Metabolic Syndrome: Definition, Relationship with Insulin Resistance, and Clinical Utility1

Metabolic Syndrome: Definition, Relationship with Insulin Resistance, and Clinical Utility1

Dominic N. Reeds

The term metabolic syndrome (MS) is used to describe a cluster of metabolic disorders: insulin resistance (IR) or hyperglycemia, abdominal obesity, dyslipidemia (high very-low-density lipoprotein-triglyceride [VLDL-TG] concentration and low plasma high-density lipoprotein cholesterol [HDL-C]), and essential hypertension (HTN). These factors are important because each component increases the risk of development of type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). Recognition of the association between the components of MS with both DM and CVD has been known since the 1930s. Progress in understanding the pathogenesis of the syndrome has been hindered by the challenge of understanding the complex relationships among features of MS, IR or insulin sensitivity, pancreatic β-cell function, and host factors.


Until the 1960s, the prevailing belief was that an absolute insulin deficiency was the primary metabolic defect in type 2 DM. This belief persisted despite studies performed as early as the 1930s that indicated that resistance to insulin-mediated stimulation of glucose clearance was present in subjects with type 2 DM (1, 2, 3, 4, 5). The availability of the insulin immunoassay, developed by Yalow and Berson in 1960, established that most patients with DM had higher plasma insulin levels than healthy subjects (6). This new ability to measure both plasma glucose and insulin concentration allowed the development of oral glucose tolerance testing (7) and the glucose clamp techniques (8). Various glucose clamp techniques exist; however, the most commonly performed is probably the euglycemic hyperinsulinemic clamp. In this protocol, a constant infusion of insulin is administered to the subject to cause hyperinsulinemia, and the rate of glucose infusion (glucose disposal) necessary to maintain euglycemia is determined. Concomitant infusion of stable isotope-labeled tracers of amino acids, glucose, and fatty acids (FAs) during clamps may be performed to allow for calculation of glucose production, amino acid deposition, VLDL-TG synthesis, and lipolysis, among other metabolic measures (9, 10, 11, 12, 13). These methods have proved critical in dissecting the complex relationships between organ-specific IR and insulin secretion.

Subsequent studies showed that most subjects with type 2 DM had resistance to insulin action in adipose tissue (inhibition of lipolysis), liver (inhibition of glucose production), and skeletal muscle (stimulation of glucose disposal) (14, 15, 16). Curiously, insulin-mediated stimulation of amino acid deposition may be normal in subjects with DM, but it is impaired in subjects with other forms of IR, such as that of the human immunodeficiency virus (HIV)- associated MS (17). It is widely believed in the United States that IR almost always precedes the development of DM. This paradigm is supported by studies that have shown that IR is seen at an early age in first-degree relatives of people with type 2 DM (18), and IR indicates an increased risk of development of DM (19, 20, 21, 22, 23).

The relationship between IR and insulin secretion is complex. In general, IR causes increased insulin secretion and reduced hepatic insulin clearance, resulting in systemic hyperinsulinemia. Although a focus is often placed on insulin as a regulator of blood glucose, insulin plays a key role in the regulation of lipid and protein metabolism, in addition to cellular growth and development. Seminal studies by Hollenbeck and Reaven and Yeni-Komshian
et al (24, 25) systematically examined IR in nondiabetic individuals. Insulin-mediated glucose uptake was found to vary by up to eightfold in healthy subjects.

These and subsequent studies showed that more insulin-resistant subjects had greater plasma insulin concentration, VLDL-TG, and plasma glucose during the oral glucose tolerance test than did insulin-sensitive subjects, findings supporting the relationship between IR and MS (26). During his Banting lecture, Reaven proposed that DM was not the only adverse outcome associated with hyperinsulinemia, but that elevated insulin concentrations could activate metabolic pathways and result in dyslipidemia and HTN (27). He termed this collection of metabolic disturbances syndrome X. Subsequently, several articles described the associations among IR, dyslipidemia, HTN, elevated waist circumference (WC), and the risk of CVD and DM (28, 29, 30, 31, 32).

The first formal definition of MS was by the World Health Organization (WHO) in 1998 (Table 62.1) (33). This initial definition focused on IR as the main contributor to the syndrome and required the presence of IR in addition to two of the following: obesity, HTN, high TG, low HDL-C, or microalbuminuria. In 2001, the report of the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program also noted the relationship between IR and known CVD risk factors (Table 62.2) (34). The committee suggested that these lipid and nonlipid abnormalities were all metabolically related and used the term metabolic syndrome. In contrast to the WHO, this definition did not require the presence of IR, but rather a focus was placed on abdominal obesity, thus suggesting an additional risk posed by abdominal fat.

Since these initial definitions, MS has entered the clinical vernacular and is used to define a clinical state associated with an increased risk for the development of CVD and DM. Reaven himself did not propose syndrome X for use as a diagnostic entity but rather to provide a framework for understanding the complex relationships among abdominal obesity, IR, and the adverse consequences of hyperinsulinemia. The rest of this chapter describes the components of MS, a critical appraisal of the role of IR as the pathogenic factor for MS, and the utility of MS in clinical practice.


Insulin resistance identified by one of the following:

Type 2 diabetes

FBG >110 mg/dL

IGT >140 mg/dL

FBG >110 mg/dL but in lowest quartile of glucose disposal during hyperinsulinemic, euglycemic conditions

And any two of the following:

TG ≥150 mg/dL

HDL-C <35 mg/dL (men), <39 mg/dL (women)

BMI >30 kg/m2 and/or waist-to-hip ratio >0.9 (men), >0.85 (women)

Urinary albumin excretion rate >20 μg/min or albumin-to-creatinine ratio ≥30 mg/g

BMI, body mass index; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; IGT, impaired glucose tolerance; TG, triglycerides.

From Grundy SM. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-8, with permission.



HDL-C (mg/dL)

<40 (men), <50 (women)

TG (mg/dL)


Waist circumference (in)

>40 (men), >35 (women)

BP (mm Hg)

Systolic >130 and/or diastolic ≥85

FBG (mg/dL)


ATP III, Adult Treatment Panel III; BP, blood pressure; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride concentration.

From Grundy SM. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-8, with permission.

Waist Circumference

Obesity (body mass index [BMI] >30 kg/m2) is associated with an increased risk of CVD and DM (35, 36) (Table 62.3). Upper body obesity, in particular visceral obesity, may confer a greater cardiometabolic risk than obesity alone. Because precise measurement of abdominal fat requires expensive imaging techniques, WC is often used as a marker of both obesity and increased
abdominal fat (37, 38, 39). Currently, no uniform approach for measurement of WC exists; however, the reproducibility of WC measurement is high when performed by trained technicians (40). The most commonly used sites for measurement of WC are the midpoint between the lowest rib and the iliac crest, the umbilicus, and the site of the narrowest measured WC. WC correlated well with abdominal fat in large studies (41). The cutoff values for WC were obtained following regression analysis of the relationship between BMI and WC in a large Scottish study. A WC value of 40 in. in men and 35 in. in women was chosen because these values corresponded to a BMI of 30 kg/m2.




Elevated waist circum ference

Population and country specific definitions

Plasma TG or drug treatment

≥150 mg/dL

Plasma HDL-C or drug treatment

<40 (men) mg/dL, <50 (women) mg/dL

BP (mm Hg) or drug treatment

Systolic >130 and/or diastolic ≥85

FBG or drug treatment

≥100 mg/dL

BP, blood pressure; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride.

Adapted from Grundy SM. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.

The reasons for the close relationships among WC, visceral adiposity, and cardiometabolic risk are unknown; however, several mechanisms have been proposed. IR has been closely linked to adipose tissue macrophage content in both human and animal studies. Immune cells, in particular macrophages, may be trafficked into fat tissue by increases in interstitial and/or plasma FA concentration (42, 43). These cells may release various factors such as tumor necrosis factor-α and interleukin-6 that act directly on surrounding adipocytes, thus impairing insulin action and promoting release of FAs. Curiously, animal studies suggest that inhibition of this inflammatory response protects against obesity-associated IR (44).

Another hypothesis centers on the belief that visceral adipose tissue (VAT) has a direct effect on insulin sensitivity, lipid metabolism, and blood pressure. The venous drainage of abdominal visceral fat leads directly to the hepatic portal vein, so that FA released by the visceral fat depot would dramatically increase hepatic FA delivery (see Fig. 62.3). FA delivered to the liver can be exported as VLDL-TG, oxidized, or stored. Failure to export or oxidize these FA would therefore promote hepatic steatosis and, as a result, hepatic IR. This process would be exacerbated by mild hyperglycemia because elevated blood glucose concentration reduces hepatic FA oxidation. Elegantly performed studies showed that a greater proportion of FA delivery to the liver originates from VAT and that hepatic free FA (FFA) delivery increases with increasing VAT mass (45).

Because intrahepatic triglyceride (IHTG) and VAT are strongly correlated with one another, it is not clear whether increased WC (and by imputation, increased VAT) or increased IHTG are independent risk factors for dyslipidemia and IR. Fabbrini et al (46) measured insulin sensitivity using euglycemic hyperinsulinemic clamps (Fig. 62.1) and VLDL-TG production (Fig. 62.2) in a cohort of obese subjects. Subjects were then separated into groups by matching on visceral fat mass and in a second analysis on IHTG content. VLDL-TG production rates were increased, and insulin sensitivity in liver, muscle, and adipose tissue was impaired in subjects with high IHTG. In contrast, VLDL-TG production and insulin sensitivity were not impaired when subjects were matched for IHTG and then divided into high and low VAT. This finding suggests that differences in hepatic FA handling (i.e., FFA oxidation versus storage) and resultant hepatic steatosis play major roles in determining whether abdominal obesity causes metabolic abnormalities.

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Jul 27, 2016 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on Metabolic Syndrome: Definition, Relationship with Insulin Resistance, and Clinical Utility1
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