Jonathan K Ehrman (editor), Paul Gordon (editor), Paul Visich (editor), Steven J. Keteyian (editor) - Clinical Exercise Physiology_ Exercise Management for Chronic Diseases and Special Populations-Hum (dragged) 2.pdf

192 Churilla PATHOPHYSIOLOGY Insulin resistance, measured by the homeostatic model assessment of insulin resistance (HOMA-IR), is positively associated with BMI and WC (28). In the United States, annual health care costs are elevated by $3,429 and $9,601 for each U.S. adult with obesity and diabetes...

192 Churilla PATHOPHYSIOLOGY Insulin resistance, measured by the homeostatic model assessment of insulin resistance (HOMA-IR), is positively associated with BMI and WC (28). In the United States, annual health care costs are elevated by $3,429 and $9,601 for each U.S. adult with obesity and diabetes, respectively (12, 24). The total annual health care costs in the United States for obesity and diabetes are $342.2 billion (year 2013) and $327 billion (year 2017), respectively. The relationship between BMI and health care costs is nonlinear (follows a J shape), which means that in the range of obesity classes II and III, the increment in health care costs is exponential. This is because morbid obesity increases the risk for diabetes mellitus, CVD, and other comorbidities, thus imposing a large economic burden as BMI increases beyond 30 kg ∙ m-2. Data indicate there is a six-fold increase in diabetes risk in patients with class III obesity (BMI >40 kg ∙ m-2) in comparison with normal-weight individuals. The presence of diabetes plus obesity significantly increases health care utilization. The health care cost of a 50 yr old patient with diabetes, for example, is approximately three times higher than for someone of the same age without diabetes (119). Metabolic syndrome is characterized by a co-occurrence of atherogenic dyslipidemia, HTN, elevated glucose, chronic low-grade inflammation, and prothrombosis (81). In conjunction with several behavioral factors (i.e., sedentary behavior and atherogenic diet), genetic predisposition, and advancing age, the clustering of multiple risk components within metabolic syndrome is widely thought to occur as a result of obesity (more specifically, android obesity) and insulin resistance (81, 152, 181) (figure 12.1). However, although obesity and insulin resistance are considered two hallmarks of chronic health risk, not all obese or insulin-resistant individuals develop metabolic syndrome (141). The specific trajectory of cardiometabolic decline leading to or coinciding with excessive accumulation of adiposity, altered fat partitioning, and diminished insulin sensitivity is a multifactorial, complex issue to disentangle. Age Physical inactivity Obesity Insulin resistance Oxidative stress Chronic inflammation Abdominal obesity High fasting blood sugar Low HDL cholesterol High blood pressure High triglycerides Metabolic syndrome Type 2 diabetes ASCVD Figure 12.1 Schematic of the components of metabolic syndrome. 12 Ehrman E8177 C12 187-204.indd 192 E8177/Ehrman/F12.02/680795/mh-R1 3/7/22 10:15 AM Chapter 12 Metabolic Syndrome Insulin Resistance and Metabolic Syndrome Gradual decreases in cardiometabolic health start to occur long before an individual reaches obesity or is diagnosed as insulin resistant. For that reason, metabolic syndrome is often referred to as a premorbid condition (177). In a healthy, insulin-sensitive person, glucose stimulates the release of insulin from pancreatic beta cells, which in turn reduces plasma glucose concentration through suppression of hepatic glycogenolysis and gluconeogenesis and simultaneous glucose uptake, utilization, and storage by the liver, muscle, and adipose tissue. Conversely, under conditions of insulin resistance, there is a chronic failure of insulin to maintain glucose homeostasis. The role of insulin resistance and hyperinsulinemia in the development of metabolic syndrome has been controversial because a direct causal link has not yet been identified (103); however, some data suggest that hyperinsulinemia may be more sensitive than BMI or WC in identifying those with metabolic syndrome (39). Part of this confusion has been driven by the consistently oversimplified definition of insulin resistance, which, although useful in the clinical context, does not account for the fact that insulin regulates various other processes in addition to glucose metabolism (87) and cannot discern the origin of the resistance (i.e., defects in insulin signaling vs. those in the insulin receptor ). It is postulated that the insulin resistance associated with metabolic syndrome is indeed pathway specific (87) and that multiple forms of molecular insulin resistance could contribute to abnormal glucose homeostasis (22). In the clinical setting, insulin resistance is characterized as the extent to which the liver manifests insulin resistance in proportion to the periphery (i.e., skeletal muscle insulin resistance) (181). Over time, resistance to insulin and compensatory hyperinsulinemia in metabolic syndrome result in increased lipogenesis, hypertriglyceridemia, HTN, and steatosis (22, 87, 181). Although a thorough discussion of insulin action and insulin signaling is beyond the scope of this chapter, research continues to emerge that confirms a pathophysiologic link not only between insulin resistance, metabolic syndrome, and glucose intolerance but also with ASCVD (87). Evidence also links systemic inflammation (142), oxidative stress (195), and endothelial dysfunction in both animal (187) and human models (151) to metabolic syndrome. Thus, if metabolic syndrome is indeed a premorbid condition, as it has been suggested (103), identifying and treating at-risk individuals before the emergence of categorical insulin resistance or hyperglycemia is a vitally important directive. Obesity and Adiposity Distribution Abnormalities Obesity is an independent risk factor for insulin resistance, hyperglycemia, dyslipidemia, and HTN. Left untreated, this combination of pathophysiologic factors precipitates increased 12 Ehrman E8177 C12 187-204.indd 193 193 risk for chronic diseases and premature all-cause mortality (48, 112). Despite the robust association between obesity and poor cardiometabolic health, it is a heterogeneous condition that must be considered in a broader biological and public health context. For example, BMI is suggested to account for only 60% of the variance in insulin resistance among adults (3). Rather, in conjunction with several abnormalities in adipose tissue metabolism, abnormal regional fat distribution and partitioning may actually be the pathophysiologic link between obesity and the numerous hormonal and metabolic derangements that compose metabolic syndrome (66). Accumulation of fatty acids in nonadipose tissue depots is a dynamic, lipotoxic (170) process that occurs as a result of chronic disequilibrium between energy intake and energy expenditure— and it is robustly associated with skeletal muscle insulin resistance (95, 109, 115). Specifically, visceral adipose tissue (VAT) is broadly recognized to have metabolic, endocrine, and immune system interactions; and increases in VAT precipitate heightened risk for metabolic and cardiovascular disorders. However, during conditions in which fat infiltrates the muscle (i.e., intra- and intermuscular adipose tissue [IMAT]), it appears to independently contribute to impaired glucose metabolism and decreased insulin sensitivity (115). Fat infiltration has been identified in aging adults (i.e., muscle attenuation on computed tomography or localized IMAT with magnetic resonance imaging ), as well as in certain diseases and morbid conditions such as Duchenne muscular dystrophy (118), T2D (71), spinal cord injury (79, 173), cerebral palsy (146) obesity (80, 106, 178), excessive sedentary behavior (123), and vitamin D insufficiency (73). IMAT is a dynamic tissue with both paracrine and endocrine properties (74) and is suggested to arise from satellite stem cells or distinct fibrocyte–adipocyte progenitor cells, which form adipocytes within skeletal muscle during conditions of metabolic dysregulation and hyperglycemia (4). Moreover, evidence reveals a robust link between IMAT and elevated levels of proinflammatory, adipocyte-derived hormones and cytokines (18, 207), which also lead to insulin resistance (108) and muscle dysfunction (194). An important distinction is when lipids (sequestered in lipid droplets) are stored within muscle fibers as intramyocellular triglycerides (IMTGs). These IMTGs are a vital energy source during skeletal muscle contraction and are often seen in greater levels in endurance athletes. Evidence indicates that unlike IMAT, IMTGs do not cause insulin resistance (191). Mitochondrial Dysfunction Concurrent with an increased storage of ectopic adiposity, reductions in mitochondrial size, density, and function (144, 150, 171) have been implicated in the etiology of insulin resistance, metabolic syndrome, and diabetes. More specifically, obese, sedentary, and insulin-resistant individuals have smaller and fewer mitochondria, with impaired function. Diminished mitochondrial density 3/7/22 10:15 AM 194 Churilla and function may lead to or coincide with decreased or incomplete lipid oxidation and subsequent accumulation of lipid metabolites (diacylglycerol, ceramides, and acyl coenzyme A [CoA]), impaired insulin signaling, metabolic inf lexibility, and oxidative stress (35, 129, 140). Moreover, each of these outcomes is also thought to cause further impairment of mitochondrial function and thus provokes a chronic circular cause and consequence of cardiometabolic events. Impaired mitochondrial function may also lead to diminished adenosine triphosphate (ATP) production, energy deficit, and decreased functional capacity. Sedentariness may lead to hypokinetic disease, which is a robust predictor of mitochondrial dysfunction (51); and more important, evidence has long suggested (92) improvements in ATP synthesis and fatty acid oxidation after exercise interventions (96), independent of weight loss. Proinflammatory and Prothrombotic Characteristics Adipose tissue is considered a dynamic organ with pleiotropic properties (197). Previous research among obese adults with diabetes has revealed significantly elevated levels of adipocyte-derived hormones and cytokines, which are significant contributors to insulin resistance (108). Specifically, ectopic adiposity is known to play a role in secreting proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]), adipocytokines (e.g., leptin, resistin, and adiponectin), and chemokines (e.g., monocyte chemoattractant protein [MCP-1]). Produced by adipose tissue macrophages, the inflammatory cytokines IL-6 and TNF-α are positively associated with triglycerides and total cholesterol, are inversely associated with HDL-C, are capable of interfering with insulin signaling (174), and can result in cellular oxidative stress (i.e., accumulation of reactive oxygen species [ROS]) (206). Moreover, IL-6 stimulates hepatic production of C-reactive protein (CRP) (17), an acute-phase protein and robust predictor of various features in metabolic syndrome (68). Clinically, high-sensitivity CRP (hs-CRP) has become accepted as a useful biomarker for chronic, low-grade inflammation. Augmented levels of hs-CRP (>3.0-