Introduction
Metabolic syndrome is a biochemical–clinical condition characterized by resistance to insulin action associated with a proinflammatory and prothrombotic state. It represents an important cardiovascular risk factor with a constantly increasing incidence in the general population; therefore, its early detection is fundamental to implement preventive interventions. This chapter describes the main characteristics of metabolic syndrome and the criteria used to diagnose it.
Definition
Metabolic syndrome is a condition in which the interaction among biochemical, clinical, and metabolic factors results in an increased risk of developing cardiovascular diseases, type 2 diabetes mellitus, and mortality. It is present in about 20–25% of the general population and is characterized by visceral obesity, hypertension, and lipid and glucose metabolism alterations.
Beginning with its initial description as the “android obesity syndrome” by Vague in 1956, the syndrome has taken on several names over time, including “dyslipid emic hypertension syndrome,” “syndrome X,” “insulin resistance syndrome,” “dysmetabolic syndrome,” and “plurimetabolic syndrome.”
Pathogenesis
The metabolic syndrome has a multifactorial etiology that includes genetic and environmental factors. The underlying pathophysiological mechanism is insulin resistance (IR), defined as an inadequate response of target organs (striated muscle, liver, and adipose tissue) to the physiological effects of insulin.
The consequences of reduced insulin sensitivity are:
1. Reduced insulin-mediated uptake of glucose in striated muscle and adipose tissue.
2. Reduced insulin-mediated inhibition of glucose production by the liver.
3. Significant reduction in lipolysis inhibition in adipose tissue.
Obesity, physical inactivity, and genetic factors predispose to the development of IR. In particular, the most important cause of IR is the increase of adipose tissue, especially at the abdominal-perivisceral level. Obesity alters mechanisms that regulate the activity of the insulin receptor. Specifically, mediators, such as the excess of circulating free fatty acids (FFAs) and tumor necrosis factor-alpha “shut down” the receptor’s activity.
Abdominal-visceral obesity results in an overflow of FFA into the circulation and a consequent increase in FFA uptake by muscle tissue, liver, and adipose tissue. FFAs are normally metabolized through two pathways:
• Oxidation
• Deposition (triglycerides)
However, when the overflow of FFAs exceeds the metabolic capacity of these two pathways, FFAs and their metabolites accumulate in the tissues, where they cause the activation of specific serine kinases, which, in turn, act by blocking the insulin signal.
Diagnosis
Currently, there are no single criteria for diagnosing metabolic syndrome, but scientific societies and organizations have proposed several. In general, the diagnosis of metabolic syndrome is based on the evaluation of biochemical parameters, such as glycemia and lipid alterations, and clinical parameters, such as arterial hypertension and obesity. The different diagnostic criteria proposed so far for metabolic syndrome are shown in Table 1.
Table1. Diagnostic criteria of the metabolic syndrome.
Although IR represents the pathogenic mechanism under lying the metabolic syndrome, the assessment of this condition is not recommended for diagnosis. However, once the diagnosis of metabolic syndrome is made, several tests are available to assess the insulin resistance severity.
The fasting insulin measurement is not reliable because insulin may have normal values leading to false negative results. IR can be assessed by direct or indirect methods. The direct methods are the insulin measurement during the oral glucose tolerance test (OGTT) curve, the insulin suppression test, and the hyperinsulinemic-euglycemic clamp, which is the gold standard. Among the indirect methods, two indices are commonly used: the Homeostatic Model Assessment (HOMA) index and the Quantitative Insulin sensitivity Check Index (QUICKI). OGTT is performed after fasting for 8–10 h (overnight fasting) by giving the patient 75 g of glucose dissolved in 300 mL of water. Insulin measurement is performed before the administration of the glucose solution (basal) and then at precise time intervals (30′, 60′, 120′, 150′, and 180′). In healthy subjects, insulinemia reaches a concentration peak 6–10 times higher than the basal value after 30–60 min, then its levels begin to decrease, reaching a value approximately 2–3 times the basal value around 180 min and normal around 240 min (Fig. 1). In a subject with insulin resistance, the peak at 30–60 min will reach higher concentrations than in a subject and persist for a longer period because insulin is metabolized more slowly (Fig. 1).
Fig1. Insulin curve after oral glucose tolerance test. (Copyright EDISES 2021. Reproduced with permission).
The insulin suppression test is based on administering an octreotide and somatostatin solution to suppress insulin secretion; subsequently, blood glucose trends are assessed in response to a continuous infusion of glucose and insulin.
The hyperinsulinemic-euglycemic clamp is based on the infusion of an insulin quota to bring the hormone’s blood values, for a time of 120 min, to a constant value of 100 μU/ mL. At the same time, glycemia is constantly maintained at a basal level of about 90 mg/dL through a variable infusion of glucose, punctually adjusted by a feedback mechanism based on glycemic determinations repeated during the test. In conditions of constant insulinemia, in the last 40 min of the test, the amount of glucose infused in the unit of time to maintain euglycemia corresponds to the amount of glucose used by peripheral tissues, with transport dependent on the action of insulin. It is, therefore, an index (“M value” in mol/min/kg) of the tis sues sensitivity to the insulin action. Although this test represents the gold standard for assessing insulin resistance, it is not commonly used in clinical practice because it is difficult to perform and requires time and expert personnel.
The HOMA index is based on a mathematical model that relates fasting serum glucose and insulin concentrations. The QUICKI (less used because it is more complex than the HOMA) is derived by calculating the inverse of the sum of the logarithms of fasting blood glucose and fasting insulin.
Therapy
In 2001, the Adult Treatment Panel III (ATP III) recommended two primary treatment goals for patients with metabolic syndrome. These goals have been reinforced by a report from the American Heart Association (AHA) and the National Institutes of Health (NIH) and clinical guidelines from The Endocrine Society:
• Treat the underlying causes (overweight, obesity, and physical inactivity) by modifying lifestyle and eating habits
• Treat cardiovascular risk factors if they persist despite lifestyle modifications
All components of the metabolic syndrome benefit from weight loss, maintained over time, achieved through caloric restriction and physical activity. There is no direct evidence that attempting to prevent type 2 diabetes and cardiovascular disease by treating the metabolic syndrome is effective. It is possible to treat IR with drugs that potentiate the action of insulin (e.g., thiazolidinediones and metformin).
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