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Biochemistry Of Diabetes And Atherosclerosis



Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.




Biochemistry of Diabetes and Atherosclerosis


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Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease. Atherosclerosis accounts for virtually 80% of all deaths among diabetic patients. Prolonged exposure to hyperglycemia is now recognized a major factor in the pathogenesis of atherosclerosis in diabetes. Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerate the atherosclerotic process. Animal and human studies have elucidated three major mechanisms that encompass most of the pathological alterations observed in the diabetic vasculature: 1) Nonenzymatic glycosylation of proteins and lipids which can interfere with their normal function by disrupting molecular conformation, alter enzymatic activity, reduce degradative capacity, and interfere with receptor recognition. In addition, glycosylated proteins interact with a specific receptor present on all cells relevant to the atherosclerotic process, including monocyte-derived macrophages, endothelial cells, and smooth muscle cells. The interaction of glycosylated proteins with their receptor results in the induction of oxidative stress and proinflammatory responses 2) oxidative stress 3) protein kinase C (PKC) activation with subsequent alteration in growth factor expression. Importantly, these mechanisms may be interrelated. For example, hyperglycemia-induced oxidative stress promotes both the formation of advanced glycosylation end products and PKC activation.


The effects of hyperglycemia are often irreversible and lead to progressive cell dysfunction [8]. For example, in diabetic patients with functioning pancreatic transplants renal pathology continues to progress for at least 5 years after diabetes has been cured [8]. The mechanism for these observations is unclear, but suggests that cellular perturbations may persist despite the return of normoglycemia (the so-called memory effect). Thus, persistent rather than transient, acute metabolic changes are of pivotal importance in the pathogenesis of diabetic complications.


One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction [9]. Glucose forms chemically reversible early glycosylation products with reactive amino groups of circulating or vessel wall proteins (Schiff bases), which subsequently rearrange to form the more stable Amadori-type early glycosylation products. Equilibrium levels of Schiff-base and Amadori products (the best known of which is hemoglobin A1C) are reached in hours and weeks, respectively [10] (Figure 1). Some of the early glycosylation products on long-lived proteins (e.g. vessel wall collagen) continue to undergo complex series of chemical rearrangement to form advanced glycosylation end products (AGEs) [10]. Once formed, AGE-protein adducts are stable and virtually irreversible. Although AGEs comprise a large number of chemical structures, carboxymethyl-lysine-protein adducts are the predominant AGEs present in vivo [11, 12].


Glycosylation of proteins and lipoproteins can interfere with their normal function by disrupting molecular conformation, alter enzymatic activity, reduce degradative capacity, and interfere with receptor recognition (Table 1). Thus, changes in the normal physiology of proteins that are relevant to atherogenesis, may promote atherosclerosis in diabetic individuals.


Clinical studies have shown an increased level of AGEs on LDL obtained from diabetics compared with normal individuals [19, 20]. Glycosylation of LDL apo B (the surface protein of LDL) occurs mainly on a positively charged lysine residues within the putative LDL receptor binding domain which are essential for the specific recognition of LDL by the LDL receptor [20]. LDL glycosylation is increased in correlation with glucose levels, and AGE-ApoB levels are up to 4-fold higher in diabetic patients [19, 20]. Glycosylation of ApoB results in a significant impairment of LDL-receptor-mediated uptake decreasing the in vivo clearance of LDL compared to native LDL [21] (Figure 2). Several studies have shown that degradation of glycated LDL is impaired in cultured human fibroblasts (which posses LDL receptor) compared with normal LDL, and that this impairment is proportional to the extent of glycation [21]. In contrast to fibroblasts, human monocyte-derived macrophages recognize glycated LDL to a greater extent than native LDL [22]. The uptake of glycated LDL by these cells, however, is not mediated by the LDL receptor pathway, but by a high-capacity, low-affinity receptor pathway [22]. Thus, glycated LDL are poorly recognized by the specific LDL receptor and are preferentially recognized by a nonspecific (scavenger) receptor present on human macrophages. Because LDL glycosylation enhances its uptake by human aortic intimal cells [23] and monocyte-derived macrophages [22] with stimulation of foam cells formation, the recognition of glycated LDL by the scavenger receptor pathway is thought to promote intracellular accumulation of cholesteryl esters and promote atherosclerosis (Figure 2).


Binding of soluble AGEs to RAGE-bearing monocytes induces chemotaxis [36], followed by mononuclear infiltration through an intact endothelial monolayer [37, 38]. Pathological studies of human atherosclerotic plaques showed infiltration of RAGE-expressing cells in the expanded intima [28]. Monocyte-macrophage interaction with AGEs results also in the production of mediators such as interleukin-1, tumor necrosis factor-α, platelet-derived growth factor, and insulin growth factor-I [37, 39, 40], which have a pivotal role in the pathogenesis of atherosclerosis [41].


The potential role of RAGE in the atherogenic process in diabetes has been demonstrated by Park and associates [43]. In the model of atherosclerosis-prone mice due to homozygous deletion of apolipoprotein E (apoE) gene, the induction of diabetes using streptozotocin resulted in atherosclerosis of increased severity compared to euglycemic apoE controls. The development of vascular was more rapid with the formation of more complex lesions (fibrous caps, extensive monocyte infiltration, etc) and atherosclerosis extending distally in the aorta and major arteries. Increased expression of RAGE and the presence of AGEs in the vessel wall, especially at sites of vascular lesions were also evident. Blockade of AGE-RAGE interaction using a truncated soluble extracellular domain of RAGE resulted in a striking suppression of lesions in diabetic mice, with lesions largely arrested at the fatty streak stage and a large reduction in complex lesions. These effects were independent of glucose and lipid levels [43].


PKC is a family of at least 12 isoforms of serine and threonine kinases. Although several PKC isoforms are expressed in vascular tissue, in the rat model of diabetes there is a preferential activation of PKC β2 in the aorta, heart, and retina, and PKC β1 in the glomeruli [48, 49].


Oxidative stress is widely invoked as a pathogenic mechanism for atherosclerosis. Among the sequelae of hyperglycemia, oxidative stress has been suggested as a potential mechanism for accelerated atherosclerosis [7, 55, 56]. Hyperglycemia can increase oxidative stress through several pathways. A major mechanism appears to be the hyperglycemia-induced intracellular reactive oxygen species (ROS), produced by the proton electromechanical gradient generated by the mitochondrial electron transport chain and resulting in increased production of superoxide [7].


Relationship between rates of oxidant generation, antioxidant activity, oxidative stress, and oxidative damage in diabetes. [O2]* represents various forms of reactive oxygen species [ROS]. The overall rate of formation of oxidative products leading to oxidative tissue damage is dependent on ambient levels of both [O2]* and substrate. Increased generation of [O2]* depends on several sources including glucose autoxidation, increased mitochondrial superoxide production, and as a result of the receptor for advanced glycosylation end products activation. [O2]* deactivation is reduced because antioxidant defenses are compromised in diabetes. Note that oxidative stress also promotes other hyperglycemia-induced mechanisms of tissue damage. Oxidative stress activates protein kinase C (PKC) and accelerates the formation of advanced glycosylation endproducts (AGEs).


Fat accumulation in the pancreas associated with obesity and the metabolic syndrome (MetS) has been defined as "non-alcoholic fatty pancreas disease" (NAFPD). The aim of this review is to describe the association of NAFPD with obesity, MetS, type 2 diabetes mellitus (T2DM) and atherosclerosis and also increase awareness regarding NAFPD. Various methods are used for the detection and quantification of pancreatic fat accumulation that may play a significant role in the differences that have been observed in the prevalence of NAFPD. Endoscopic ultrasound provides detailed images of the pancreas and its use is expected to increase in the future. Obesity and MetS have been recognized as NAFPD risk factors. NAFPD is strongly associated with non-alcoholic fatty liver disease (NAFLD) and it seems that the presence of both may be related with aggravation of NAFLD. A role of NAFPD in the development of "prediabetes" and T2DM has also been suggested by most human studies. Accumulation of fat in pancreatic tissue possibly initiates a vicious cycle of beta-cell deterioration and further pancreatic fat accumulation. Additionally, some evidence indicates a correlation between NAFPD and atherosclerotic markers (e.g., carotid intima-media thickness). Weight loss and bariatric surgery decreases pancreatic triglyceride content but pharmacologic treatments for NAFPD have not been evaluated in specifically designed studies. Hence, NAFPD is a marker of local fat accumulation possibly associated with beta-cell function impairment, carbohydrate metabolism disorders and atherosclerosis. 041b061a72


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