Clinical background

In individuals with IR, cells become less sensitive to the effects of insulin and do not absorb enough glucose from the bloodstream. IR can progress to prediabetes and type 2 diabetes. IR is also associated with other clinical conditions, including hypertension, cardiovascular disease (CVD), stroke, metabolic dysfunction associated steatotic liver disease (formerly NAFLD), polycystic ovary syndrome (PCOS), and certain forms of cancer.1 Early recognition and intervention can help reverse IR or prevent its progression and thereby reduce the risk of these clinical conditions.1

The onset of IR can be gradual and difficult to recognize. In early stages of IR, before prediabetes develops, pancreatic beta-cells may produce high levels of insulin to offset the reduced insulin sensitivity. This increased insulin production can maintain normal levels of blood glucose and hemoglobin A1c (HbA1c). Consequently, monitoring glycemic indices alone will not detect the onset of IR. As insulin sensitivity continues to decline (and IR increases), the increased insulin production will not be able to maintain normal glucose levels. Glucose levels rise, and prediabetes and type 2 diabetes can develop.

Methods used in a research setting, such as the hyperinsulinemic euglycemic glucose clamp2 or the insulin suppression test,3 can detect IR even in individuals with normal fasting glucose levels. However, these methods are time-consuming and labor-intensive, making them impractical for use in a primary-prevention clinic. A simpler surrogate marker is the homeostatic model assessment (HOMA), which uses fasting glucose levels and insulin or C-peptide to derive an IR score.4 C-peptide is co-secreted with insulin in similar amounts from the beta-cells.4 Compared with insulin, C-peptide has a longer half-life in circulation, is present at 3- to 6-fold higher levels, and exhibits less fluctuation.4,5 However, C-peptide measurements are not typically performed because of the costs and inconvenience associated with collecting additional samples and performing an additional assay for C-peptide.4 In addition, measurement of IR is not currently recommended as a screening tool in guidelines for diabetes6 or PCOS.7

Quest Diagnostics offers the Cardio IQ® Insulin Resistance Score as a simple surrogate marker that combines fasting insulin and C-peptide measurements to evaluate the likelihood that an individual has IR. The analytes are simultaneously quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as intact molecules, eliminating both the need for multiple samples and the possibility of cross-reactivity that can affect some immunoassays.

The IR score (a probability score [%]) was developed in a study of 535 apparently healthy individuals. The odds ratio for a study participant having IR, measured using the insulin suppression test, was estimated using the score as summarized in the Table.8 In a follow-up study, the risk of type 2 diabetes was assessed in a population of older Europeans (median follow-up time 9.1 years).9 Being in the top (IR score >20%) versus the bottom tertile (IR score <7%) was associated with incident type 2 diabetes after adjusting for established risk factors (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.7-2.5; P<.001) except for prediabetes status, which attenuated risk (HR, 1.5; 95% CI, 1.3-1.8; P<.001).9

Table. Association Between IR Score and IR Determined During an Insulin Suppression Test8

CI, confidence interval; IR, insulin resistance.

Compared to lower IR scores, higher IR scores have also been associated with an increased risk of incident CVD and all-cause mortality10 and incident coronary heart disease (fatal and non-fatal myocardial infarction and coronary revascularization).11