A rise in caloric consumption combined with a decrease in physical activity has contributed to a boom of metabolic diseases, such as type 2 diabetes mellitus and cardiovascular diseases (e.g., heart failure and stroke). Over the last couple of decades, studies exploring these diseases have uncovered some of the complex pathophysiological mechanisms involved, resulting in the identification of a plethora of interconnected physiological, pathophysiological, biochemical, and clinical factors that play a role in their development. These factors include obesity/abdominal adiposity, insulin resistance, dyslipidemia, a low-grade state of chronic inflammation, hypoxia, oxidative stress, fasting hyperglycemia, high blood pressure (hypertension), endothelial dysfunction, a hypercoagulable state, genetics, and more. This constellation of interconnected risk factors that play a role in the development of metabolic and cardiovascular diseases has been dubbed metabolic syndrome (figure below).

The concept of this complex syndrome was first introduced by Gerald M. Raven during the prestigious Banting Medal Address during the 1988 American Diabetes Association meeting. He proposed that cardiovascular risk was high among insulin-resistant, hyperinsulinemic individuals who were glucose intolerant and who exhibited a collection of other risk factors, such as increased levels of plasma triglyceride, low HDL-cholesterol, and essential hypertension. He called the collection of these factors Syndrome X, as the significance of these abnormalities and their precise role in cardiovascular diseases was not fully understood at the time. While the condition has been given several definitions over the years based on improved understanding, a harmonized definition for metabolic syndrome was the result of a 2009 joint meeting of the American Heart Association, the National Heart Lung and Blood Institute, the International Diabetes Foundation, the World Heart Federation and the International Association for the Study of Obesity. Accordingly, metabolic syndrome is diagnosed based on the presence of any three of five criteria:

• Increased waist circumference (as a measure of abdominal obesity that is specific to populations and ethnic groups); • Triglycerides levels at 150mg/dl or higher; • HDL-c levels at 40 mg/dL or lower in men and 50 mg/dL or lower in women; • Blood pressure at 130/85 or higher; and • Fasting plasma glucose (glycemia) at 100mg/dL or higher.

Diagnosed with these criteria, metabolic syndrome confers a five-fold increased risk for type 2 diabetes and a three-fold increased risk for cardiovascular disease, including an up to four-fold increased risk for stroke or heart failure. Metabolic syndrome also is associated with several other diseases, including many cancers, polycystic ovarian syndrome, and neurological disorders.

Metabolic Percentages.pngWith approximately 35% of all adults and 50% of individuals aged 60 years or older estimated to have metabolic syndrome, it is a major public health issue and is changing what was thought of as a “normal” individual. The presence of metabolic syndrome in an increasing percentage of individuals suggests an altered metabolic, physiological, and pathophysiological state that may change or exacerbate the toxic responses to drugs and/or environmental toxicants. And this syndrome is not limited to the adult population. It increasingly is diagnosed in the pediatric population with a prevalence rate of about 11.9% in overweight children and 29% in obese children.

While several intricate pathways and mechanisms are at play in metabolic syndrome, obesity (abdominal obesity in particular) and insulin resistance are considered to be at the core of this syndrome. For example, a positive energy balance leads to adipose tissue expansion and obesity resulting in consequences, which include the following:

• Infiltration of macrophages and other immune cells into the adipose tissue, giving rise to an inflamed adipose tissue with an increased secretion of proinflammatory cytokines and adipokines and a concomitant decrease in the anti-inflammatory adipokine, adiponectin. • Ectopic deposition of fat in key organs such as the liver, heart, skeletal muscle, and pancreas due to spill over from expanded adipose tissue, resulting in tissue lipotoxicity and consequent inhibition of insulin signaling. • Binding of circulating free fatty acids to toll receptors on various organs, augmenting inflammatory signaling via the downstream activation of NFκB and JNK pathways resulting in a vicious cycle of inflammation, which further inhibits insulin signaling in these tissues. • Free fatty acid accumulation in tissues and in its breakdown to intracellular diacylglycerol and ceramide, which interferes with insulin signaling and insulin-stimulated glucose uptake. This accumulation of free fatty acids and its incomplete oxidation mediates mitochondrial dysfunction, which triggers formation of reactive oxygen species that induce oxidative stress, which further impairs mitochondrial function. Increased reactive oxygen species levels also hinder insulin signaling and impair GLUT4 translocation.

A failure of cells to respond to insulin results in the pathological condition of insulin resistance. Insulin, by activating complex signaling pathways involving pI3K/AKT, MAPK, and clb and by binding to transcriptions factors such as FOXO and PPARg, regulates glucose uptake and glucose and lipid metabolism in peripheral tissues. Insulin resistance disrupts these pathways, resulting in hyperglycemia and dyslipidemia. Dyslipidemia also results from the accumulation of free fatty acids in the liver along with insulin-augmented lipogenesis, increasing triglyceride production and release, together with an increased hepatic uptake and renal clearance of HDL-c resulting in a dysregulated lipid profile of low levels of HDL-c and high triglyceride seen in metabolic syndrome. Glucotoxicity and lipotoxicity mediate pancreatic β-cell dysfunction in insulin resistance and hyperinsulinemia. This combination of insulin resistance and hyperinsulinemia, additionally, plays a role in the development of hypertension by tipping the balance between endothelial cell secretion of the vasodilator, NO, and the vasoconstrictor, ET-1.

Although obesity and IR are at the core of the pathophysiological mechanisms of metabolic syndrome, several other factors also are implicated, including dysregulation of the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system, the autonomic nervous system, impact of gut microbiome on metabolism, the cellular and metabolic alterations in response to drugs, alcohol, and environmental toxicants. Both genetic and epigenetic mechanisms are thought to play a role besides environmental and lifestyle causes of MS.

An examination of the metabolic disturbances associated with metabolic syndrome reveals that many of the pathways and mechanisms involved overlap with those affected by drugs and environmental toxicants and can result in similar types of cellular and organ toxicities. It also is conceivable that drug responses and toxicities may be altered in subjects with metabolic syndrome in whom several metabolic and signaling pathways have gone awry.

To help further understanding and expand your knowledge of the complex and multidimensional condition of metabolic syndrome, SOT is hosting a Contemporary Concepts in Toxicology (CCT) meeting titled “Metabolic Syndrome and Associated Diseases: From the Bench to the Clinic” on March 11, in Baltimore, Maryland. Scheduled for the day before the start of the SOT Annual Meeting and ToxExpo, the CCT meeting aims to explore several aspects of metabolic syndrome, including the risk factors, causes, and the manifestations of diseases associated with it; the various cellular and pathophysiological mechanisms that may play a role; and the current and potential therapeutic strategies and risk assessment, which together will enable the development of safer drugs and potential new therapeutics.

The CCT organizers hope that a “focus on understanding the pathways and risk factors leading to disease and on how these pathways can be perturbed to develop drugs for disease interventions will create a unique combination that is likely to lead to new thought processes and scientific collaborations in addition to defining knowledge gaps, identifying research needs, protecting public health, and empowering product development.”

Author: Vijayalakshmi Varma, PhD, Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Studies, US Food and Drug Administration, Jefferson, AR

Disclaimer: The views presented in this article do not necessarily reflect those of the US Food and Drug Administration