The Metabolic Syndrome in the Modern World Rodeen Rahbar, Kirti Malhotra and Anton Sidawy In 2010, it was estimated that among all industrialized Western countries, between one in three to one in five people had the metabolic syndrome. In the United States alone that amounted to approximately 50 million to 75 million people. This population seems to be expanding at an alarming rate. It is estimated that by 2020, nearly one half of people in the United States will have the metabolic syndrome. The metabolic syndrome plays an important role in cardiac, vascular, and kidney disease. Definition Experts disagree on the precise definition of the metabolic syndrome. According to the National Cholesterol Education Program Adult Treatment Panel (ATP III), any three of the following criteria meet the definition: abdominal obesity (waist circumference), elevated serum triglycerides, lower high-density lipoprotein (HDL) cholesterol, high blood pressure, and elevated fasting blood glucose. The World Health Organization has slightly different criteria: abdominal obesity, cholesterol derangements, high blood pressure, and high insulin levels. Etiology Obesity Many experts now agree that visceral, but not necessarily subcutaneous, obesity leads to the development of the metabolic syndrome. It may be surprising to note that subcutaneous fat accumulation is actually protective rather than harmful. Subcutaneous adiposity is a normal physiologic response to caloric excess, serving protective functions during times of starvation or stress. However, problems begin to arise when these adipocytes begin to accumulate too much fat. At first, subcutaneous adipocytes disseminate warning signals involving hormones that regulate the hypothalamus’s appetite center and also stimulate non-adipocytes to begin oxidizing free fatty acids. If caloric surplus continues despite compensatory warning signals, subcutaneous adipocytes eventually become resistant to insulin. The body is forced to store fatty acids in the viscera rather than subcutaneously. A cascade of inflammatory events rooted in dysfunctional hormonal signaling results in an inflammatory syndrome known as lipotoxicity. This leads to mineralocorticoid abnormalities with salt and water retention, oxidative stress damage, atherosclerosis, and hepatic lipid dysregulation. Chronic caloric surplus that continues unabated after the body’s compensatory mechanisms have reached their saturation point has been proposed to be the sine qua non of the metabolic syndrome. The mechanisms behind this require further discussion. Chronic Caloric Surplus: The Sine Qua Non Modern societies have revolutionized the food supply by producing a plethora of inexpensive, readily available calorie-rich foods. In the United States this began in the 1960s. It is termed the gastronomic revolution, a phrase that characterizes the preparation of food at home as a chore and commercially produced food, available at reasonable prices, as the more attractive alternative. Further exacerbating the revolution, the composition of food was also dramatically changed to heighten sales by encouraging consumption of larger portions. In addition, commercially available food and beverages were made rich in salt, fat, glucose, and simple sugars. They were also low in protective antiinflammatory antioxidants. This gastronomic experiment, though profitable for some, became a general recipe for poor public health several decades later. Approximately two thirds of all Americans are now at least overweight, and nearly one third of them carry the diagnosis of metabolic syndrome. This profound abundance of high-calorie foods will continue to encourage overindulgence. Obesity and the Metabolic Syndrome: Adipocyte Saturation The metabolic syndrome occurs at a saturation point, a resistance to the healthy storage of excess calories. Subcutaneous fat stores release adipokines, a family of adipocyte-derived hormones, to signal that they are nearing capacity and that behavior and metabolism must change appropriately. Despite these protective signals, when calorie intake remains high, cells are forced to metabolize and store extra calories in places ill equipped to handle the metabolic byproducts; these include the visceral organs: the liver, pancreas, and heart. In stark contrast to subcutaneous obesity, this mode of fat storage, known as visceral obesity, generates a profound inflammatory response. In the endothelium it results in decreased nitric oxide (NO) bioavailability and atherosclerosis. In the liver it results in nonalcoholic steatohepatitis (NASH), decreasing serum HDL cholesterol and increasing serum LDL. In insulin-responsive cells, it damages insulin receptors, both directly and by affecting insulin receptor downstream signaling pathways, potentiating diabetes mellitus. In fat tissue it also enhances mineralocorticoid excess, leading to hypertension. Understanding this complex, seemingly broad metabolic paradox requires a sound understanding of the interaction between insulin and its target tissues. Muscle, fat, and liver tissues are induced by insulin to sequester blood glucose and either metabolize or store it. During the normal physiologic state, calories are broken down to simple sugars in the intestines and/or liver, the most basic being glucose. As blood glucose rises, insulin is secreted by the pancreas to decrease the blood glucose concentration to a level that will optimize nervous system function. Conversely, if blood glucose gets too low, the pancreas secretes glucagon, and in certain cases the adrenal glands secrete epinephrine, to restore normal levels required for nervous system function. Because nervous tissue itself cannot store glucose, it relies on non-nervous tissues such as skeletal muscle, the liver, and fat to sequester excess glucose (or provide glucose) so that blood concentrations stay within an ideal range for optimal neuron function. Ideally, calories in the diet are closely matched to the metabolic demands of muscle tissue and never actually need to be stored anywhere except in muscle glycogen reserves and a limited reserve in fat cells. In reality, there is often a caloric excess that necessitates excess storage in fat cells. Insulin is the signal that simply tells tissues that excess glucose is available for use, but it does not dictate where that energy is stored. When muscle is under heavy loads, it requires much energy. To meet that demand and ensure that the metabolic requirements of muscle tissue are matched to available energy sources, insulin sensitivity, or the ability of muscle tissue to sequester glucose upon insulin stimulation, is in fact enhanced by this excess metabolic demand. Lifting heavy weights, for example, can require large amounts of energy expenditure that is simply not available or is too slow to mobilize if skeletal muscle did not have its own energy reserves. Therefore, skeletal muscle is designed to store excess glucose as glycogen that can be quickly converted to glucose for use at peak times. “Fast-twitch” skeletal muscle requires quick bursts of energy by way of the anaerobic metabolism of glucose into lactic acid, and this glucose must come from stored glycogen energy reserves. Aerobic “slow-twitch” skeletal muscle can use fatty acids through oxidative phosphorylation for more enduring energy and glycogen for other metabolic needs. When skeletal muscle, both slow and fast twitch, is used repeatedly and frequently, glycogen stores need constant replenishment. Consequently, insulin sensitivity is directly affected by exercise, and the more one exercises the more sensitive muscle becomes to insulin. This has been proved experimentally: GLUT4 (the gene for the glucose transporter) transcription has been shown to be up-regulated in muscle tissue after exercise. In addition, the arteries are working at maximum capacity after exercise. The muscular arteries, including the tibial arteries, are stimulated to relax to provide maximum oxygen delivery to muscles under stress. Muscular artery endothelium is highly responsive to insulin, but its sensitivity is modulated by metabolic demands. In response to insulin and after periods of high metabolic demand by muscles, muscular arteries release NO, an important vasodilator, thereby resulting in increased delivery of both oxygen and glucose to tissues. This vasodilatation is important because skeletal muscle’s energy demands can skyrocket during and after exercise. This response is noted after both aerobic and anaerobic exercise. During times of inactivity, skeletal muscle energy demands become stagnant, and insulin sensitivity is likewise down-regulated. The medium-sized arteries such as the tibial and brachial arteries are particularly vulnerable to insulin sensitivity, and with reduced metabolic demands they become chronically vasoconstricted. With muscle insulin sensitivity down-regulated and blood flow to skeletal muscles also diminished, glucose uptake by muscle tissue is minimized. This is purely physiologic because muscle tissue matches its insulin sensitivity to glucose based on actual demand. An important gene receptor, peroxisome proliferator activated receptor δ (PPARδ), can regulate use of muscle energy and is being intensely studied because the link between how effectively muscle tissue matches energy requirements to glucose sequestration is only partly understood. Evolutionarily, PPARD gene regulation functioned to keep muscle metabolic demand low so that food, which was often scarce, would be used efficiently. Today, when food is abundant, people with more favorable PPARD gene regulation burn more calories to perform the same amount of work and hence maximize muscle’s insulin sensitivity to excess calories. At some point, depending on an individual person’s inherited biochemistry, muscle tissue becomes minimally responsive to insulin because it simply does not need the extra calories for its daily metabolic processes. Now, other tissues more suited for surplus calorie storage not needed by inactive muscles become the dominant tissue that responds to insulin. This tissue is known as fat and consists of adipocytes, macrophages, and fibroblasts. Subcutaneous Fat Tissue: The “Good” Type Subcutaneous fat tissue is a highly hormonal tissue that can regulate insulin sensitivity, the hypothalamus, the desire to eat or not eat, and the metabolic processing of extra calories. It is actually the key regulator of healthy metabolism in times of caloric excess. Each cell in fat tissue plays a role in regulating hormones and cytokines in response to calorie storage. During times of caloric surplus and low muscle metabolic requirements, extra glucose, in response to insulin, is sequestered by fat cells and converted to triacylglycerol fat and then stored. As adipocytes store fat, they release important signaling molecules known as adipokines; these hormones then help the organism to regulate caloric intake and metabolism appropriately. Two adipokines, leptin and adiponectin, are the major fat hormones that regulate healthy lipid metabolism. Leptin is an adipokine that protects vital organs from the saturation of free fatty acids onto the viscera by limiting them to adipocytes. It is secreted in response to the excessive storage of fat and is likely regulated by PPARγ. Additionally, leptin has antilipotoxic effects through leptin-induced fatty acid oxidation, a process that stimulates oxidative phosphrylation of free fatty acids in all tissues. Leptin serves to limit overeating by acting on the appetite center in the hypothalamus. These protective effects could explain the years of lapse between onset of obesity and development of the metabolic syndrome. In fact, it has been proposed that the development of obesity is a normal and necessary physiologic response to caloric excess that may even be protective and initially beneficial. In fact, the highly vascular and minimally fibrotic fat pads composed of smaller adipocytes at the onset of early obesity can actually reduce necrosis and scar formation of viscera and therefore reduce local and systemic inflammation. However, too many calories over too long a period of time can overwhelm the storage capacity of adipocytes, at which point the gradual accumulation of deranged fatty acids’ metabolic byproducts from food sources is initiated. Leptin resistance is a precursor to this frankly dysfunctional metabolic state. Several experiments have delineated the role of leptin. During the first 24 hours after a heavy meal, leptin levels in plasma begin to increment. Studies by Unger and Scherer in 2010 in rodents have validated leptin’s protective effect on vital organs by limiting free fatty acid storage to subcutaneous adipocytes instead of the viscera. After feeding a diet composed of 60% fat to leptin-responsive rats for 8 weeks, it was found that almost 100% of the increase in body fat was confined to subcutaneous adipocytes. On the other hand, in the leptin-unresponsive rats, nonadipose tissues such as the liver, heart, and pancreas were overloaded with fatty acids, even while they were fed a diet composed of only 6% of fat for the same amount of time. In the same study, it was demonstrated that lipids actually cause apoptosis of important visceral cells. For example, in the leptin-unresponsive rats, there was a concurrent decrease of beta-cell function as the lipid content of the pancreas rose. The decrease in beta-cell mass leads to hyperglycemia and eventually to the development of type 2 diabetes. Not only was the pancreas affected but also myocardial apoptosis was seen after the increase in triglyceride content of the myocardium, which can lead to serious morbidities such as dilated lipotoxic cardiomyopathy and premature death. Hence, it is leptin that helps ensure that lipids are stored in subcutaneous adipocytes and not in ectopic tissues and therefore plays a key role in preventing lipotoxcicity. This is further confirmed by the fact that exogenous administration of leptin can reverse the steatosis in humans and rodents. Adiponectin, similar to leptin, is also a protective adipokine. It is a vasoprotective agent in that it acts as an insulin sensitizer, an antiinflammatory, and an antiapoptotic agent by increasing release of free fatty acids during increased metabolic demand. It also serves to increase vasodilation via endothelial NO production. Not surprisingly, adiponectin levels are high in healthy, subcutaneously obese patients. Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Technical Aspects of Percutaneous Carotid Angioplasty and Stenting for Arteriosclerotic Disease In-Situ Treatment of Aortic Graft Infection with Prosthetic Grafts and Allografts Treatment of Dyslipidemia and Hypertriglyceridemia Intraoperative Assessment of the Technical Adequacy of Carotid Endarterectomy Stay updated, free articles. Join our Telegram channel Join Tags: Current Therapy in Vascular and Endovascular Surgery Aug 25, 2016 | Posted by admin in CARDIOLOGY | Comments Off on The Metabolic Syndrome in the Modern World Full access? Get Clinical Tree
The Metabolic Syndrome in the Modern World Rodeen Rahbar, Kirti Malhotra and Anton Sidawy In 2010, it was estimated that among all industrialized Western countries, between one in three to one in five people had the metabolic syndrome. In the United States alone that amounted to approximately 50 million to 75 million people. This population seems to be expanding at an alarming rate. It is estimated that by 2020, nearly one half of people in the United States will have the metabolic syndrome. The metabolic syndrome plays an important role in cardiac, vascular, and kidney disease. Definition Experts disagree on the precise definition of the metabolic syndrome. According to the National Cholesterol Education Program Adult Treatment Panel (ATP III), any three of the following criteria meet the definition: abdominal obesity (waist circumference), elevated serum triglycerides, lower high-density lipoprotein (HDL) cholesterol, high blood pressure, and elevated fasting blood glucose. The World Health Organization has slightly different criteria: abdominal obesity, cholesterol derangements, high blood pressure, and high insulin levels. Etiology Obesity Many experts now agree that visceral, but not necessarily subcutaneous, obesity leads to the development of the metabolic syndrome. It may be surprising to note that subcutaneous fat accumulation is actually protective rather than harmful. Subcutaneous adiposity is a normal physiologic response to caloric excess, serving protective functions during times of starvation or stress. However, problems begin to arise when these adipocytes begin to accumulate too much fat. At first, subcutaneous adipocytes disseminate warning signals involving hormones that regulate the hypothalamus’s appetite center and also stimulate non-adipocytes to begin oxidizing free fatty acids. If caloric surplus continues despite compensatory warning signals, subcutaneous adipocytes eventually become resistant to insulin. The body is forced to store fatty acids in the viscera rather than subcutaneously. A cascade of inflammatory events rooted in dysfunctional hormonal signaling results in an inflammatory syndrome known as lipotoxicity. This leads to mineralocorticoid abnormalities with salt and water retention, oxidative stress damage, atherosclerosis, and hepatic lipid dysregulation. Chronic caloric surplus that continues unabated after the body’s compensatory mechanisms have reached their saturation point has been proposed to be the sine qua non of the metabolic syndrome. The mechanisms behind this require further discussion. Chronic Caloric Surplus: The Sine Qua Non Modern societies have revolutionized the food supply by producing a plethora of inexpensive, readily available calorie-rich foods. In the United States this began in the 1960s. It is termed the gastronomic revolution, a phrase that characterizes the preparation of food at home as a chore and commercially produced food, available at reasonable prices, as the more attractive alternative. Further exacerbating the revolution, the composition of food was also dramatically changed to heighten sales by encouraging consumption of larger portions. In addition, commercially available food and beverages were made rich in salt, fat, glucose, and simple sugars. They were also low in protective antiinflammatory antioxidants. This gastronomic experiment, though profitable for some, became a general recipe for poor public health several decades later. Approximately two thirds of all Americans are now at least overweight, and nearly one third of them carry the diagnosis of metabolic syndrome. This profound abundance of high-calorie foods will continue to encourage overindulgence. Obesity and the Metabolic Syndrome: Adipocyte Saturation The metabolic syndrome occurs at a saturation point, a resistance to the healthy storage of excess calories. Subcutaneous fat stores release adipokines, a family of adipocyte-derived hormones, to signal that they are nearing capacity and that behavior and metabolism must change appropriately. Despite these protective signals, when calorie intake remains high, cells are forced to metabolize and store extra calories in places ill equipped to handle the metabolic byproducts; these include the visceral organs: the liver, pancreas, and heart. In stark contrast to subcutaneous obesity, this mode of fat storage, known as visceral obesity, generates a profound inflammatory response. In the endothelium it results in decreased nitric oxide (NO) bioavailability and atherosclerosis. In the liver it results in nonalcoholic steatohepatitis (NASH), decreasing serum HDL cholesterol and increasing serum LDL. In insulin-responsive cells, it damages insulin receptors, both directly and by affecting insulin receptor downstream signaling pathways, potentiating diabetes mellitus. In fat tissue it also enhances mineralocorticoid excess, leading to hypertension. Understanding this complex, seemingly broad metabolic paradox requires a sound understanding of the interaction between insulin and its target tissues. Muscle, fat, and liver tissues are induced by insulin to sequester blood glucose and either metabolize or store it. During the normal physiologic state, calories are broken down to simple sugars in the intestines and/or liver, the most basic being glucose. As blood glucose rises, insulin is secreted by the pancreas to decrease the blood glucose concentration to a level that will optimize nervous system function. Conversely, if blood glucose gets too low, the pancreas secretes glucagon, and in certain cases the adrenal glands secrete epinephrine, to restore normal levels required for nervous system function. Because nervous tissue itself cannot store glucose, it relies on non-nervous tissues such as skeletal muscle, the liver, and fat to sequester excess glucose (or provide glucose) so that blood concentrations stay within an ideal range for optimal neuron function. Ideally, calories in the diet are closely matched to the metabolic demands of muscle tissue and never actually need to be stored anywhere except in muscle glycogen reserves and a limited reserve in fat cells. In reality, there is often a caloric excess that necessitates excess storage in fat cells. Insulin is the signal that simply tells tissues that excess glucose is available for use, but it does not dictate where that energy is stored. When muscle is under heavy loads, it requires much energy. To meet that demand and ensure that the metabolic requirements of muscle tissue are matched to available energy sources, insulin sensitivity, or the ability of muscle tissue to sequester glucose upon insulin stimulation, is in fact enhanced by this excess metabolic demand. Lifting heavy weights, for example, can require large amounts of energy expenditure that is simply not available or is too slow to mobilize if skeletal muscle did not have its own energy reserves. Therefore, skeletal muscle is designed to store excess glucose as glycogen that can be quickly converted to glucose for use at peak times. “Fast-twitch” skeletal muscle requires quick bursts of energy by way of the anaerobic metabolism of glucose into lactic acid, and this glucose must come from stored glycogen energy reserves. Aerobic “slow-twitch” skeletal muscle can use fatty acids through oxidative phosphorylation for more enduring energy and glycogen for other metabolic needs. When skeletal muscle, both slow and fast twitch, is used repeatedly and frequently, glycogen stores need constant replenishment. Consequently, insulin sensitivity is directly affected by exercise, and the more one exercises the more sensitive muscle becomes to insulin. This has been proved experimentally: GLUT4 (the gene for the glucose transporter) transcription has been shown to be up-regulated in muscle tissue after exercise. In addition, the arteries are working at maximum capacity after exercise. The muscular arteries, including the tibial arteries, are stimulated to relax to provide maximum oxygen delivery to muscles under stress. Muscular artery endothelium is highly responsive to insulin, but its sensitivity is modulated by metabolic demands. In response to insulin and after periods of high metabolic demand by muscles, muscular arteries release NO, an important vasodilator, thereby resulting in increased delivery of both oxygen and glucose to tissues. This vasodilatation is important because skeletal muscle’s energy demands can skyrocket during and after exercise. This response is noted after both aerobic and anaerobic exercise. During times of inactivity, skeletal muscle energy demands become stagnant, and insulin sensitivity is likewise down-regulated. The medium-sized arteries such as the tibial and brachial arteries are particularly vulnerable to insulin sensitivity, and with reduced metabolic demands they become chronically vasoconstricted. With muscle insulin sensitivity down-regulated and blood flow to skeletal muscles also diminished, glucose uptake by muscle tissue is minimized. This is purely physiologic because muscle tissue matches its insulin sensitivity to glucose based on actual demand. An important gene receptor, peroxisome proliferator activated receptor δ (PPARδ), can regulate use of muscle energy and is being intensely studied because the link between how effectively muscle tissue matches energy requirements to glucose sequestration is only partly understood. Evolutionarily, PPARD gene regulation functioned to keep muscle metabolic demand low so that food, which was often scarce, would be used efficiently. Today, when food is abundant, people with more favorable PPARD gene regulation burn more calories to perform the same amount of work and hence maximize muscle’s insulin sensitivity to excess calories. At some point, depending on an individual person’s inherited biochemistry, muscle tissue becomes minimally responsive to insulin because it simply does not need the extra calories for its daily metabolic processes. Now, other tissues more suited for surplus calorie storage not needed by inactive muscles become the dominant tissue that responds to insulin. This tissue is known as fat and consists of adipocytes, macrophages, and fibroblasts. Subcutaneous Fat Tissue: The “Good” Type Subcutaneous fat tissue is a highly hormonal tissue that can regulate insulin sensitivity, the hypothalamus, the desire to eat or not eat, and the metabolic processing of extra calories. It is actually the key regulator of healthy metabolism in times of caloric excess. Each cell in fat tissue plays a role in regulating hormones and cytokines in response to calorie storage. During times of caloric surplus and low muscle metabolic requirements, extra glucose, in response to insulin, is sequestered by fat cells and converted to triacylglycerol fat and then stored. As adipocytes store fat, they release important signaling molecules known as adipokines; these hormones then help the organism to regulate caloric intake and metabolism appropriately. Two adipokines, leptin and adiponectin, are the major fat hormones that regulate healthy lipid metabolism. Leptin is an adipokine that protects vital organs from the saturation of free fatty acids onto the viscera by limiting them to adipocytes. It is secreted in response to the excessive storage of fat and is likely regulated by PPARγ. Additionally, leptin has antilipotoxic effects through leptin-induced fatty acid oxidation, a process that stimulates oxidative phosphrylation of free fatty acids in all tissues. Leptin serves to limit overeating by acting on the appetite center in the hypothalamus. These protective effects could explain the years of lapse between onset of obesity and development of the metabolic syndrome. In fact, it has been proposed that the development of obesity is a normal and necessary physiologic response to caloric excess that may even be protective and initially beneficial. In fact, the highly vascular and minimally fibrotic fat pads composed of smaller adipocytes at the onset of early obesity can actually reduce necrosis and scar formation of viscera and therefore reduce local and systemic inflammation. However, too many calories over too long a period of time can overwhelm the storage capacity of adipocytes, at which point the gradual accumulation of deranged fatty acids’ metabolic byproducts from food sources is initiated. Leptin resistance is a precursor to this frankly dysfunctional metabolic state. Several experiments have delineated the role of leptin. During the first 24 hours after a heavy meal, leptin levels in plasma begin to increment. Studies by Unger and Scherer in 2010 in rodents have validated leptin’s protective effect on vital organs by limiting free fatty acid storage to subcutaneous adipocytes instead of the viscera. After feeding a diet composed of 60% fat to leptin-responsive rats for 8 weeks, it was found that almost 100% of the increase in body fat was confined to subcutaneous adipocytes. On the other hand, in the leptin-unresponsive rats, nonadipose tissues such as the liver, heart, and pancreas were overloaded with fatty acids, even while they were fed a diet composed of only 6% of fat for the same amount of time. In the same study, it was demonstrated that lipids actually cause apoptosis of important visceral cells. For example, in the leptin-unresponsive rats, there was a concurrent decrease of beta-cell function as the lipid content of the pancreas rose. The decrease in beta-cell mass leads to hyperglycemia and eventually to the development of type 2 diabetes. Not only was the pancreas affected but also myocardial apoptosis was seen after the increase in triglyceride content of the myocardium, which can lead to serious morbidities such as dilated lipotoxic cardiomyopathy and premature death. Hence, it is leptin that helps ensure that lipids are stored in subcutaneous adipocytes and not in ectopic tissues and therefore plays a key role in preventing lipotoxcicity. This is further confirmed by the fact that exogenous administration of leptin can reverse the steatosis in humans and rodents. Adiponectin, similar to leptin, is also a protective adipokine. It is a vasoprotective agent in that it acts as an insulin sensitizer, an antiinflammatory, and an antiapoptotic agent by increasing release of free fatty acids during increased metabolic demand. It also serves to increase vasodilation via endothelial NO production. Not surprisingly, adiponectin levels are high in healthy, subcutaneously obese patients. Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Technical Aspects of Percutaneous Carotid Angioplasty and Stenting for Arteriosclerotic Disease In-Situ Treatment of Aortic Graft Infection with Prosthetic Grafts and Allografts Treatment of Dyslipidemia and Hypertriglyceridemia Intraoperative Assessment of the Technical Adequacy of Carotid Endarterectomy Stay updated, free articles. Join our Telegram channel Join Tags: Current Therapy in Vascular and Endovascular Surgery Aug 25, 2016 | Posted by admin in CARDIOLOGY | Comments Off on The Metabolic Syndrome in the Modern World Full access? Get Clinical Tree
