How effective is Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) with C-peptide for detecting insulin resistance?

HOMA-IR with C-Peptide for Detecting Insulin Resistance

HOMA-IR with C-peptide is not recommended for routine clinical detection of insulin resistance, as current guidelines explicitly state that routine testing for insulin or C-peptide to assess insulin resistance is not recommended in most people with diabetes or cardiovascular disease risk. 1

Guideline-Based Recommendations

Primary Position on Insulin Resistance Testing

• The American Diabetes Association (2023) explicitly recommends against routine testing for insulin or proinsulin in most people with diabetes or at risk for diabetes or cardiovascular disease, stating these assays are useful primarily for research purposes (Grade B, moderate evidence). 1

• It is unclear whether assessing insulin resistance through insulin or C-peptide measurement has any advantage over assessment of physical signs of insulin resistance such as BMI and presence of acanthosis nigricans. 1

• The American College of Obstetricians and Gynecologists (ACOG) does not recommend routine measurements of C-peptide or insulin for conditions like polycystic ovary syndrome where insulin resistance is a key feature. 1

Limited Clinical Applications Where C-Peptide Is Useful

C-peptide measurements have specific, narrow clinical indications that do not include routine insulin resistance screening:

• Distinguishing type 1 from type 2 diabetes in ambiguous cases (e.g., individuals with type 2 phenotype presenting in ketoacidosis) - Grade B recommendation. 1

• Investigating nondiabetic hypoglycemia to rule out surreptitious insulin administration - this is an essential use. 1

• Insurance coverage requirements for insulin pump therapy (measuring fasting C-peptide when simultaneous fasting glucose ≤220 mg/dL). 1

HOMA-IR Specific Considerations

When HOMA-IR Has Some Validity

• HOMA-IR is most valid for assessing insulin resistance in non-diabetic individuals when insulin secretion can adapt to insulin resistance, according to European guidelines (EASL/EASD/EASO, A1 level recommendation). 2

• HOMA-IR may be used to evaluate metabolic dysfunction-associated steatotic liver disease (MASLD) in adults without established type 2 diabetes. 2

• HOMA-IR can serve as a metabolic outcome measure in clinical trials for polycystic ovary syndrome assessment. 2

Critical Limitations of HOMA-IR

• The validity of HOMA-IR is questionable in overt diabetes, as it depends on the pancreatic beta-cell's ability to adapt to insulin resistance. 2

• HOMA-IR has limited utility for NAFLD diagnosis in patients with metabolic risk factors (B2 recommendation). 2

• There is no universal agreement on cut-off values defining insulin resistance using HOMA-IR. 2

• Research demonstrates that HOMA-IR failed to detect marked diet-induced insulin resistance in a controlled study, with 13 of 36 animals showing artifactual decreases in HOMA-IR despite confirmed insulin resistance by gold-standard clamp studies. 3

• The ability of HOMA-IR to detect insulin resistance is particularly limited when insulin secretory function is compromised. 3

Alternative Approaches Supported by Evidence

• Fasting glucose, lipid profile (TG/HDL ratio), and body fat percentage may estimate insulin resistance better than HOMA-IR in Japanese patients with type 2 diabetes, with adjusted R² of 57-60% versus 52.5% for HOMA-IR. 4

• A simple index 20/(fasting C-peptide × fasting plasma glucose) showed stronger correlation with gold-standard glucose clamp (r=0.83) than HOMA-IR (r=-0.74) in patients with type 2 diabetes, particularly in those with mild insulin resistance (r=0.90 vs r=-0.49). 5

• Clinical assessment using BMI and acanthosis nigricans is recommended over laboratory testing for insulin resistance screening. 1

Common Pitfalls to Avoid

• Do not use HOMA-IR in patients with established diabetes - the model breaks down when beta-cell function is significantly impaired. 2, 3

• Do not rely on HOMA-IR to detect longitudinal changes in insulin sensitivity with interventions - it has demonstrated failure to detect confirmed insulin resistance changes. 3

• Do not order C-peptide or insulin levels routinely for insulin resistance assessment in clinical practice outside the specific indications listed above. 1

• Recognize that HOMA requires robust primary input data and careful interpretation, as it is a mathematical model with inherent limitations. 6