The biological logic behind the index is elegant in its simplicity. Insulin resistance refers to the reduced ability of peripheral tissues, primarily skeletal muscle, liver and adipose tissue, to respond adequately to insulin signaling, resulting in impaired cellular glucose uptake. When tissues resist insulin, the pancreatic beta cells compensate by secreting more of the hormone to maintain normal blood sugar. C-peptide, a short peptide cleaved from proinsulin when insulin is produced, is released in a one-to-one ratio with insulin but is not cleared by the liver as rapidly, making it a stable and convenient proxy for insulin secretion. By combining fasting C-peptide with fasting glucose in a single formula, the new index attempts to capture the essence of insulin resistance: how much insulin the body must produce to keep glucose in check.

What makes the commentary timely is the shifting landscape of pediatric metabolic disease. Childhood obesity continues to rise worldwide, and with it the incidence of type 2 diabetes in young people, a condition once considered exclusively adult. At the same time, a new generation of therapies, most notably glucagon-like peptide-1 receptor agonists, has been approved for use in adolescents, giving clinicians genuine pharmacological options for the first time. But identifying which children would benefit from such interventions requires a dependable, accessible measure of insulin resistance, and that is precisely where the current toolkit falls short, according to Kennedy and Hawkes.

The most widely used surrogate in pediatric research is the homeostatic model assessment of insulin resistance, or HOMA-IR, originally described by Matthews and colleagues in 1985. HOMA-IR multiplies fasting insulin by fasting glucose and applies a correction constant, exploiting the same compensatory logic as the new index. It has been validated against the euglycemic-hyperinsulinemic clamp, the gold-standard physiological test in which insulin is infused at a fixed rate and glucose metabolism is measured directly. Yet HOMA-IR depends on fasting insulin assays, which vary considerably between laboratories and lack standardization, a problem that has plagued pediatric studies for decades. Schwartz and colleagues demonstrated in 2008 that surrogate measures can diverge meaningfully from clamp-derived insulin sensitivity in children, and George and colleagues showed that their performance degrades further as glucose tolerance deteriorates from normal to prediabetes to frank diabetes.

An alternative approach sidesteps insulin assays altogether. The triglyceride glucose index, or TyG index, developed by Simental-Mendía, Rodríguez-Morán and Guerrero-Romero in 2008, uses fasting triglycerides and fasting glucose, both cheap and highly standardized laboratory measurements, to estimate insulin resistance. Studies in overweight youth, including work by Hannon and colleagues, have shown that lipid markers can help identify insulin-resistant adolescents, lending the TyG index practical appeal for large-scale screening. Glycosylated hemoglobin, or HbA1c, offers yet another window, reflecting average glycemia over roughly three months, though it captures the downstream consequences of insulin resistance rather than the underlying physiological defect itself.

Against this backdrop, El Amrousy and colleagues set out to determine whether the 20/(fasting C-peptide x fasting plasma glucose) formula could outperform these established surrogates in children with obesity. The index was first proposed by Ohkura and colleagues in 2013 as a simple and effective marker of insulin resistance in adults with type 2 diabetes, where preliminary evidence suggested it might be superior to more commonly used alternatives. Its theoretical advantage over HOMA-IR rests on the properties of C-peptide: because C-peptide is secreted equimolarly with insulin but avoids first-pass hepatic extraction and exhibits less assay variability, the formula may offer a more reproducible window into beta-cell compensation. Whether that advantage translates to children, whose insulin dynamics are shaped by growth hormone surges, puberty and developmental stage, was an open question until now.

The developmental context matters enormously. The EarlyBird cohort study by Jeffery and colleagues demonstrated that insulin resistance begins to rise before the onset of puberty, tracking with age rather than pubertal stage alone, and that the physiological insulin resistance of adolescence compounds any obesity-related resistance. This means a biomarker validated in adults cannot simply be transplanted into pediatric practice without careful testing against age-appropriate reference physiology. Kennedy and Hawkes emphasize that the definition of insulin resistance itself affects reported prevalence rates in children, as a systematic review by van der Aa and colleagues made clear, with different cutoffs and different surrogate measures yielding strikingly different estimates of how many young people are affected.

The implications of a validated, easy-to-calculate pediatric index would extend well beyond the research laboratory. A single fasting blood draw yielding C-peptide and glucose could, in principle, allow pediatricians to stratify children with obesity by metabolic risk, identifying those who might benefit most from lifestyle intervention, closer surveillance or pharmacotherapy with GLP-1 receptor agonists. It could also standardize outcome measures across clinical trials, enabling meaningful comparisons between studies that currently use heterogeneous definitions and assays. Conversely, if the index performs no better than HOMA-IR or the TyG index in children, the field would be spared the cost and complexity of adding C-peptide assays to routine pediatric testing, a result that would be almost as informative as a positive one.

Kennedy and Hawkes frame the moment as one that demands rigor rather than enthusiasm. The commentary’s title, pointing to the need to test the foundations of insulin resistance measurement in children, reflects a broader concern that decades of pediatric research have been built on surrogate measures whose validity in young populations has never been fully established. With new medications now available and childhood metabolic disease accelerating, the stakes of getting measurement right have never been higher. The study by El Amrousy and colleagues represents exactly the kind of foundational validation work the field needs, comparing a promising adult-derived formula head-to-head with the surrogates most commonly used in pediatric studies.

For now, the message for clinicians and researchers alike is one of cautious optimism paired with methodological vigilance. Insulin resistance is a treatable precursor to some of the most burdensome chronic diseases of our time, and children deserve diagnostic tools designed and validated for their unique physiology. As GLP-1 receptor agonists and other metabolic therapies move into pediatric care, the humble formula scrawled on a lab report, 20 divided by the product of two fasting blood values, may prove to be either a genuine advance or a reminder that in medicine, as in science generally, every new tool must earn its place through evidence. The Pediatric Research commentary makes clear that this evidence is finally being gathered, one carefully designed study at a time.

Subject of Research: Validation of a novel fasting C-peptide and glucose index as a surrogate biomarker of insulin resistance in children with obesity

Article Title: Insulin resistance in children: time to test the foundations

Article References: Kennedy, E. C., & Hawkes, C. P. (2026). Insulin resistance in children: time to test the foundations. Pediatric Research. https://doi.org/10.1038/s41390-026-05458-7

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05458-7

Keywords: insulin resistance, children, obesity, C-peptide, HOMA-IR, TyG index, HbA1c, type 2 diabetes, pediatric research, biomarkers, GLP-1 receptor agonists, beta-cell function