also induce the expression of adhesion molecules. [9] Though normal arterial endothelium resists prolonged contact with leukocytes, including the blood monocytes, with increased expression of adhesion molecules, there is an increased recruitment of monocytes and their adhesion to endothelium. Once they become adherent to the activated endothelium, the monocytes diapedese between intact endothelial cells to penetrate into the tunica intima. The directed migration requires a chemoattractant gradient, which is provided by interaction of MCP-1 with its receptor CCR2. On entering the intima, the monocytes acquire characteristics of tissue macrophages. In the atheroma, the macrophages express scavenger receptors to bind modified lipoprotein particles. After internalization, macrophages are converted to foam cells, the hallmark of atherosclerotic lesion. [9] These foam cells secrete pro-inflammatory cytokines that amplify the inflammatory response, and the vicious cycle continues [Figure - 1]. T-lymphocytes also enter the intima after binding to VCAM-1 and in response to lymphocyte-selective chemoattractants, which include interferon-γ-inducible chemokines [inducible protein-10, monokine induced by interferon-γ (IFN-γ) and IFN-inducible T-cell α-chemoattractant] of CXC family. [10] Once they become resident in the arterial intima, the T-cells interact with ox LDL and heat shock proteins and become activated to produce cytokines which influence the behavior of other cells present in the atheroma. In general, TH1 cells predominate in the atheroma, and they secrete pro-inflammatory cytokines like IL-1, TNF and IFN-γ[9] [Figure - 2]. The leukocytes infiltrating within atheromatous plaques also include an important population of mast cells. In this case, Eotaxin, a chemoattractant, interacts with the chemokine receptor CCR3 and mediates the trans-endothelial migration of mast cells. [11] In the intima, mast cells undergo degranulation and release preformed TNF-α, tryptase and chymase. Chymase has a very important role in the conversion of Angiotensin I to Angiotensin II, which is an important culprit in endothelial dysfunction. [9] Platelets also have an important role in inflammation. The activated platelets may mediate the homing of leukocytes by interaction with subendothelial matrix under shear stress that does not allow neutrophil adhesion. They contribute to the oxidative modification of LDL, to the smooth muscle proliferation, to inflammatory reaction by expressing and releasing CD40L, resulting in matrix metaloproteinase (MMP) activation and pro-coagulant activity. [12] Inflammation in atheroma progression and complications After formation of the fatty streak, the nascent atheroma develops into a more complex lesion, which can lead to different clinical manifestations. The evolution of a fatty streak into a complex lesion is characterized by smooth muscle proliferation, their migration toward the intima and their synthesis of abundant extracellular matrix. With the expansion of lesion, clinical manifestations start appearing due to the narrowing of the lumen, hampering the blood flow. The continued release of cytokines like MCP-1 by activated endothelial cells is responsible for lesion growth as it influences smooth muscle activity, besides perpetuating inflammation and lipid accumulation. [2] The most important dreaded complication in arteriosclerosis is the plaque disruption. There are three most common mechanisms of plaque disruption involving inflammation [Figure - 3]. First, the locally produced inflammatory mediators and activated killer T-cells cause a catalytic attack on endothelial cells, leading to endothelial cell death and desquamation. [9] Second, inflammatory mediators (IL-1β, TNF-α) and oxidized lipoprotein stimulate the expression and activation of matrix metaloproteinases (MMPs) specialized in degradation of subepithelial extracellular matrix on which endothelial cells adhere, leading to loss of endothelium. [13] Third, interstitial collagen molecules provide the tensile strength on the fibrous cap. Certain pro-inflammatory cytokines, such as INF-γ, can inhibit collagen production by smooth muscle cells, which is the principal source of extracellular matrix in the arterial wall. [9] Diabetes, oxidative stress and inflammation There are four hypotheses explaining the mechanisms of hyperglycemia-induced endothelial dysfunction and diabetic complications. [14] They include (1) increased polyol pathway, (2) increased advanced glycation end products (AGEs) formation, (3) activation of protein kinase C (PKC) isoforms and (4) increased hexosamine pathway flux. In polyol pathway, glucose is first reduced to sorbitol by the enzyme aldose reductase, and then sorbitol dehydrogenase oxidizes sorbitol to fructose. At normal glucose concentration found in nondiabetics, metabolism of glucose by this pathway is minimum; but in hyperglycemia, there is increased conversion to polyalcohol sorbitol with subsequent decrease in NADPH. Reduction of glucose to sorbitol consumes NADPH, which is required for regenerating reduced glutathione (GSH). Thus there will be decreased level of GSH, leading to oxidative stress. The oxidation of sorbitol by NAD+ increases cytosolic NADH: NAD+ ratio, leading to inhibition of activity of the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and increase in the concentration of triose phophate. Increased triose phosphate concentration in turn increases the formation of methylglyoxal, a precursor of AGEs and diacylglycerol, thus activating PKC. In hyperglycemia there is increased production of AGEs, and they damage target cells by three mechanisms. First, AGEs modify the intracellular proteins; hence their function is altered. Second, AGEs modify extracellular matrix components, which interact abnormally with the receptors for matrix proteins (integrins) on cell. Third, plasma proteins modified by AGE precursors bind to AGE receptors [15] on endothelial cells, mesangial cells and macrophages, inducing receptor-mediated production of reactive oxygen species (ROS). This AGE receptor ligation activates transcription factor NF-kB, leading to pro-inflammatory gene expression. [16] It includes expression of cytokines and growth factors by macrophages and mesangial cells (IL-1, IGF-1, TNF-α, TGF-β, macrophage-colony-stimulating factor, granulocyte-macrophage-colony-stimulating factor and platelet-derived growth factor) and expression of pro-coagulatory and pro-inflammatory molecules by endothelial cells (thrombomodulin, tissue factor and VCAM-1). In addition, binding of ligands to endothelial AGE receptors seems to mediate in part the hyperpermeability of the capillary wall induced by diabetes, probably through the induction of VEGF. [14] Hyperglycemia increases diacylglycerol (DAG) content, which activates PKC - mainly β and δ-isoforms. [17,18] Activation of PKC inhibits insulin-stimulated expression of mRNA for endothelial nitric oxide synthase (eNOS), increases endothelin-1-stimulated MAP-kinase activity, induces expression of permeability-enhancing factor VEGF in smooth muscle cells, increases microvascular matrix protein accumulation by inducing expression of Tissue Growth Factor-β1 (TGF-β1), overexpression of fibrinolytic inhibitor Plasminogen Activator Inhibitor-1 (PAI-1), activation of NF-kB and activation of various membrane-associated NADPH-dependent oxidases. [14] In hyperglycemia, excess of intracellular glucose is shunted into the hexosamine pathway, leading to increased formation of UDP-N-acetylglucosamine, which in turn causes covalent modification of transcription factor Sp-1; and finally, there is increased expression of PAI-1, TGF-α and TGF-β1. [19],[20] Recent discovery has found a common element linking these four pathogenic mechanisms. Overproduction of superoxide by the mitochondrial electron-transport chain is the unifying process of the hyperglycemia-induced damages. Increased hyperglycemia-derived electron donors from the TCA cycle (NADH and FADH2) generate a high mitochondrial membrane potential by pumping protons across the mitochondrial inner membrane. This inhibits electron transport at complex III, increasing the half-life of free-radical intermediates of coenzyme Q, which reduces O2 to superoxide. [19],[21] Type 2 diabetes is now recognized as a disease of the innate immune system. Included among the risk factors of type 2 diabetes mellitus, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Thus, the dysregulation of the innate immunity may be seen as the unifying mechanism linking diabetes and premature atherosclerosis. Platelet dysfunction in diabetes mellitus Accelerated atherosclerosis and the increased risk of thrombotic vascular events in diabetes mellitus may result from dyslipidemia, endothelial dysfunction, platelet hyper-reactivity, impaired fibrinolytic balance, abnormal blood flow and chronic inflammation. The complications of type 2 diabetes mellitus are associated with dysfunction of platelets and the neurovascular unit. Platelets in type 2 diabetes mellitus adhere to vascular endothelium and aggregate more readily than those in healthy people. The major defect in platelet function is its loss of sensitivity to prostacyclin (PGI2) and nitric oxide (NO) generated by vascular endothelium. Insulin, a natural antagonist of platelet hyperactivity, sensitizes platelets to PGI2 and enhances endothelial generation of PGI2 and NO. [22] Insulin also down-regulates the number of α2 -adrenergic receptors on platelets. [23] But a defective insulin action in diabetes mellitus leads to hyperactive platelets. Actually, the entire coagulation cascade becomes dysfunctional in diabetes mellitus. Increased levels of fibrinogen and PAI-1 favor both thrombosis and defective dissolution of clots already formed. Altered response to PGI2 is manifested due to decreased level of Gi in the membrane of platelets of type 2 diabetes mellitus patients, although a decrease in receptor number has not been described in diabetes mellitus. [24] The endothelium also contributes to platelet activation by releasing von Willebrand Factor (vWF), which promotes platelet aggregation by binding the platelet GPIb-IX and IIb-IIIa complexes. Plasma von Willebrand Factor (vWF) has been found to be elevated in diabetic patients. [25] Along with vWF, fibrinogen, factorVII, factorVIII, factorXI, factorXII, kallikrein, prothrombin activation fragment 1 and 2 and thrombin-antithrombin complexes are also elevated in diabetes mellitus. Conversely, the level of anticoagulant protein C is decreased. The fibrinolytic system is relatively inhibited in diabetes due to abnormal clot structures that are more resistant to degradation and due to an increase in PAI-1. [26] The increased extent of glycosylation of platelet membrane protein in diabetes appears to be related to reduced membrane fluidity, [27] which modulates cell function, possibly through alteration in receptor availability. Thus the reduced membrane fluidity leads to hyperfunction of platelets in diabetic patients. Platelets have been shown to be targets of insulin action because they retain a functional insulin receptor capable of insulin binding and autophosphorylation. [28] Insulin reduces platelet responses to ADP, collagen, thrombin, arachidonate and platelet activating factors, and this function was supported by the finding that insulin down-regulates the number of α2 -adrenergic receptors on platelets. [29] The decrease in insulin receptor number and affinity on platelets in patients with type 2 diabetes mellitus suggests that reduced insulin sensitivity may be responsible for platelet hyperactivity in these patients. [30] Thus, increased circulatory platelet aggregates, increased platelet aggregation in response to platelet agonists, increased platelet contractile force (PCF) and the presence of higher plasma levels of platelet release products (β-thromboglobulin, Platelet Factor 4, Thromboxane B2) have made diabetes mellitus a hypercoagulable state. [26] Inflammatory biomarkers The concept of inflammatory pathophysiology in atherosclerosis can be used practically to predict future cardiovascular risk. It has been proven that there are some inflammatory mediators whose elevated levels have predictive value for future cardiovascular events. Multiple prospective epidemiological studies have showed that increased levels of cytokines (IL-1, IL-6, TNF-α), cell adhesion molecules (VCAM-1, ICAM-1, P-selectin, E-selectin) and acute phase reactants (CRP, fibrinogen, serum Amyloid-A) are associated with increased cardiovascular risk. [31],[32],[33],[34] Some traditional cardiovascular risk factors like body mass index and central obesity have been found to track with these inflammatory biomarkers. [1] CRP, an important contributor in endothelial dysfunction and atherosclerosis, with the advent of high-sensitivity assays, has emerged as one of the most powerful independent predictors of cardiovascular disease [Figure - 4]. [2],[35],[36],[37],[38] In comparison to LDL cholesterol, CRP has been found to be a stronger and reliable predictor of incident cardiovascular events, and it adds prognostic information at all levels of calculated Framingham risk and at all levels of the metabolic syndrome. [38] Some epidemiological studies indicated statistically significant association of coronary heart disease (CHD) with low serum albumin level and high total leukocyte count; though for leukocyte count, a causal relationship with CHD is difficult to establish because of its wide range of biological effects. [39] High WBC count has been found to be associated with a worsening of insulin sensitivity and can predict the development of type 2 diabetes mellitus. [40],[41] A cross-sectional cohort study was carried out in the Prince of Wales Hospital, Chinese University of Hong Kong, to determine association between WBC count and the presence of macro- and microvascular complications in type 2 diabetes mellitus. This study has concluded that elevated WBC count, even within normal range, is associated with both macro- and microvascular complications in type 2 diabetes mellitus, and chronic inflammation as mediated by higher WBC count may play a linkage role in the development of the complications in diabetes mellitus. [42] So total leukocyte count can serve as a marker for inflammation in diabetes-accelerated atherosclerosis. Recently some new novel inflammatory markers have been identified. Among them, Lectin-like ox LDL receptor-1 (LOX-1), protease-activated receptors (PARs), lipoprotein-associated phospholipase A2 (Lp-PLA2), matrix metaloproteinase-9 (MMP-9) and endothelial progenitor cells (EPCs) are important. [43] Cardiovascular risk in diabetes mellitus People with diabetes mellitus are at a particularly high risk of coronary heart disease (CHD). According to statistics, cardiovascular diseases kill 75% of all diabetic people with myocardial infarction, which accounts for 30% of all deaths. The National Cholesterol Education Program (NCEP) recommends that diabetic patients do not need specific CHD risk assessment; but instead, they may be managed as if they had CHD. [44] The Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC) recommends that hypertension should be aggressively managed in diabetic patients. [45] A community-based prospective study showed that compared with nondiabetic individuals, most people with diabetes have elevated risk of incident CHD (at least 1% per year). [46] Both genders are affected, and diabetic women lose their normal premenopausal protection against cardiovascular disease. Certain ethnic groups (e.g., South Asians) are particularly susceptible, while others (e.g., Pima Indians) are relatively protected; clustering of conventional cardiovascular risk factors and procoagulant changes may be responsible. Atherothrombotic disease is responsible for most of the burden of cardiovascular disease in diabetes mellitus. The structural and functional abnormalities of vessels, along with dyslipidemia and hypertension, lead to ischemic heart diseases. Type 2 diabetes mellitus carries a twofold to fourfold increased risk of fatal myocardial infarction. [47],[48],[49],[50] The prevalence of raised total cholesterol concentration in type 2 diabetes mellitus is similar to that in the general population, but subjects with type 2 diabetes mellitus show the characteristic lipid profile of normal or only slightly raised LDL cholesterol, with low HDL cholesterol and mildly elevated triglyceride concentration. Measurement confined to LDL cholesterol may therefore underestimate the risk associated with the concentration of atherogenic lipoprotein particles in diabetes. Indeed, in some cohorts of patients with diabetes, total cholesterol and LDL cholesterol levels did not associate with cardiovascular risk, whereas high triglyceride levels or low HDL cholesterol concentration levels were powerful predictors of CHD events. [51],[52] Hypertension is up to twice as common in diabetic people as in the general population, affecting 10-30% of type 1 diabetic patients and 30-50% of those with type 2 diabetes mellitus. Hypertension is also present in 20-40% of people with impaired glucose tolerance (IGT). Insulin resistance could raise blood pressure by loss of insulin's normal vasodilator activity or through effects of the accompanying hyperinsulinemia, viz., Na + and water retention, increased intracellular Na + concentration that enhances the contractility of vascular smooth muscle and sympathetic overactivity. These changes would all increase peripheral resistance. Hypertension worsens both macro- and microvascular complications in diabetes mellitus. The effects of blood pressure on the risk of fatal coronary heart disease are two to five times greater in diabetic patients than in nondiabetic patients, and hypertension accentuates the deleterious influence of diabetes on left ventricular mass and function. Myocardial ischemia may present atypically or without pain, and 'silent' ischemia carries a worse prognosis in diabetic patients than in nondiabetic people. Coronary artery disease and hypertension can account for most of the myocardial abnormalities that occur in diabetes. However, postmortem, experimental and observational studies also provide evidence for a specific cardiomyopathy in diabetes, which may contribute to myocardial dysfunction in the absence of coronary artery atheroma. [53] Features include functional defect (e.g., in calcium transport), microvascular changes (including microaneurysm formation) and interstitial fibrosis. Diastolic dysfunction and poor systolic ejection contribute to heart failure, and risk of arrhythmias may also be increased. Potential pharmacological interventions A series of large, randomized, controlled trials have been already carried out making inflammation as a therapeutic target in atherosclerosis. Evidence is emerging that many drugs that have apparent 'anti-inflammatory' properties may reduce the incidence and/or delay the onset of type 2 diabetes. Evaluation of recent clinical trials demonstrated the correlation of Statin, Angiotensin receptor blocker and Glitazone therapy with decreased levels of CRP. PRINCE trial evaluated the anti-inflammatory effects of pravastatin and found a mean 16.9% reduction in CRP levels, whereas AFCAPS/TexCAPS researchers found that Lovastatin proved a 14.8% reduction in mean CRP levels. [54],[55] Results of REVERSAL study linked Atorvastatin with a 36.4% decrease in CRP. [55] Statins have been also found to lower inflammatory markers, and a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) suggested that pravastatin may reduce the risk of developing diabetes, although the Lipid Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) found no statistically significant effect of Atorvastatin on risk of developing diabetes. Fibrates have been found to lower some markers of inflammation, and a prospective trial found that Bezafibrate reduces risk of developing diabetes. [56] The Heart protection study includes a cohort of 5,963 people with type 2 diabetes who were randomly allocated to receive either Simvastatin or placebo. Simvastatin treatment resulted in reduction in LDL level and 25% reduction in the risk of major vascular events. [57] The FIELD (Fenofibrate intervention and event lowering in diabetes) trial, a study investigating the effect of Fenofibrate on cardiovascular mortality and morbidity, reported a significant reduction in nonfatal MI in diabetic patients. [58] Studies have shown the benefit of ACE inhibitors in reducing VCAM-1 levels and improving endothelial function in diabetic patients with borderline hypertension or normotension. [59],[60] Larger-scale trials like heart outcomes prevention evaluation (HOPE) study have demonstrated impressive findings with ACE inhibition in diabetic population. [61] ACE inhibition with Enalapril has also been shown to slow IMT progression in the common carotid arteries of patients with type 2 diabetes mellitus. [62] As the expression of AT1 receptor is up-regulated in the vasculature of diabetic patients, [63] Angiotensin Receptor Blockers are cardioprotective in diabetic patients. In the IDNT (Irbesartan Diabetic Nephropathy Trial), Irbesartan treatment was found to be associated with a 23% lower incidence of hospitalization for heart failure. [64] The recent study by Dandona et al. has revealed a significant fall of CRP by 30% after 1 week of therapy with Valsartan. [65] Thiazolidinediones, especially Rosiglitazone and Pioglitazone, are currently used in the treatment of type 2 diabetes mellitus as insulin sensitizing agents. In addition, they have recently been shown to interfere with other nuclear transcription factors like NF-κB and AP-1, and it is thought that this may be the major mechanism by which PPAR-γ agonists exert their anti-inflammatory effects. The study by Mohanty et al. showed the ability of Rosiglitazone to reduce CRP by approximately 20% after 4 weeks of treatment. [66] The PROACTIVE (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial concluded that Pioglitazone improves cardiovascular outcomes in patients with type 2 diabetes at high cardiovascular risk and reduces the need to add insulin to glucose lowering therapies compared with placebo. [67] A recent study by Stirban et al. has confirmed that Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. [56] Other agents including IL-10 [68] and Tenidap, an anti-inflammatory agent, [69] can reduce inflammatory process and may thus have therapeutic potential. Lifestyle and dietary modifications are also very important in this regard. Exercise is known to reduce inflammation. [70] Furthermore, the type of dietary fat consumed may have an effect upon acute phase reactants with n-3 fatty acids reducing cytokines. [71],[72],[73] Recently, data has also shown that weight loss may reduce inflammatory markers, including certain cytokines and CRP. [74],[75] Conclusion Hyperglycemia, the most obvious abnormality for diabetologists, is only the tip of the ′metabolic syndrome iceberg,′ i.e., the large body of risk factors (like hypertension, atherogenic dyslipidemia, insulin resistance, impaired fibrinolysis, inflammatory profile), which are often unsuspected or ignored. Among those factors, definitely, inflammation is the most neglected one. The understanding of the pivotal role of inflammation in the pathogenesis of atherosclerosis has opened the opportunities for a better future for management of diabetes mellitus and prevention of its complications. So risk assessment, prediction of cardiovascular events in diabetes mellitus and prevention of inflammation by add-on therapy are the needs of the present day.Acknowledgements The authors would like to thank Dr. Zubair Ahmed Karim and Dr. Raghavendra M. for their valuable suggestions, active support and encouragement. References
Copyright 2007 - Indian Journal of Medical Sciences The following images related to this document are available:Photo images[ms07047f4.jpg] [ms07047f2.jpg] [ms07047f1.jpg] [ms07047f3.jpg] |
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