What is insulin resistance and how is it treated?

What is Insulin Resistance?

Insulin resistance is a pathophysiological state where target tissues (primarily skeletal muscle, liver, and adipose tissue) exhibit decreased responsiveness to normal or elevated insulin concentrations, requiring higher insulin levels to achieve normal glucose uptake and metabolism. 1

Core Pathophysiology

Insulin resistance represents a fundamental defect in cellular insulin signaling where:

• The body's cells fail to respond adequately to circulating insulin, necessitating compensatory hyperinsulinemia to maintain euglycemia 2, 3
• This occurs at three potential levels: pre-receptor (abnormal insulin molecules, anti-insulin antibodies), receptor (insulin receptor defects, anti-receptor antibodies), and post-receptor (disrupted intracellular signaling pathways) 4, 5
• Insulin resistance can exist even with normal blood glucose levels, as hyperinsulinemia compensates for the reduced tissue sensitivity 2, 6

The American Diabetes Association emphasizes that insulin resistance precedes glucose abnormalities—patients develop compensatory hyperinsulinemia first, maintaining normoglycemia until beta-cell function deteriorates 2, 3.

Clinical Manifestations and Progression

Insulin resistance progresses through distinct stages:

• Stage 1 (Compensated): Hyperinsulinemia with normal glucose tolerance; insulin resistance present but beta-cells compensate adequately 2, 3
• Stage 2 (Impaired Glucose Tolerance): Fasting glucose 100-125 mg/dL or 2-hour OGTT 140-199 mg/dL; beta-cells can no longer fully compensate 2, 6
• Stage 3 (Type 2 Diabetes): Fasting glucose ≥126 mg/dL; significant beta-cell failure with relative insulin deficiency 1

The transition occurs when pancreatic beta-cells fail to maintain hypersecretion, leading to fasting hyperglycemia and increased hepatic glucose production 3.

Associated Metabolic Abnormalities

Insulin resistance drives a characteristic metabolic profile:

• Dyslipidemia: Elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol 1
• Hypertension: Linked through sodium retention, sodium sensitivity, and increased vascular resistance 1
• Central obesity: Visceral adiposity is both a cause and consequence of insulin resistance 1
• Metabolic syndrome: Clustering of hyperglycemia, excess weight, central obesity, hyperlipidemia, and hypertension 1

Hyperinsulinemia enhances hepatic VLDL synthesis and impairs lipoprotein lipase activity, directly contributing to the atherogenic lipid profile 1.

Risk Factors and Populations at Risk

The American Diabetes Association recommends assessing for insulin resistance in patients with: 6

• BMI ≥25 kg/m² (≥23 kg/m² for Asian Americans) 6
• First-degree relative with type 2 diabetes 6
• High-risk race/ethnicity: American Indian, African American, Hispanic/Latino, Asian/Pacific Islander 6
• Physical signs: Acanthosis nigricans, central adiposity, skin tags 6
• Associated conditions: Hypertension, dyslipidemia, polycystic ovary syndrome, history of gestational diabetes 6
• Physical inactivity 1

Age and obesity are the strongest modifiable risk factors, with obesity causing direct insulin resistance through multiple mechanisms 1.

Diagnostic Approach

Clinical diagnosis relies on identifying compensatory hyperinsulinemia and glucose abnormalities: 6

• Fasting plasma glucose 100-125 mg/dL indicates impaired fasting glucose 6
• Fasting insulin >15 mU/L directly confirms insulin resistance 6
• HbA1c 5.7-6.4% suggests prediabetes with underlying insulin resistance 6
• 2-hour OGTT glucose 140-199 mg/dL indicates impaired glucose tolerance 6
• Lipid profile: HDL <35 mg/dL, triglycerides >250 mg/dL 6

Critical diagnostic pitfall: Normal glucose levels do not exclude insulin resistance, as hyperinsulinemia can maintain euglycemia in early stages 6. Always test in the fasting state (minimum 8 hours) to avoid postprandial variations 6.

The hyperinsulinemic-euglycemic clamp technique remains the gold standard for research purposes, but is impractical for clinical use 4, 5.

Treatment Strategies

Lifestyle Interventions (First-Line)

Weight reduction and exercise are foundational:

• Weight loss improves insulin sensitivity and may restore it toward normal, though complete normalization is rare 1
• Physical activity directly enhances insulin-mediated glucose uptake in skeletal muscle 1
• Dietary modification targeting caloric restriction and reduced simple carbohydrates 1

Insulin resistance associated with sodium retention and vascular resistance is reversible with weight loss and exercise 1.

Pharmacological Treatment

When lifestyle modifications are insufficient:

• Metformin: First-line pharmacotherapy for insulin resistance and prediabetes prevention 1
• Thiazolidinediones (e.g., pioglitazone): Directly improve insulin sensitivity by enhancing cellular responsiveness to insulin and improving hepatic insulin sensitivity 7
• Treatment of hyperglycemia itself can ameliorate glucose toxicity-induced abnormalities in insulin secretion and action 3

Pioglitazone specifically enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, and improves dysfunctional glucose homeostasis, with effects persisting for at least one year 7.

Clinical Significance and Complications

Insulin resistance substantially increases cardiovascular mortality risk:

• 2- to 3-fold increased risk of cardiovascular death independent of glucose levels 8
• Endothelial dysfunction is directly associated with insulin resistance 8
• Microvascular complications: Retinopathy, nephropathy, and neuropathy correlate with degree of insulin resistance 1
• Nonalcoholic fatty liver disease (NAFLD): Common comorbidity with prevalence of 24% globally 1

The combination of elevated proinsulin, glucose, and insulin signals a critical window for intervention before irreversible beta-cell failure occurs 3.

Important Clinical Caveats

Hyperglycemia creates a vicious cycle where "hyperglycemia begets more hyperglycemia" by worsening both insulin resistance and insulin secretory abnormalities 3. Correction of hyperglycemia can ameliorate these glucose toxicity-induced abnormalities 3.

In advanced chronic kidney disease, reduced insulin clearance by damaged kidneys leads to elevated insulin levels despite decreased insulin requirements, potentially causing "burn-out diabetes" where insulin needs paradoxically decrease 3.

Insulin resistance in type 1 diabetes exhibits a unique phenotype distinct from type 2 diabetes or obesity, lacking the typical features of intramyocellular lipid accumulation, dyslipidemia, and suppressed adiponectin despite impaired exercise capacity and cardiac function 1.