Porth's Essentials of Pathophysiology, 4e

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Diabetes Mellitus and the Metabolic Syndrome

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beta cells. 20,21 This has several consequences. First, excessive and chronic elevation of FFAs can directly cause pancreatic beta cell dysfunction (lipotoxicity). Second, at the level of the peripheral tissues, FFAs inhibit glucose uptake and glycogen storage. Third, the accumulation of FFAs and triglycerides reduces hepatic insulin sensitivity, leading to increased hepatic glucose production and hyperglycemia, especially in the fasting state. In the liver, the uptake of FFAs from the por- tal blood can lead to hepatic triglyceride accumulation and nonalcoholic fatty liver disease (see Chapter 30). In addition to the metabolic effects of visceral obe- sity, adipocytes are the source of a number of impor- tant factors (e.g., adiponectin, leptin, FFAs) involved in a wide range of other processes, including glucose and lipid metabolism, inflammation, and thrombosis. 15,20–23 In obesity and type 2 diabetes, there is a reduction in the production of some factors that are normally synthesized by adipocytes (i.e., adiponectin), whereas there is an accelerated release of other factors such as angiotensinogen, plasminogen activator inhibitor-1, leptin, and proinflammatory cytokines (e.g., tumor necrosis factor- α ). Adiponectin, which is secreted by adipocytes and circulates in the blood, is the only known adipocyte-secreted factor that increases tissue sensitivity to insulin. 23 It has been shown that decreased levels of adiponectin coincide with insulin resistance in persons with obesity and type 2 diabetes. In skeletal muscle, adiponectin has been shown to decrease tissue triglyceride content by increasing the use of fatty acids as a fuel source. Adiponectin also appears to have antidiabetes, anti-inflammatory, and antiatherogenic effects. Insulin Resistance and the Metabolic Syndrome. There is increasing evidence to suggest that when people with type 2 diabetes present predominantly with insulin resistance, the diabetes may represent only one aspect of a syndrome of metabolic disorders. 24 Hyperglycemia in these people is frequently associated with intra-abdom- inal obesity, high levels of plasma triglycerides and low levels of high-density lipoproteins (HDLs), hyperten- sion, systemic inflammation (as detected by C-reactive protein [CRP] and other mediators), abnormal fibrino- lysis, abnormal function of the vascular endothelium, and macrovascular disease (coronary artery, cerebrovas- cular, and peripheral arterial disease). This constellation of abnormalities often is referred to as the insulin resis- tance syndrome, syndrome X, or, the preferred term, metabolic syndrome. 21 In clinical practice, the definition of metabolic syndrome given in the Third Report of the National Cholesterol Education Program (NCEP III) is widely used 20 (Chart 33-1). Other SpecificTypes of Diabetes The category of other specific types of diabetes, for- merly known as secondary diabetes, includes diabetes that is associated with certain other conditions and syn- dromes. Such diabetes can occur with pancreatic disease

progressively decreased (by an average of approxi- mately 4% per year), resulting in worsening hyperglyce- mia even when the degree of insulin resistance remained Stable. 17 Pathogenesis. The pathogenesis of type 2 diabetes involves genetic, epigenetic, behavioral, and environ- mentally mediated factors. A positive family history confers a twofold to fourfold increased risk for type 2 diabetes, and 15% to 25% of first-degree relatives of persons with type 2 diabetes develop impaired glucose tolerance or diabetes. 14 Despite the strong familial pre- disposition, the genetics of type 2 diabetes is poorly defined. This is probably because of the heterogeneous nature of the disorder as well as the difficulty in sort- ing out the contribution of acquired factors affecting insulin action and glycemic control. 15 However, so far more than 60 genetic loci associated with type 2 diabetes have been identified. Unfortunately, when all these loci are added together they still only account for approximately 10% of the apparent genetic causes (i.e., heritability) of type 2 diabetes. Regardless, most cases of type 2 diabetes develop in obese individuals who have a genetic predisposition to beta–cell dysfunc- tion and failure. Among the acquired factors that predispose to type 2 diabetes, obesity and physical inactivity are para- mount. 14,15,18 As the body mass index (BMI) increases, the risk of developing diabetes increases, and approxi- mately 90% of persons with type 2 diabetes are over- weight. Obesity has profound effects on sensitivity of tissues to insulin, and as a consequence, on glucose homeostasis. Not only the absolute amount of body fat, but also its distribution has an effect on insu- lin resistance. People with upper body (or central) obesity who have increased stores of visceral (intra- abdominal) fat are at greater risk for developing type 2 diabetes and metabolic disturbances than persons with lower body (or peripheral) obesity (see Chapter 10). Waist circumference and waist–hip ratio, which are both surrogate measures of central obesity, have been shown to correlate well with insulin resistance. Thus, measures such as diet and exercise that reduce visceral adiposity are important in the management of type 2 diabetes. Other acquired factors include the patient’s microbiome (i.e., the bacteria that live in or on us) related metabolic factors and inflammatory effects. Role of AdiposeTissue inType 2 Diabetes. Although many details of the relationship between adipose tis- sue, insulin resistance, and increased glucose produc- tion in obese people with type 2 diabetes remain to be elucidated, several pathways have been proposed. Primary among these is the role of an increased con- centration of free fatty acids (FFAs). 15,19 Visceral obe- sity is accompanied by an increase in postprandial FFA concentrations and subsequent triglyceride stor- age, including in sites that do not normally store fat such as the liver, skeletal muscle, heart, and pancreatic