mechanisms responsible for the overexpression of pai in diabetes
Increased expression of PAI-1 in diabetes is undoubtedly multifactorial. A direct effect of insulin on the expression of PAI-1 has been suggested by a positive correlation between the concentration of insulin and PAI-1 in vivo 93,94,96,100-103,106 . Triglycerides and their constituents fatty acids appear to contribute to the overexpression of PAI-1 in view of the fact that both insulin and triglycerides independently increase expression of PAI-1 by human hepatoma cells in vitro 105,107-109 ....
Effects of HRT on Carbohydrate Metabolism in Women With Diabetes
There is a degree of reluctance among health care professionals to prescribe HRT to women with diabetes. A community-based survey in London found that diabetic postmenopausal women were less than half as likely as the general population to be prescribed HRT 137 . Doctors and health care professionals perceive HRT as detrimental for diabetic women because of fear about glycemic control as is also the case with the oral contraceptive pill 138 . Yet there is no evidence that HRT results in...
Effects of the ReninAngiotensin System on Insulin Signaling
The effects of RAS inhibition on insulin action have been attributed to changes in both the inhibition of Ang II ATI receptor signaling and enhancement of bradykinin B2 receptor action. ACE, also called kininase II, degrades bradykinin 1-9 and thereby reduces bradykinin B2 receptor activation Fig. 2 . Several reports have shown that bradykinin B2-receptor antagonism blocks the decreases in insulin resistance and enhanced glucose uptake associated with ACE inhibition 148,149,157 and is mimicked...
abnormalities in the fibrinolytic system
The fibrinolytic system controls the patency of the vascular tree and is likely a critical regulator of thrombosis. One hypothesis is that small amounts of fibrin are constantly deposited on the endothelium and that these fibrin deposits are continually dissolved, resulting in a dynamic balance between coagulation and fibrinolysis. The generation and activity of plasmin, the enzyme responsible for the degradation of fibrin deposits and thrombi, are regulated mainly by the production of two...
Endogenous Peroxisome ProliferatorActivated Receptor Activation New Connections
The metabolic benefits seen with synthetic PPAR agonists frame a key biological question what does the body make to activate these receptors Presumably, such molecules might replicate the effects of synthetic PPAR drugs, possibly protecting individuals from diabetes mellitus, dyslipidemia, and or atherosclerosis. Early studies into endogenous PPAR agonists focused mainly on specific candidate molecules. Oxidized linoleic acid in the form of 9 or 13 hydroxyoctadecanoic acid HODE appears to...
and Receptors
The actions of the RAS are regulated both by angiotensinases in the extracellular milieu and by angiotensin receptor-coupled signaling networks. The precursor for angio- From Contemporary Cardiology Diabetes and Cardiovascular Disease, Second Edition Edited by M. T. Johnstone and A. Veves Humana Press Inc., Totowa, NJ Fig. 1. Overview of the renin-angiotensin system. Angiotensinogen and angiotensin I-derived peptides are cleaved via a number of extracellular proteases resulting in at least four...
Biology and Atherosclerosis
Early reports established not only that PPAR-y was expressed in monocytes, macrophages, and human atherosclerosis, but also that PPAR-y agonists could repress key proteins such as inflammatory cytokines and matrix metalloproteinases MMPs implicated in atherosclerosis and or its complications 30,31 . These observations were countered by the finding that PPAR-y agonists could also increase expression of CD36, a receptor mediating uptake of oxidized LDL 32 . Increased CD36 might be expected to...
fibrinolysis and arterial mural proteolysis
Results of recent work have highlighted the potential role of plasminogen activators and PAI-1 in the evolution of macroangiography in two compartments, blood in the arterial lumen as described above and in the arterial wall itself 125 . Intramural plasminogen activators and PAI-1 influence proteolytic activity of matrix metalloproteinases MMPs that are activated from zymogens by plasmin. Cell surface plasmin-dependent proteolytic activation of MMPs promotes migration of SMCs and macrophages...
Second Edition
Diabetes and Cardiovascular Disease, Second Edition, edited by Michael T. Johnstone, md, cm, frcp c and Aristidis Veves, md, dsc, 2005 Cardiovascular Disease in the Elderly, edited by Gary Gerstenblith, md, 2005 Platelet Function Assessment, Diagnosis, and Treatment, edited by Martin Quinn, mb bch bao, phd and Desmond Fitzgerald, md, frcpi, 2005 Angiogenesis and Direct Myocardial Revascularization, edited by Roger J. Laham, md and Donald S. Baim, md, 2005 Interventional Cardiology percutaneous...
PolyADPRibose Polymerase Regulates Gene Expression and Mononuclear Cell
Using pharmacological inhibitors of PARP, it has been demonstrated as briefly mentioned earlier that the activity of PARP is required for the expression of the MHC class II gene, DNA methyltransferase gene, protein kinase C PKC , collagenase, ICAM-1, and iNOS 10-14 . An oligonucleotide microarray analysis identified multiple genes that appear to be under the control of PARP-1 in resting cells 14 and even more genes are affected under conditions of immunostimulation 30 . A distinct mode of...
Advanced Glycoxidation EndProduct Crosslink Breakers
Recently, a promising therapeutic strategy has been to attack the irreversible intermolecular AGE crosslinks formed in biological systems providing prevention or reversal of various diabetes- and aging-related complications. This approach aims to break preaccumulated AGE and help renal elimination of resulting smaller peptides. PTB was originally studied 187 and more recently ALT-711 8,13,188 . Long-term studies are in progress to establish the safety of this new category of anti-AGE agents
Activation of the DAGPKC Pathway
One major advance in the understanding of diabetic vascular disease is the unraveling of changes in signal transduction pathways in diabetic states. One of the best-characterized signaling changes is the activation of DAG-PKC pathway. Such activation appears to be related to elevation of DAG, a physiological activator of PKC. Increases in total DAG contents have been demonstrated in a variety of tissues associated with diabetic vascular complications, including retina 78 , aorta, heart 79 ,...
dyslipidemia
In more than half of all diabetic patients, especially those with type 2 diabetes and insulin resistance, decreases in high-density lipoprotein HDL cholesterol and hypertriglycemia have been reported 102 . Increases in low-density lipoprotein LDL cholesterol levels are also frequently observed in diabetic patients, but such increases are more frequently in those with poor glycemic control or in parallel with hypertriglycemia. Additionally, LDLs can be modified in diabetes, as in the formation...
EndotheliumDependent Vasodilation in Animal Models
Studies using different animal models of diabetes in several different vascular beds 46-49 suggest that there is a decrease in endothelium-dependent vasodilation in the diabetic state. In two such animal models of type 1 diabetes, rats are made diabetic with streptozocin or rabbits made diabetic with alloxan, pancreatic P-cells are destroyed, with a corresponding decrease in insulin secretion. Studies evaluating endothelium-depen-dent vasodilation in these animal models have demonstrated a...
Michael T Johnstone md and Eli V Gelfand md
Endothelium-Derived Relaxing Factor Physiologic Effects of Nitric Oxide on the Vascular System Nitric Oxide and the Development of Atherosclerosis Endothelial Dysfunction and Diabetes Mellitus Possible Mechanisms of Impaired Endothelium-Dependent Vasodilation Other Risk Factors in Diabetic Endothelial Dysfunction Potential Preventive and Therapeutic Options Conclusions References Diabetes mellitus DM is a major source of morbidity in the United States, affecting between 10 and 15 million people...
Contributors
Lloyd Paul Aiello, md, PhD, Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, Boston, MA Aresh J. Anwar, md, mrcp, Division of Clinical Sciences, Warwick Medical School, University of Warwick and University Hospital of Coventry and Warwickshire, Coventry, UK Bernadette Aulivola, md, Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Edward J. Boyko, md, mph, Department of Medicine, University of...
Activation of the Polyol Pathway
Increased activity of the polyol pathway has been documented in culture studies using vascular cells exposed to diabetic level of D-glucose and in animals with diabetes 58,59 . In these studies, hyperglycemia has been shown to increase the activity of aldose reduc-tase and enhances the reduction of glucose to sorbitol, then further oxidized to fructose by sorbitol dehydrogenase. Abnormality in the polyol pathway has been suggested to cause vascular damage in the following ways a osmotic damage...
PPARa
PPAR-a is a transcription factor that enhances insulin sensitivity in adipose and other tissues 36 . In a randomized, double blind, placebo-controlled trial, patients with type 2 diabetes given 6 months of rosiglitazone, a PPAR-a agonist, had increased levels of adiponectin 37 , with a similar change being seen even in humans without insulin resistance 38 . PPAR-a agonists may mediate their effect by directly promoting adiponectin transcription or by inhibiting the actions of TNF-a 34,39 ....
Suketu Shah md Alina Gavrila md and Christos S Mantzoros md
Introduction Structure of Adiponectin Regulation of Adiponectin Adiponectin and Cardiovascular Disease Risk Factors Adiponectin's Direct Vascular Effects Adiponectin, a recently discovered protein produced exclusively by adipocytes, is thought to be a possible mediator between obesity, insulin resistance, and cardiovascular disease CVD . Although its function is not entirely known, body fat distribution, insulin, sex hormones, tumor necrosis factor TNF -a, and peroxisome proliferator-activated...
Maria F LopesVirella md phd and Gabriel Virella md phd
Introduction Endothelial Dysfunction Quantitative Qualitative Abnormalities of Lipoproteins Abnormalities in Platelet Function Abnormalities in Coagulation Abnormalities in the Fibrinolytic System References Macrovascular disease is the leading cause of mortality and morbidity in diabetes. The study of factors that may uniquely contribute to the accelerated development of atherosclerosis in diabetes has been an ongoing process for several years. However, the concepts behind both the pathogenic...
Melpomeni Peppa md Jaime Uribarri md and Helen Vlassara md
Advanced Glycoxidation End-Products Advanced Glycoxidation End-Products Advanced Glycoxidation End-Products Advanced Glycoxidation End-Products Microangiopathy Advanced Glycoxidation End-Products and Diabetic Macroangiopathy Antiadvanced Glycoxidation End-Product Strategies Conclusions References The incidence of diabetes, especially type 2 diabetes, is increasing at an alarming rate assuming epidemic proportions 1 . Worldwide, 124 million people had diabetes by 1997, although an estimated 221...
Exogenous Sources of Advanced Glycoxidation EndProducts
AGEs can also be introduced in biological systems from exogenous sources. Methods of food processing heating in particular have a significant accelerating effect in the generation of diverse highly reactive a- -dicarbonyl derivatives of glyco- and lipoxidation reactions that occur in complex mixtures of nutrients 20-23 . About 10 of a single AGE-rich meal is absorbed into the body 24,25 . Food-derived AGEs, rich in MG, CML, and other derivatives, are potent inducers of oxidative stress and...
Thrombus Formation
Thrombi may form in atherosclerotic vessels leading to tissue ischemia, tissue death, or both. Formation of thrombi starts with adhesion of platelets to areas of endothelial damage and, as a consequence, to local accumulation of platelets at sites of vascular injury. Platelet aggregation follows platelet adhesion as a result of the release of intraplatelet materials that may affect not only the clotting fibrinolytic system but also lead to the formation of microemboli. Thus, to understand the...