What are metabolic syndrome and insulin resistance?

Metabolic Syndrome and Insulin Resistance

Metabolic syndrome is a cluster of cardiometabolic conditions—including abdominal obesity, elevated blood pressure, dyslipidemia, and elevated glucose—that occur together more frequently than by chance and confer a 2-fold increased risk of cardiovascular disease and 5-fold increased risk of type 2 diabetes. 1

Definition of Metabolic Syndrome

Metabolic syndrome is diagnosed when at least 3 of the following 5 criteria are present: 1, 2

• Abdominal obesity: Waist circumference ≥102 cm in men or ≥88 cm in women 2
• Elevated triglycerides: ≥150 mg/dL (1.7 mmol/L) 2
• Low HDL cholesterol: <40 mg/dL (1.03 mmol/L) in men or <50 mg/dL (1.29 mmol/L) in women 2
• Elevated blood pressure: Systolic ≥130 mmHg and/or diastolic ≥85 mmHg 2
• Elevated fasting glucose: ≥100 mg/dL (5.6 mmol/L) 2

The syndrome represents a true clustering of factors that occur together more often than by chance alone, fulfilling the definition of a clinical syndrome even though the underlying cause remains incompletely understood. 1

Definition of Insulin Resistance

Insulin resistance is a pathophysiological state where tissues (particularly adipose tissue, skeletal muscle, and liver) exhibit decreased responsiveness to insulin, requiring higher insulin levels to achieve normal glucose disposal and suppression of hepatic glucose output. 3, 4

• Insulin resistance can exist even in states of normal blood glucose and precedes the development of glucose abnormalities. 5
• It represents decreased insulin-dependent glucose disposal in peripheral tissues and impaired suppression of hepatic glucose production. 3
• The condition is mediated through dysfunction of peroxisome proliferator-activated receptor-gamma (PPARγ) pathways and other insulin-responsive genes involved in glucose and lipid metabolism. 3

Relationship Between Metabolic Syndrome and Insulin Resistance

Most persons with metabolic syndrome have both abdominal obesity and insulin resistance, though insulin resistance is necessary but not sufficient for expression of metabolic syndrome. 1

• Approximately 52-56% of individuals meeting metabolic syndrome criteria by ATP III or IDF definitions have demonstrable insulin resistance. 6
• The WHO definition originally required evidence of insulin resistance for diagnosis, but current ATP III and IDF criteria do not mandate its demonstration. 1
• Confirmatory factor analysis suggests insulin resistance is one pathophysiological mechanism underlying metabolic syndrome, but other factors (inflammatory markers, adipocytokines, cortisol) also contribute. 1

The relationship is bidirectional: insulin resistance contributes to development of metabolic risk factors, while abdominal obesity (highly correlated with insulin resistance) drives the syndrome's manifestations. 1

Clinical Manifestations Beyond the Diagnostic Criteria

Patients with metabolic syndrome commonly manifest additional features: 1

• Atherogenic dyslipidemia: Elevated apolipoprotein B, increased small dense LDL particles, beyond just elevated triglycerides and low HDL. 1
• Prothrombotic state: Increased clotting tendency. 1
• Proinflammatory state: Elevated inflammatory markers. 1

Cardiovascular and Metabolic Risks

The presence of metabolic syndrome doubles the risk of developing cardiovascular disease over 5-10 years compared to individuals without the syndrome, with lifetime risk being substantially higher. 1, 2

• The syndrome confers a 5-fold increase in risk for type 2 diabetes. 1, 2
• Risk increases with the number of metabolic syndrome components present. 2
• Metabolic syndrome is present in 40-50% of patients with ischemic stroke. 2

Microvascular complications are also increased: 2

• Albuminuria occurs in 40.8% versus 21.8% in those without metabolic syndrome. 2
• Diabetic retinopathy occurs in 37.9% versus 28.6%. 2
• A stepwise increase in microvascular complications corresponds to the number of components present. 2

Progression to Diabetes

Insulin resistance combined with insufficient pancreatic beta-cell compensation leads to progression from normal glucose tolerance to impaired glucose tolerance and eventually type 2 diabetes. 5

• Impaired glucose tolerance (IGT) is defined as blood glucose 140-199 mg/dL (7.8-11.0 mmol/L) 2 hours after a 75g oral glucose tolerance test. 5
• IGT represents a pre-diabetic state where the body cannot process glucose properly but levels are not high enough for diabetes diagnosis. 5
• Progression occurs when pancreatic beta-cell function deteriorates significantly and can no longer compensate for insulin resistance. 5

Important Clinical Caveats

Metabolic syndrome is not an absolute risk indicator because it does not contain all factors determining absolute cardiovascular risk (age, sex, cigarette smoking, LDL cholesterol levels). 1

The simultaneous presence of metabolic syndrome and insulin resistance identifies an especially high-risk individual with approximately 6-fold increased risk for diabetes and 2.3-fold increased risk for cardiovascular disease. 6

Even metabolic syndrome without demonstrable insulin resistance increases diabetes risk approximately 3-fold, though the cardiovascular risk increase may be less pronounced depending on which diagnostic criteria are used. 6