What is Insulin Resistance
Insulin resistance is a state of reduced responsiveness of target tissues (primarily liver, skeletal muscle, and adipose tissue) to physiological levels of insulin, resulting in impaired glucose uptake and utilization despite normal or elevated insulin concentrations. 1
Core Pathophysiology
Insulin resistance represents a fundamental defect in insulin action at the cellular level, where tissues fail to respond appropriately to insulin signaling despite adequate or even excessive insulin availability. 1 This occurs through disruption of the complex intracellular signaling pathways that normally mediate insulin's metabolic effects. 2
The mechanism involves three potential levels of dysfunction: 3
- Pre-receptor defects: Antibodies against insulin or defective insulin molecules
- Receptor defects: Abnormalities of the insulin receptor itself or anti-receptor antibodies (as seen in Type B insulin resistance syndrome) 1, 4
- Post-receptor defects: Dysregulated intracellular signaling pathways (most common in type 2 diabetes) 1
Tissue-Specific Manifestations
Differential sensitivity of various tissues to insulin creates variable expression patterns of insulin resistance. 1 The liver frequently manifests insulin resistance relative to peripheral tissues, leading to: 1
- De novo lipogenesis and dyslipidemia
- Free fatty acid exportation to muscles, promoting muscle insulin resistance
- Impaired suppression of hepatic glucose output
In skeletal muscle and adipose tissue, insulin resistance impairs glucose uptake and utilization, forcing the pancreatic β-cells to compensate by secreting more insulin. 1
Compensatory Hyperinsulinemia
As long as pancreatic β-cells can adequately compensate for insulin resistance by increasing insulin secretion, blood glucose concentrations remain normal—a state called compensatory hyperinsulinemia. 1 This compensation can take the form of: 1
- Insulin hypersecretion
- Reduced insulin clearance
However, in type 2 diabetes, the capacity of the β-cell erodes over time, leading to β-cell failure and subsequent hyperglycemia. 1 Importantly, insulin levels in insulin-resistant patients may appear normal or even elevated, but these levels are insufficient relative to the degree of hyperglycemia present—indicating defective insulin secretion. 1
Clinical Context and Associated Conditions
Obesity itself causes significant insulin resistance, with most patients having increased body fat distributed predominantly in the abdominal region. 1 The American Diabetes Association notes that insulin resistance is strongly associated with a genetic predisposition, occurring more frequently in certain racial and ethnic groups. 1, 5
Insulin resistance is the central feature of type 2 diabetes, which accounts for 90-95% of all diabetes cases and represents a combination of insulin resistance with inadequate compensatory insulin secretion. 1
Additional conditions associated with insulin resistance include: 1, 6
- Metabolic syndrome
- Polycystic ovary syndrome (PCOS)
- Non-alcoholic fatty liver disease
- Cardiovascular disease
- Acanthosis nigricans (dark, velvety skin changes indicating severe insulin resistance)
Physiological Insulin Resistance
A transient insulin-resistant state occurs normally during pubertal development, peaking at mid-puberty and returning to near-prepubertal levels by the end of puberty. 1 This is mediated by increases in growth hormone, sex hormones, and insulin-like growth factor-1 levels. 1, 5
Clinical Significance
Fasting insulin levels in childhood predict future cardiovascular risk factors and weight gain, demonstrating that insulin resistance has independent cardiovascular effects beyond glucose metabolism. 1 The Bogalusa Heart Study showed a strong relationship between persistently high fasting insulin levels and development of cardiovascular risk factors over an 8-year observation period. 1
The presence of both body fatness and insulin resistance together creates a synergistic effect, producing cardiovascular risk greater than either condition alone. 1