Wednesday, June 7, 2023
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The incidence of insulin resistance, the metabolic syndrome, and type 2 diabetes is rising rapidly due to the epidemic of obesity in the industrialized world.[1] Although insulin resistance and type 2 diabetes lead to a number of complications, the leading cause of morbidity and mortality is cardiovascular disease. Because cardiovascular disease is usually caused by atherothrombotic vascular occlusion, there has been great interest in understanding the mechanisms through which diabetes promotes the progression of atherosclerosis. Identifying these mechanisms will likely lead to further advances in therapy. In this context, the relationship between diabetes and cardiovascular disease, with an emphasis on mechanisms and potential therapies, was the focus of a recent workshop held at the 2007 Drugs Affecting Lipid Metabolism (DALM) meeting.[2]
The evidence linking type 2 diabetes with coronary vascular disease was reviewed by Marja-Riitta Taskinen, MD, from the University of Helsinki, Finland.[2] As one of many examples, a recent study using multisplice computed tomography to assess coronary artery disease showed that diabetics have a marked increase in coronary plaque burden.[3] It is interesting that patients undergoing coronary artery angiography are often found to have previously unrecognized diabetes.[4]
Type 2 diabetes is associated with multiple abnormalities, all of which can contribute to vascular disease. The most notable of these abnormalities include obesity, insulin resistance, hyperglycemia, dyslipidemia, hypertension, and renal disease. Although a number of these disorders are often grouped together in an entity termed "metabolic syndrome," Dr. José Werbe from Milan University in Milan, Italy, reported that the increased risk for atherosclerotic disease in insulin-resistant patients correlates best with these abnormalities when each is considered individually.[2] These abnormalities promote heart disease by inducing atherosclerosis, endothelial cell dysfunction, oxidative stress, inflammation, and vascular remodeling.
The critical terminal event in atherosclerosis that leads to acute coronary syndromes (ie, unstable angina, heart attack [myocardial infarction], stroke, and sudden cardiac death) is a phenomenon called plaque instability. When plaques become unstable and rupture or erode, platelets in the bloodstream are exposed to plaque elements that can trigger acute thrombotic vascular occlusion.[5] Dr. Taskinen highlighted a number of processes that promote plaque instability and are likely to be increased in type 2 diabetes. These processes include heightened angiotensin activity, macrophage activation, macrophage and smooth muscle cell death, inflammation, physical stress on the arterial wall, and decreased arterial wall collagen.
In terms of specific cellular mechanisms accounting for some of these effects, Dr. Taskinen put forth a fascinating hypothesis regarding insulin signaling in cells responsible for the aforementioned proatherogenic responses. According to this concept, insulin signaling in these cells can result in both anti- and proatherogenic effects. In insulin resistance, the antiatherogenic effects of insulin are blocked, but the proatherogenic processes remain intact. While this overall concept has good experimental proof in liver cells,[6] its application to vascular wall cells has not been proven experimentally.
Atherosclerotic vascular disease is the chief cause of heart failure, and diabetics have an increased incidence of heart failure after acute coronary events.[7] In this regard, Dr. Taskinen reviewed data suggesting that diabetes can have direct adverse effects on heart muscle cells (cardiomyocytes). According to one idea, a defect in glucose uptake by cardiomyocytes in the setting of type 2 diabetes can have detrimental effects on heart muscle function.[8] In addition, the increase in circulating free fatty acids in type 2 diabetes may have adverse effects on cardiomyocytes and on endothelial function in the vessels that supply the heart muscle.[9,10]
Ira Tabas, MD, PhD, Columbia University Medical Center, New York, NY, presented evidence supporting a specific link between insulin resistance and atherothrombotic vascular disease.[2] Macrophage death, or apoptosis, in advanced atherosclerosis causes plaque necrosis, which promotes plaque disruption and acute atherothrombotic vascular events.[11] It is of interest that plaque necrosis and atherothrombotic disease are markedly increased in diabetes.[12] The Tabas laboratory discovered a macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis. The major components of the pathway involve combinatorial signaling through 2 major pathways: a pathway triggered by engagement of a family of cell surface receptors called pattern recognition receptors (PRRs) and a cell stress pathway known as the unfolded protein response (UPR), which involves a critical set of membranes in cells called the endoplasmic reticulum. This mechanism of macrophage death is referred to as the PRR-UPR model. The UPR, which is highly and specifically activated in the most dangerous types of human coronary artery plaque,[13] promotes macrophage death by inducing a proapoptotic molecule called CHOP. Dr. Tabas and his collaborators, Alan Tall, MD, and Domenico Accili, MD, of Columbia University, showed that macrophages with defective insulin signaling have an enhanced PRR-UPR macrophage death pathway. Most important, the advanced lesions of atherosclerosis-prone mice reconstituted with insulin-resistant macrophages show increased macrophage apoptosis and plaque necrosis.[14]
Finally, Dr. Tabas reported preliminary studies related to a well-known phenomenon in type 2 diabetes and obesity, namely a decrease in a fat tissue-derived hormone called adiponectin. Work by a number of other laboratories has shown a strong correlation between low adiponectin levels and increased incidence of coronary artery disease.[15] Dr. Tabas found that normal levels of adiponectin, which occur in most thin, nondiabetic individuals, protect macrophages from PRR-UPR-induced macrophage death. This finding raises the possibility that the decrease in adiponectin in type 2 diabetes may enhance advanced lesional macrophage death and thus promote plaque necrosis and disruption. In summary, the data from the Columbia group suggest that one mechanism of increased plaque necrosis and atherothrombotic vascular disease in insulin-resistant syndromes is amplification of a signal transduction pathway involved in advanced lesional macrophage death.
The most important approach to decreasing the incidence of diabetic heart disease is to lower the coronary risk factors of dyslipidemia, hypertension, and obesity. In particular, aggressive lowering of plasma low-density lipoprotein (LDL) levels, which can be achieved with statins or statins combined with other hypocholesterolemic drugs, has been shown to be extremely beneficial.[16] Whether tight glucose control, which has major benefits related to microvascular disease in diabetes, has a beneficial effect on heart disease is controversial.[17,18] Although the United Kingdom Prospective Diabetes Study showed a correlation between blood glucose levels in type 2 diabetics and heart disease, the association was relatively weak compared with other coronary risk factors.[19]
The issue of whether tight control of blood glucose can decrease the risk for heart disease in type 2 diabetics is being addressed in a comprehensive fashion in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.[20] On the other hand, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study found that lowering blood glucose on a long-term basis substantially lessened the incidence of heart disease in type 1 diabetics.[21] The DCCT/EDIC study also found that early institution of intensive glucose-lowering therapy in type 1 diabetics was associated with less coronary artery calcification, which is a measure of plaque burden.[22]
Another potential therapeutic approach to decreasing the risk for heart disease in diabetics is through diet. David Jenkins, MD, PhD, DSc,[2] and colleagues at the University of Toronto, Ontario, Canada, are exploring the potential benefits on cardiovascular risk factors of a diet with a low-glycemic index (eg, avoidance of simple sugars and certain complex carbohydrates, such as potatoes) and a high content of fiber-rich foods (eg, whole-grain cereals). There is some evidence in the literature that such diets may improve type 2 diabetes,[23] although the benefits need further exploration. So far, this group has found that persons on the low-glycemic index, high-fiber diet have lower glycated hemoglobin (A1C) and fasting plasma glucose levels and trend toward increased plasma high-density lipoprotein (HDL), decreased plasma triglycerides, and decreased body weight. Longer-term follow-up is needed to substantiate these findings and, most important, to specifically address the issue of cardiovascular events. If long-term cardiovascular benefit is observed, potential mechanisms include weight control, decrease in saturated fat intake, improvement in insulin resistance, and possibly lowering of blood glucose.
Efforts to increase the previously mentioned "beneficial" fat-derived hormone adiponectin may be part of a future strategy to decrease the incidence of heart disease in type 2 diabetics. In addition to potentially antiatherosclerotic effects of adiponectin on macrophage survival and other processes, Geesje Dallinga-Thie, PhD,[2] Erasmus University Medical Center, Rotterdam, the Netherlands, reported that the subgroup of diabetics with relatively high levels of adiponectin have higher plasma HDL levels. Whether the mechanism is related to increased production of the HDL protein apolipoprotein A1 or to decreased catabolism of HDL needs further investigation.[24,25]
Another strategy for the future may be to target a key cause of insulin resistance: high levels of circulating free fatty acids. As described by Arvinder Dhalla, PhD,[2] of CV Therapeutics in Palo Alto, California, fatty acids can be lowered by activating A1-adenosine receptors (A1AR) in adipose tissue. Preclinical studies have shown that an A1AR agonist called CVT-3619 lowers plasma free fatty acids, triglycerides, and glucose levels and increases insulin sensitivity in insulin-resistant rats.
The rising epidemic of obesity, insulin resistance, and type 2 diabetes is placing modern-day society at extremely high risk for the devastating effects of atherothrombotic heart disease. Effective drugs and guidelines for lifestyle changes are available to control cardiovascular risk factors, notably plasma LDL and hypertension, as well as insulin resistance and hyperglycemia. However, further therapeutic approaches are needed. Novel therapies can be best conceived through a thorough understanding of the cellular and molecular mechanisms of diabetes-induced heart disease. Innovative work in this area, as evidenced by the studies reported in this session, holds promise in this regard.
Supported by an independent educational grant from Reliant Pharmaceuticals
