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Inflammation, Lipids and Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies
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The Lancet May 24, 2008; 371:1800-1809
Prof Theodore Mazzone MD a , Prof Alan Chait MD b and Jorge Plutzky MD c
a. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
b. Department of Medicine, University of Washington, Seattle, WA, USA
c. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Conclusions
Data from in-vitro and animal model studies support the argument that the absence of intensive glycaemic control in the ACCORD trial3 should not eliminate hyperglycaemia as an important therapeutic target for reduction of cardiovascular disease in diabetes; the absence of effect might relate to an unfavourable benefit to risk ratio of the presently available glucose-lowering treatments in the patients recruited for that trial. In the ACCORD trial,3 the elderly at risk patients might have had increased susceptibility to the adverse effects of hypoglycaemia, off-target drug effects, or the risk imposed by ectopic fat deposition that usually accompany intensification of glucose-lowering treatments.130 The lipid arm of the ACCORD trial131 will provide information about the value of adding a fibrate (which can increase HDL concentrations) to statin treatment in patients with type 2 diabetes. Information obtained from animal models about the complexity of HDL metabolism and HDL's potent atheroprotective effect argues that, despite the apparent failure of torcetrapib, other mechanisms for increasing HDL-cholesterol concentrations warrant assessment. Although therapeutic interventions in people can never be as targeted or specific as the experimental manipulations achievable in isolated cells or in animal models, pathophysiological and mechanistic information from these models provide key insights for the design and assessment of new treatment options to reduce cardiovascular disease in type 2 diabetes.
".....increased pathogenicity from visceral fat.......Increased concentrations of inflammatory cytokines released from visceral fat in diabetes and obesity can act directly on the liver to increase the circulating concentrations of proinflammatory molecules such as C-reactive protein and serum amyloid A.....Inflammation is implicated in the pathogenesis of type 2 diabetes and atherosclerosis...
.....Diabetic dyslipidaemia is strongly related to atherosclerosis...a cornerstone of the management of cardiovascular disease risk in diabetes is the use of LDL-cholesterol-lowering drugs-ie, statins. These drugs generally reduce cardiovascular disease events by 25-50%....Type 2 diabetes is characterised by reduced HDL-cholesterol concentrations, increased triglyceride-rich lipoprotein concentrations, and abnormalities in the composition of HDL, LDL, and triglyceride-rich lipoprotein particles.....The triglyceride-rich lipoproteins-which can be increased in the fasting or postprandial state-in patients with type 2 diabetes are VLDL and metabolites of VLDL......Reduction in triglyceride-rich lipoprotein concentrations and hyperlipidaemia prevented disruption of atherosclerotic plaques in a mouse model of type 1 diabetes.....Patients with type 2 diabetes might not have substantially higher concentrations of LDL cholesterol than matched individuals without diabetes, but for any LDL-cholesterol concentration, those with diabetes generally have an increase in LDL particles43,45 because small, dense lipid-poor LDL particles accumulate in the circulation.....Individuals with type 2 diabetes mellitus have reduced HDL cholesterol and circulating apolipoprotein AI-the major apolipoprotein in HDL cholesterol.70 Abnormalities in the size and composition of the HDL particle have also been noted in diabetic patients. HDL and apolipoprotein AI remove excess cholesterol from atherosclerotic plaque cells, and their reduced concentrations in diabetes would be expected to have a detrimental effect on cholesterol content in vessel walls.....Mice without apolipoprotein AI and with very low HDL cholesterol concentrations have increased rates of atherosclerosis because of both reduced cholesterol transport and increased inflammation.....In addition to changes in HDL-cholesterol and apolipoprotein-AI concentrations, patients with type 2 diabetes have changes in HDL composition. HDL is perhaps the most heterogeneous and complex of all lipoprotein particles, and changes in its composition might affect HDL atheroprotective properties (figure 2).79 In isolated cells, HDL particles of different sizes and composition show different abilities to remove cholesterol from cells.....Mice without apolipoprotein AI and with very low HDL cholesterol concentrations have increased rates of atherosclerosis because of both reduced cholesterol transport and increased inflammation.....The roles of hyperglycaemia and hyperlipidaemia in atherogenesis have been difficult to separate in animal models of diabetes. Hyperlipidaemia is usually exacerbated by the onset of hyperglycaemia-eg, in mouse models of LDL-receptor deficiency and apolipoprotein-E deficiency-thereby confounding the effect of hyperglycaemia. However, in two animal models, hyperglycaemia seems to have an independent role..... Inflammation is implicated in the pathogenesis of type 2 diabetes and atherosclerosis.93,94 Since diabetes promotes atherosclerosis and increases cardiovascular events, a distinction might exist between inflammation that fosters diabetes and inflammation that arises after the type 2 diabetes and promotes atherosclerosis directly....The endothelium-as the cellular interface between the circulation and hyperglycaemia and dyslipidaemia that characterise type 2 diabetes mellitus-responds to hyperglycaemia and dyslipidaemia by showing an inflammatory response...."
Summary
Introduction
Hyperglycaemia and the vessel wall
Diabetic dyslipidaemia and the vessel wall
Glycaemia versus hyperlipidaemia in pathogenesis of atherosclerosis
Chronic subclinical inflammation and the vessel wall
Conclusions
Introduction
Several mechanisms are likely to contribute to the accelerated atherosclerosis and increased cardiovascular disease risk noted in patients with type 2 diabetes mellitus. We focus on areas in which basic mechanistic studies have high relevance to present clinical controversies to understand and address cardiovascular disease risk in people with diabetes. We assess pathophysiological information linking hyperglycaemia, diabetic dyslipidaemia (other than the control of LDL cholesterol concentrations), and inflammation to the accelerated vascular injury and cardiovascular disease risk in type 2 diabetes and discuss clinical considerations.
Hyperglycaemia and the vessel wall
Although a consistent association between glycaemic control and cardiovascular disease has been noted in epidemiological studies,1 the effect of tight glycaemic control did not seem to reduce the cardiovascular risk in clinical trials.2 Intensive glycaemic control in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study3 was stopped because of an increase in the number of cardiovascular deaths. A formal analysis of the results has not yet been reported. The ADVANCE (Action in Diabetes and Vascular Disease) study4 will provide information about whether a good glycaemic control is of benefit for cardiovascular disease. Results of basic studies in vitro, in animal models, and in patients with diabetes mellitus suggest several mechanisms by which hyperglycaemia might affect atherogenesis at the level of the artery wall (figure 1).
Hyperglycaemia can lead to vascular complications by several mechanisms. First, high glucose concentrations can activate nuclear factor ΚB (NF-ΚB),5,6 which in turn can increase the expression of various genes in the endothelial cells, monocyte-derived macrophages, and vascular smooth-muscle cells. Advanced glycation end-products (AGEs)-including protein cross-links, fluorophors, and other low molecular-weight residues-are formed by sustained exposure of proteins and lipids to high concentrations of glucose, which can generate reactive oxygen species. Ligation of AGEs to specific cell-surface receptors can regulate gene expression in vessel-wall cells.
Glucose increases oxidative stress, which has several possible harmful effects on the artery wall-eg, auto-oxidation of glucose leads to the formation of several reactive oxygen species, such as the superoxide anion, which can promote LDL oxidation in vitro.7 Indirect observational evidence suggests that lipoprotein oxidation might be increased in patients with type 2 diabetes8 and is related to glycaemic control.9 However, many of the studies relied on non-specific assays of oxidative stress. The absence of highly specific markers in collagen,10 plasma, or urine from individuals with diabetes11 does not support a generalised increase in oxidative stress in diabetes. Glycoxidation reactions are thought to contribute to macrovascular disease in diabetes by damaging tissues in the local microenvironment of the arterial wall.11 The pathways leading to these reactions include the generation of superoxide in the mitochondria, NADPH generation by monocyte-derived macrophages, or a redox-sensitive mechanism that generates hydroxyl radicals. Accumulation of the products of hydroxyl radicals locally in arterial tissue of diabetic monkeys is consistent with a redox-sensitive mechanism.12
Postprandial hyperglycaemia as an important index of glycaemic exposure and potential oxidative stress has had a resurgence in interest. 24 h excretion of 8-iso-prostaglandin F2-an indicator of free radical production derived from arachidonic acid in cell membranes13-was increased in patients with diabetes compared with that in non-diabetic controls.14 The concentrations of this prostaglandin were highest in patients with the greatest glycaemic variability. Moreover, this variability was a strong predictor of total free radical production, whereas postprandial blood glucose concentrations were not. Indeed, fluctuations in blood glucose concentrations accelerated atherosclerosis in apolipoprotein-E-deficient mice.15 Further studies are needed to assess the importance of oxidative stress that results from glycaemic variability.
Glucose and the endothelium
An important initial event in the pathogenesis of atherosclerosis is the adhesion of circulating monocytes to arterial endothelial cells, followed by their transmigration into the subendothelial space along a chemotactic gradient (figure 1). Hyperglycaemia enhances monocyte adhesion to cultured aortic endothelial cells16 by activation of NF-ΚB,5,6 which increases the expression of several inflammatory genes, including adhesion molecules that promote monocyte adhesion to the endothelial cells (figure 1).5
Expression of adhesion molecules might result from impaired nitric oxide production, since agents that increase the production of nitric oxide reduce the expression of adhesion molecules.17 Glucose-mediated and AGE-mediated inhibition of nitric oxide production by endothelial cells is associated with impaired endothelial-dependent relaxation,18-20 an early marker of vascular injury. In addition to substantial impairment of endothelium-dependent relaxation, diabetic mice show evidence of increased peroxynitrite generation, nitrotyrosine expression, and lipid peroxidation in the aortic tissues.21 Hyperglycaemia and AGEs stimulate the production of superoxide by endothelial cells, partly by activation of NADPH oxidase,6,22 thereby providing a link between hyperglycaemia, AGEs, and oxidative stress.
Glucose and monocyte-derived macrophages
Both high glucose concentrations23-25 and AGEs are associated with an increased state of activation of circulating monocytes in vitro and in vivo. Monocytes grown in the presence of high glucose concentrations or isolated from individuals with poorly controlled diabetes are in an activated and inflammatory state, as shown, for example, by the increased expression of cytokines23-interleukin 1_, and interleukin 6-and expression of CD36 and monocyte chemoattractant protein 1.26 These inflammatory changes are associated with induction of protein-kinase C, NF-ΚB activation, and increased release of superoxide, and all three could play a part in the oxidative stress that occurs in the presence of hyperglycaemia.27
Monocytes entering the endothelial space in response to chemotactic factors, proliferate and differentiate into intimal macrophages, which accumulate in the artery wall in diabetes (figure 1).27 Hyperglycaemia is not sufficient to stimulate macrophage proliferation in lesions of atherosclerosis or in isolated murine macrophages; in combination with hyperlipidaemia, it stimulates macrophage proliferation by a pathway that might include glucose-dependent oxidation of LDL.28
Arterial wall macrophages can accumulate lipid from modified forms of LDL, which are taken up by scavenger receptors. The modifications include LDL that has become oxidised as a result of glucose-mediated oxidative stress29 and AGE-modified LDL.30 Additionally, AGE-modified albumin can inhibit the selective uptake of cholesteryl esters from HDL,31 an essential step in reverse cholesterol transport. Thus, modification of lipoproteins and other proteins resulting from an increased exposure to high glucose concentrations can change the delivery and removal of lipids from macrophages in a way that is likely to promote atherosclerosis.
Glucose and vascular smooth-muscle cells
High glucose concentrations can stimulate the proliferation of vascular smooth-muscle cells in vitro.32 As atherosclerotic lesions progress, smooth-muscle cells migrate from the media to the intima, in which they proliferate, generate growth factors, and participate in the formation of a fibrous cap. Similar findings were noted after exposure of cells to AGEs33 and high insulin concentrations,34 which often accompany hyperglycaemia in type 2 diabetes.
Vascular smooth-muscle cells generate several matrix molecules that are implicated in atherogenesis. Vascular proteoglycans bind atherogenic lipoproteins, leading to their retention in the subendothelial space.35 At post-mortem examination, the expression of chondroitin sulphate and dermatan sulphate is increased and that of heparan sulphate proteoglycans is reduced in the atherosclerotic lesions of patients with diabetes compared with lesions from non-diabetic individuals.36 The increase in chondroitin and dermatan sulphate proteoglycans might contribute to the increased atherosclerosis in patients with diabetes by increasing LDL retention in the artery wall.35 In the rat37 and pig38 models, diabetes is associated with a loss of intimal elastin content and increased elastin fragmentation. Reduced intimal elastin content, whether through reduced production or increased breakdown, seems to promote atherosclerosis by mechanisms that are unclear.38 Therefore, elastin fragmentation might be another mechanism by which hyperglycaemia increases atherosclerosis in diabetes. Collagen-synthesised by vascular smooth-muscle cells-accumulates in atherosclerosis. In the presence of hyperglycaemia, collagen undergoes increased non-enzymatic glycation that increases its ability to bind LDL, which could result in increased LDL retention in the vessel wall. This increased retention could promote vessel wall accumulation and inflammation.39
Diabetic dyslipidaemia and the vessel wall
Diabetic dyslipidaemia is strongly related to atherosclerosis. Even though patients with type 2 diabetes might not have substantially increased concentrations of LDL-cholesterol compared with matched individuals without diabetes, a cornerstone of the management of cardiovascular disease risk in diabetes is the use of LDL-cholesterol-lowering drugs-ie, statins. These drugs generally reduce cardiovascular disease events by 25-50%40,41 but the excess residual cardiovascular disease risk remains for treated patients with diabetes compared with those without diabetes.42 Some of this residual risk could be attributed to lipoprotein abnormalities in patients with type 2 diabetes that are not adequately managed by statin treatment. Type 2 diabetes is characterised by reduced HDL-cholesterol concentrations, increased triglyceride-rich lipoprotein concentrations, and abnormalities in the composition of HDL, LDL, and triglyceride-rich lipoprotein particles (panel).43,44
Panel: Lipoprotein changes in type 2 diabetes mellitus
Triglyceride-rich lipoproteins
·Increased particle numbers
·Increased postprandial concentrations
·Triglyceride-enriched and cholesterol-enriched particles
LDL
·Increased particle numbers
·Small, dense particles
HDL
·Decreased particle numbers
·Several changes in particle composition
Triglyceride-rich lipoproteins
The triglyceride-rich lipoproteins-which can be increased in the fasting or postprandial state-in patients with type 2 diabetes are VLDL and metabolites of VLDL, and chylomicron remnants. The role of these lipoproteins in diabetic atherosclerosis remains controversial. Triglyceride concentrations vary inversely with HDL-cholesterol concentrations, confounding interpretations related to increases in concentrations of triglyceride-rich lipoproteins to atherosclerosis.45 Postprandial triglyceride concentrations might be a better predictor of cardiovascular disease events than fasting triglyceride concentrations, independently of HDL cholesterol concentrations.46,47 A proatherogenic effect of triglyceride-rich lipoproteins in the vessel wall is supported by substantial in-vitro evidence (figure 2). Triglyceride-rich lipoproteins enhance the proinflammatory phenotype of endothelial cells and macrophages and produce apoptosis in endothelial cells.48 They increase expression of tumour necrosis factor Α(TNFΑ) and adhesion receptors in macrophages, resulting in increased adherence of monocytes and monocyte-derived macrophages to endothelial cells.49 Apolipoprotein CIII-a component of triglyceride-rich lipoproteins and an inhibitor of lipoprotein lipase-increases adhesion of monocytic cells to endothelial cells.50
LDL
Patients with type 2 diabetes might not have substantially higher concentrations of LDL cholesterol than matched individuals without diabetes, but for any LDL-cholesterol concentration, those with diabetes generally have an increase in LDL particles43,45 because small, dense lipid-poor LDL particles accumulate in the circulation. Each LDL particle contains one apolipoprotein-B molecule and therefore patients with type 2 diabetes will also have a parallel increase in concentrations of apolipoprotein B. An increased number of LDL particles, measured directly or indirectly by concentrations of apolipoprotein B, might contribute to atherogenesis and cardiovascular disease risk.63-65 An increase in the number of LDL particles in diabetes can be treated by statins. However, a separate issue is whether or not small, dense LDL particles are inherently more atherogenic on a per-particle basis than the larger buoyant particles. An increased atherogenicity of small, dense LDL particles is supported by results of in-vitro studies, showing that small LDL particles rapidly enter the arterial wall and can be toxic to endothelial cells, cause greater production of procoagulant factors, be oxidised more readily, and be more readily immobilised by proteoglycans present in the arterial wall than can the large buoyant particles.66 The small particles do not bind very well to the LDL receptor, which might lead to impaired clearance by the liver.66 How these in-vitro results translate to the in-vivo milieu, however, remains unclear. A satisfactory in-vivo model for testing atherogenicity of small, dense LDL particles on a per-particle basis compared with large particles is needed. In non-human primates fed fat-modified diets, LDL-particle size was not independently atherogenic.67 Results from studies of healthy individuals68 and those with coronary heart disease69 showed that both large and small LDL particles are related to atherosclerosis and cardiovascular disease.
HDL
Individuals with type 2 diabetes mellitus have reduced HDL cholesterol and circulating apolipoprotein AI-the major apolipoprotein in HDL cholesterol.70 Abnormalities in the size and composition of the HDL particle have also been noted in diabetic patients.43,45,71,72 HDL and apolipoprotein AI remove excess cholesterol from atherosclerotic plaque cells, and their reduced concentrations in diabetes would be expected to have a detrimental effect on cholesterol content in vessel walls (figure 2). The cell type of most interest is the monocyte-derived macrophage because cholesterol-ester-engorged macrophages (ie, foam cells) are hallmarks of the atherosclerotic plaque. Removal of cholesterol from macrophages is thought to be an important first step in the process of reverse cholesterol transport, and might be important for the prevention of progression and for regression of atherosclerotic plaques.73 The HDL particle and its apolipoprotein-AI component might act through distinct cellular sterol transporters for removal of cholesterol from cells. The HDL particle seems to rely mainly on the ATP-binding cassette transporter G1 to facilitate sterol efflux, and expression of this transporter in cells can be inhibited by exposure to glycosylated proteins.74 Additionally, glycation of apolipoprotein AI, which acts mainly through the ATP-binding cassette transporter A1, suppresses its ability to remove cholesterol from cells.75 HDL has anti-inflammatory and antioxidant properties in cells of the vessel wall.76,77 Monocyte-derived macrophages isolated from individuals with low HDL cholesterol concentrations manifest a proinflammatory phenotype.78
In addition to changes in HDL-cholesterol and apolipoprotein-AI concentrations, patients with type 2 diabetes have changes in HDL composition. HDL is perhaps the most heterogeneous and complex of all lipoprotein particles, and changes in its composition might affect HDL atheroprotective properties (figure 2).79 In isolated cells, HDL particles of different sizes and composition show different abilities to remove cholesterol from cells.80 Changes in the content of many proteins associated with HDL, for example paroxonase (opposes oxidation of lipoprotein lipid),81 might change its atheroprotective properties.82 Compositional abnormalities of HDL isolated from patients with type 2 diabetes have been linked to impaired antiatherogenic properties.71 Cholesterol-ester transfer protein inhibition with torcetrapib did not protect against cardiovascular disease events, underscoring the notion that HDL-particle composition might be more important than HDL-cholesterol concentrations for reduction of cardiovascular disease risk.83
Mice without apolipoprotein AI and with very low HDL cholesterol concentrations have increased rates of atherosclerosis because of both reduced cholesterol transport and increased inflammation.84 Conversely, increased expression of apolipoprotein AI with high HDL-cholesterol concentrations reduces the amount of atherosclerosis in the apolipoprotein-E-/- mouse-a model of accelerated and progressive atherosclerosis.85 An increase in HDL-cholesterol concentrations in patients with type 2 diabetes has been linked to reduced carotid atherosclerosis.86,87 HDL has been proven to improve mobilisation and function of endothelial precursor cells88 and to protect the myocardium from ischaemia and reperfusion injury.89
Glycaemia versus hyperlipidaemia in pathogenesis of atherosclerosis
The roles of hyperglycaemia and hyperlipidaemia in atherogenesis have been difficult to separate in animal models of diabetes. Hyperlipidaemia is usually exacerbated by the onset of hyperglycaemia-eg, in mouse models of LDL-receptor deficiency and apolipoprotein-E deficiency-thereby confounding the effect of hyperglycaemia. However, in two animal models, hyperglycaemia seems to have an independent role.90,91 First, fat-fed diabetic pigs had more atherosclerosis than equally dyslipidaemic fat-fed animals without diabetes.90 Second, consumption of a cholesterol-free diet by LDL-receptor-deficient mice with a novel form of diabetes induced by a Β-cell-directed viral antigen resulted in hyperglycaemia without changes in lipids and lipoproteins.91 Hyperglycaemia was associated with lesion initiation. Addition of increasing amounts of dietary cholesterol led to dyslipidaemia, which was the major factor in atherosclerosis progression, independent of hyperglycaemia.91
Chronic subclinical inflammation and the vessel wall
Evidence ranging from pathological studies in people to in-vivo mouse models has established the role of inflammatory cells (such as macrophages and T lymphocytes) and inflammatory mechanisms (such as cytokine release) in the pathogenesis of atherosclerosis.92 Because type 2 diabetes and atherosclerosis are chronic conditions that take decades to arise, the cause and effect are difficult to discern (figure 3). Inflammation is implicated in the pathogenesis of type 2 diabetes and atherosclerosis.93,94 Since diabetes promotes atherosclerosis and increases cardiovascular events, a distinction might exist between inflammation that fosters diabetes and inflammation that arises after the type 2 diabetes and promotes atherosclerosis directly (figure 3). Most of the inflammatory mechanisms discussed also seem to be implicated in the atherosclerosis seen in prediabetic and non-diabetic states. Although the evidence implicating inflammation in atherosclerosis and type 2 diabetes is wide-ranging, a specific mechanism or an integrated framework has not been identified to explain precisely why patients with diabetes are at increased risk of inflammation or atherosclerosis.
Mechanisms of inflammation in diabetic atherosclerosis
The endothelium-as the cellular interface between the circulation and hyperglycaemia and dyslipidaemia that characterise type 2 diabetes mellitus-responds to hyperglycaemia and dyslipidaemia by showing an inflammatory response.95 Most of the responses induced in atherosclerosis are common to both diabetic and non-diabetic atherosclerosis. Classic proatherosclerotic endothelial responses-adhesion-molecule expression, secretion of chemokines, and coagulation proteins (plasminogen activator inhibitor 1, total plasminogen activator, and tissue factor), release of vasoactive mediators (endothelial nitric oxide and bradykinin)-are induced or regulated by inflammatory stimuli in diabetes models in vitro or in vivo, or both.96,97
Lymphocytes provide crucial proinflammatory signals to monocyte-derived macrophages and vascular smooth-muscle cells, and are activated by metabolic stimuli.98-100 Macrophages directly respond to the common abnormalities in type 2 diabetes-eg, glucose, free fatty acids, and hypertriglyceridaemia-by augmentation of the inflammatory responses.92,101 Several stimuli and cellular pathways are implicated in the effects of macrophages (figure 4), including increased foam-cell formation, release of matrix metalloproteinases, and secretion of growth factors and cytokines.94,102 These effects emphasise the important link between insulin resistance, inflammation, and atherosclerosis. When bone marrow from insulin-receptor-deficient mice was transplanted into LDL-receptor-deficient mice, lesions of increased complexity were noted.103 Macrophage-specific deficiency of the nuclear receptor PPAR_ in mice worsens insulin resistance,104,105 suggesting that the presence of this ligand-activated transcription factor in macrophages regulates insulin sensitivity, which could be related to PPAR_-mediated inhibition of inflammation.106 Similar issues apply to retinoid signalling through the retinoid-X receptor, the essential partner of PPAR_ and many other nuclear receptors.102,107
The available data suggests cellular responses to injury, inflammation, and metabolism might converge on control points that are important in atherosclerosis. A central regulator of inflammation is NF-ΚB,108 a transcriptional complex activated by various stimuli, including cytokines, oxidised LDL, lipopolysaccharide, and oxidative stress (figure 4).94 NF-ΚB is reported to regulate LDL oxidative modification, chemokine and cytokine expression, macrophage growth and differentiation, apoptosis, and vascular smooth-muscle cell proliferation. NF-ΚB, its regulatory proteins (eg, inhibitor ΚB), and distal targets (eg, c-Jun N-terminal kinase) have all been strongly implicated in insulin sensitivity and in atherosclerosis (figure 4).94,102,109,110 NF-ΚB might have a role in the common pathway, linking many inputs that are activated in type 2 diabetes mellitus to atherosclerotic responses. It is activated by factors commonly abnormal in type 2 disease mellitus, including fatty acids, glucose, AGE pathways, and some toll like receptors-a family of pattern recognition receptors expressed in various inflammatory cells.111 Several NF-ΚB-regulated targets are implicated in diabetic atherosclerosis, including TNF_, which increases insulin resistance, toll-like receptors, and resistin. In mice, inhibition of NF-ΚB activation can improve insulin sensitivity and reduce atherosclerosis; this inhibition (eg, by high-dose salicylates) is also being investigated in people.94 PPAR_'s anti-inflammatory and antiatherosclerotic effects in vitro and in mice might work through NF-ΚB inhibition (figure 4).106
Several mechanistic pathways have been proposed for how glucose brings about cellular injury and subsequent inflammation. Cells that do not have the ability to counter the increase in intracellular glucose concentrations might activate pathways of cellular injury and inflammation.112 These mechanisms include activation of protein-kinase C, formation of polyols, which promotes intracellular oxidative stress, and increased hexosamine activation, with subsequent increases in reactive oxidant species and mitochondrial stress.113-115 Although much of this evidence was linked to diabetic microvascular disease, increased flux of free fatty acids into the endothelium might cause macrovascular disease through similar pathways, inducing inflammation.
All secretory and membrane proteins, many nutrients, and many pathogens pass through the endoplasmic reticulum. Several lines of study implicate endoplasmic reticulum stress in the promotion of inflammation.116 Hypoxia, hyperglycaemia, and increased fatty-acid concentrations can all induce endoplasmic reticulum stress and a specific cellular process known as the unfolded protein response,117 which is a homoeostatic mechanism that restores normal endoplasmic reticulum function. Endoplasmic reticulum stress, present in the liver and adipose tissue, can activate pathways leading to oxidation and inflammation and has been implicated in both diabetes and atherosclerosis.118
Adipose tissue inflammation
Adipose tissue is a biologically active endocrine and paracrine organ. The theory that it could be involved in diabetic atherosclerosis has many implications for the intersection of inflammation, atherosclerosis, and type 2 diabetes mellitus, especially since clinical data suggests that adiposity is a core defect in the metabolic abnormalities that arise before and during diabetes.96 Inflammation in adipose tissue might contribute to abnormal metabolism and atherosclerosis in type 2 diabetes.
Oxidative stress, endoplasmic reticulum stress, and NF-ΚB activation pathways also operate in adipocytes.96,102 Oxidative stress and inflammation in adipose tissue can be exacerbated by hyperglycaemia.119 Fatty acids released from adipose tissue might signal to macrophages through pathways that involve toll-like receptors, leading to NF-ΚB activation. Many of the same pathways involved in the recruitment of leucocytes to the arterial wall also recruit inflammatory cells to fat, including monocyte chemoattractant protein 1.120 Indeed, mice deficient in C-C chemokine receptor-2-ie, the receptor for monocyte chemoattractant protein 1-are afforded some degree of protection from diet-induced insulin resistance and induction of inflammation.121 Excess lipid accumulation in other tissues-eg, skeletal muscle and the liver-might modulate inflammation, contributing to insulin resistance and atherosclerosis.122,123
Increased concentrations of inflammatory cytokines released from visceral fat in diabetes and obesity can act directly on the liver to increase the circulating concentrations of proinflammatory molecules such as C-reactive protein and serum amyloid A.124 C-reactive protein might directly amplify injury at the vessel wall and serum amyloid A unfavourably modifies the composition and function of HDL. The expression of adipose tissue apolipoproteins, which affect adipocyte lipid metabolism, is modified by inflammatory cytokines.125,126 Several adipocyte-specific mediators have been implicated in the inflammation contributing to insulin resistance and atherosclerosis. Leptin is an adipocyte-specific signal that seems to exert systemic proinflammatory effects.127 It produces proinflammatory changes in endothelial cells and macrophages, and its administration to apolipoprotein-E-deficient mice promotes atherosclerosis.124 Adiponectin, which circulates in the plasma in various multimeric forms, restricts inflammatory and atherosclerotic responses.128,129 Adiponectin concentrations are reduced in obesity and diabetes.124,128 and the treatment of apolipoprotein-E-deficient mice with an adiponectin-expressing adenovirus has proven to reduce atherosclerotic plaque formation.124 Adiponectin is present at higher concentrations in the subcutaneous fat adipocytes than in visceral fat adipocytes, one of many examples that suggest both depot-specific differences in fat and increased pathogenicity from visceral fat.124
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