What tests are used to detect insulin resistance in non-diabetic individuals at high risk for diabetes?

Tests to Detect Insulin Resistance in Non-Diabetic High-Risk Individuals

The American Diabetes Association recommends against routine testing for insulin or insulin resistance in most people at risk for diabetes, stating these assays are primarily useful for research purposes rather than clinical practice. 1

Recommended Screening Approach

Standard Clinical Tests (First-Line)

The appropriate tests for detecting prediabetes and diabetes risk in high-risk individuals are:

• Hemoglobin A1C: 5.7-6.4% defines prediabetes (must be performed in NGSP-certified laboratory) 2, 3
• Fasting plasma glucose (FPG): 100-125 mg/dL defines impaired fasting glucose 2, 3
• 2-hour oral glucose tolerance test (OGTT): 140-199 mg/dL after 75g glucose load defines impaired glucose tolerance 2, 3

All three tests are equally appropriate for detecting prediabetes and diabetes risk. 3 These tests identify individuals at high risk for progression to diabetes, which is the clinically meaningful outcome rather than insulin resistance per se. 3

Clinical Assessment Over Laboratory Testing

BMI measurement and examination for acanthosis nigricans are recommended over laboratory testing for insulin resistance screening. 1 This approach is more practical and cost-effective than biochemical testing.

When Insulin/C-Peptide Testing May Be Useful

Direct insulin resistance testing has very limited clinical applications:

• Distinguishing type 1 from type 2 diabetes in ambiguous cases (e.g., ketoacidosis in apparent type 2 diabetes) using C-peptide measurement 1
• Investigating nondiabetic hypoglycemia to rule out surreptitious insulin administration 1
• Insurance requirements for insulin pump therapy coverage 1

HOMA-IR Considerations

If insulin resistance quantification is specifically needed (primarily for research or specialized clinical scenarios):

• HOMA-IR is most valid in non-diabetic individuals when pancreatic beta-cells can still adapt to insulin resistance 1, 4
• HOMA-IR validity is questionable in overt diabetes because it depends on preserved beta-cell function 1, 4
• No universal cut-off values exist for defining insulin resistance using HOMA-IR 1, 4
• Research suggests HOMA-IR ≥4.65 or fasting insulin ≥20.7 μU/mL may indicate insulin resistance in non-diabetic individuals 5
• HOMA-IR correlates highly with fasting insulin alone (r=0.98), providing minimal additional information beyond measuring fasting insulin 6, 7

Limited Clinical Applications for HOMA-IR

• Evaluating metabolic dysfunction-associated steatotic liver disease (MASLD) in adults without established type 2 diabetes 1, 4
• Metabolic outcome measure in polycystic ovary syndrome clinical trials 1, 4

Important Caveats

Test Selection Considerations

• In conditions with increased red blood cell turnover (anemia, hemoglobinopathies, pregnancy, hemodialysis, recent blood loss/transfusion, erythropoietin therapy), only plasma glucose criteria should be used, not A1C 3
• For OGTT: ensure adequate carbohydrate intake (≥150 g/day) for 3 days prior to testing 3
• Glucose sample handling: plasma should be separated immediately or kept on ice to prevent glycolysis, as preanalytical stability is poor 3
• A1C advantages: no fasting required and greater preanalytical stability than glucose tests 3

Who Should Be Screened

Testing should be performed in adults with:

• BMI ≥25 kg/m² (≥23 kg/m² in Asian Americans) plus one or more risk factors 3
• Risk factors include: first-degree relative with diabetes, high-risk ethnicity, cardiovascular disease history, hypertension (≥130/80 mmHg), dyslipidemia, polycystic ovary syndrome, physical inactivity, acanthosis nigricans 3
• All other patients starting at age 35 3

Follow-Up Testing

• Annual screening for those with prediabetes 3
• Every 3 years minimum for those with normal results 3

Clinical Bottom Line

Focus on standard prediabetes screening tests (A1C, fasting glucose, or OGTT) rather than direct insulin resistance measurements. 2, 1, 3 These tests identify individuals who will benefit from diabetes prevention interventions, which is the clinically meaningful outcome. Direct insulin or HOMA-IR testing adds minimal clinical value for most patients and is not recommended by major guidelines for routine screening. 1