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

The team, led by Michael Rickels and including first author Juan Alvarez-Dominguez, examined peri-transplant metabolic outcomes in all eleven recipients who received allogeneic islet transplantation between 2008 and 2012. The cohort, four men and seven women with a median age of 49 years and a median diabetes duration of 34 years, received a median of 7,879 islet equivalents per kilogram of body weight, with each infusion drawn from a single donor pancreas. Immunosuppression followed the CIT07 regimen, combining anti-thymocyte globulin and etanercept for induction with low-dose tacrolimus and sirolimus for maintenance. Blood glucose was monitored more than four times daily, and insulin requirements, glycemic lability, and endogenous insulin secretion were tracked systematically through the first 75 days after transplant.

The peri-transplant management strategy centers on a concept the authors call islet rest. After islets are infused into the portal vein, they must revascularize, arterialize, and secure adequate oxygen supply before they can be asked to carry a full secretory load. To protect them during this vulnerable window, clinicians administer intensive exogenous insulin with the goal of near-normoglycemia, targeting fasting and pre-prandial glucose values of 80 to 120 mg/dL and post-prandial values below 180 mg/dL for at least several weeks. This approach shields the newly delivered cells from glucose toxicity while minimizing the demand placed on them to secrete insulin. Yet because primary islets isolated from deceased donors are developmentally and functionally mature, they continue to sense glucose and release insulin immediately, even under the stress of isolation and the relatively hypoxic environment of the transplant site.

The data show that this immediate function translates into rapid clinical benefit. Median blood glucose fell from 148 mg/dL before transplant to 104 mg/dL afterward, and glycemic lability, a measure of temporal glucose variability, dropped from 14.5 to 1.0 (mmol/L)²/hour, both within the first week following infusion. Insulin requirements declined from a median of 27 units per day to 12 units per day, falling week by week until they plateaued between weeks 4 and 8 at less than half the pre-transplant dose. Between days 56 and 75, all eleven recipients tapered off exogenous insulin entirely, and although blood glucose rose modestly during this interval, all met glucose targets with minimal variability and completed a mixed-meal tolerance test at day 75 without any exogenous insulin support.

Perhaps the most striking evidence of early graft function comes from C-peptide measurements, which serve as a proxy for endogenous insulin secretion. Before transplantation, fasting and stimulated C-peptide were undetectable in all recipients, below 0.05 ng/mL, consistent with long-standing type 1 diabetes. By day 3 after infusion, C-peptide was already detectable at clinically meaningful concentrations, and it rose progressively through the day 75 mixed-meal tolerance test. At that point, all recipients had fasting glucose below 120 mg/dL. Seven of the eleven achieved a 90-minute post-meal glucose below 180 mg/dL, while the remaining four qualified for a second islet infusion. All seven recipients with adequate post-meal glucose control had stimulated C-peptide levels above the 2.93 ng/mL threshold identified by the Collaborative Islet Transplant Registry as predictive of insulin independence, and among the four who needed a second infusion, two fell below and two above that same threshold.

The authors emphasize that these early metabolic effects occur despite the deliberate suppression of secretory demand through insulin therapy. The gradual increases in fasting and stimulated C-peptide indicate that graft oxygenation and functionality improve over time, while the immediate contribution to glucose control demonstrates that mature primary islets do not require a prolonged maturation period to become metabolically active. Previous work from the same cohort showed that full graft function was established by day 75, with beta-cell secretory capacity measured by glucose-potentiated arginine testing remaining comparable between day 75 and day 365. The day 75 C-peptide values also align with those identified through long-term registry follow-up as predicting optimal outcomes for islet transplant alone recipients.

This rapid timeline stands in sharp contrast to what has been observed with stem cell-derived islets, the emerging alternative to donor pancreases that could one day eliminate the constraints of organ supply. Unlike primary islets, SC-islets are molecularly and functionally immature, lacking the precision, kinetics, and extent of insulin release characteristic of adult islets. In a recent clinical trial of intraportally delivered SC-islets, recipients needed more than 120 days on average to reduce exogenous insulin requirements by 50 percent, compared with roughly 21 days for primary islet recipients in the CIT07 cohort. The authors attribute this more than fivefold delay to a genuine maturation process that SC-islets must undergo in vivo, gaining glucose-dependent insulin secretion beyond the initial engraftment period, rather than to an insufficient transplanted cell mass.

Notably, the SC-islet trial used the same dosing logic, delivery route, and immunosuppression protocol as CIT07, and its ultimate outcomes were comparable. Ten of twelve SC-islet recipients eventually became insulin-independent with a single infusion, similar to the seven of eleven in the primary islet cohort. Because achieving insulin independence supports the establishment of a reserve capacity for insulin secretion, the authors argue that delayed functional maturation, not inadequate engrafted mass, explains the slower glucose improvement. This distinction matters enormously for how SC-islet products are evaluated, since the tools used to assess primary islet graft function in the first days and weeks may not be interpretable when applied to a product that is still maturing.

The practical implications extend to clinical decision-making and regulatory science alike. In primary islet transplantation, primary graft non-function, instant blood-mediated inflammatory response, and acute rejection can all be detected through metabolic function testing within the first days to weeks after infusion. For SC-islets, these same mechanisms of graft failure may go unidentified while clinicians wait for in vivo maturation to unfold, delaying the ability to judge whether a given dose was adequate, whether engraftment succeeded, and whether immune evasion strategies are working. The authors suggest that early metabolic control outcomes from primary islet transplantation can serve as functional benchmarks for a fully mature SC-islet product when assessing longer-term outcomes, and that future advances enabling earlier functional assessment will help align expectations with evolving regulatory standards.

As stem cell-derived islet products advance toward broader clinical testing, the timeline documented here provides a reference point against which their performance can be measured. The message from the CIT07 cohort is unambiguous: mature islets act fast, and the speed of metabolic rescue is itself a signal of graft quality. Bridging the gap between that standard and the slower maturation of stem cell-derived alternatives is now one of the central challenges in the field of beta-cell replacement therapy.

Subject of Research: Early metabolic control timeline after primary islet transplantation and its implications for stem cell-derived islet product development in type 1 diabetes

Article Title: Rapid metabolic control after primary islet transplantation: relevance for stem cell-derived islet product development

Article References: Alvarez-Dominguez, J. R., Liu, M., Sawan, C., Soleimanpour, S. A., Liu, C., Naji, A., & Rickels, M. R. (2026). Rapid metabolic control after primary islet transplantation: relevance for stem cell-derived islet product development. Transplant International, 39, Article 17176. https://doi.org/10.3389/ti.2026.17176

Image Credits: AI Generated

DOI: 10.3389/ti.2026.17176

Keywords: islet transplantation, type 1 diabetes, stem cell-derived islets, C-peptide, glucose control, beta-cell replacement, CIT07 protocol, insulin independence, Transplant International, islet rest, glycemic lability, functional maturation

The research, published in BMC Endocrine Disorders, enrolled 1,158 adults who underwent acanthosis nigricans screening at the hospital’s Endocrinology Clinic between 2010 and 2021. Rather than treating metabolic health as a simple diabetic-versus-nondiabetic binary, the team sorted every participant into one of five mutually exclusive stages spanning the full arc of metabolic deterioration. The five categories were Normal, Isolated Insulin Resistance, Hyperinsulinemia, Prediabetes with Insulin Resistance, and Diabetes with Insulin Resistance. This stratification allowed the investigators to ask a question that simpler study designs cannot answer: does the skin sign track with metabolic disease in general, or does it point to one particular physiological moment along the road from health to diabetes?

The answer was both surprising and clinically useful. Prevalence of acanthosis nigricans varied across the five stages in a distinctly non-monotonic pattern. It reached its highest point, 71.3 percent, in the Hyperinsulinemia stage, when fasting insulin levels are elevated but blood glucose remains within normal limits. The prevalence then fell to 51.7 percent among participants with prediabetes and insulin resistance and dropped further to 44.6 percent among those with outright diabetes and insulin resistance, a gradient that was statistically significant at P less than 0.001. In other words, the skin sign was most common not at the end of the metabolic road, when the disease is most advanced, but at a middle waypoint where the body is still successfully compensating for insulin resistance by secreting ever-larger amounts of the hormone.

The physiological logic behind this pattern begins at the cellular level. Insulin resistance means that target tissues, chiefly skeletal muscle, liver, and adipose tissue, respond poorly to insulin’s normal signaling. To maintain glucose homeostasis, pancreatic beta cells compensate by secreting more insulin, driving circulating insulin concentrations upward. Acanthosis nigricans is thought to arise as a byproduct of this compensatory flood. Insulin at high concentration spills over onto insulin-like growth factor 1 receptors, or IGF-1R, on keratinocytes and fibroblasts in the skin. Activation of these receptors triggers the phosphatidylinositol 3-kinase, or PI3K, and protein kinase B, or AKT, signaling cascades, which stimulate proliferation of epidermal cells and deposition of the velvety, papillomatous texture that defines the condition. The skin, in this framing, is a visible readout of how hard the pancreas is working to keep glucose under control.

Consistent with this mechanism, participants with the skin sign were, on average, younger than those without it and carried higher body mass index. They also had markedly higher fasting insulin and C-peptide levels, the latter a co-secreted fragment of proinsulin that serves as an independent index of beta-cell secretory activity. All of these differences were statistically robust at P less than 0.001. The combination of younger age, greater adiposity, and higher insulin output paints a coherent portrait: acanthosis nigricans tends to appear in people whose metabolic machinery is straining hardest, often years before laboratory tests of glucose would raise any alarm.

Of course, cross-sectional data are vulnerable to confounding, and the team addressed this concern with a carefully layered statistical strategy. Using multinomial logistic regression, the researchers examined the association between the skin sign and each metabolic stage, progressively adjusting for demographic and metabolic covariates. Even in the fully adjusted model, the Hyperinsulinemia stage retained by far the strongest link to acanthosis nigricans, with an odds ratio of 4.69 and a 95 percent confidence interval spanning 1.58 to 13.95. By contrast, the associations observed for the prediabetes and diabetes stages attenuated and lost statistical strength once full covariate adjustment was applied. The specificity of the signal survived scrutiny: this is a marker of compensatory hyperinsulinemia with preserved glycemia, not a generic badge of advanced metabolic disease.

Subgroup analyses probing whether the association varied by age, sex, or body mass index added further texture to the findings, and the investigators also asked a practical question that matters for any screening context: how much does seeing the skin actually help? Receiver operating characteristic analysis showed that adding acanthosis nigricans to existing information modestly but significantly improved discrimination for hyperinsulinemia, raising the area under the curve from 0.730 to 0.776, a difference significant at P less than 0.001. The improvement is not dramatic enough to turn the skin sign into a diagnostic test on its own, but it is meaningful as an adjunctive cue. A clinician who spots the velvety plaques during a routine examination gains measurable incremental information about a patient’s likelihood of silent insulin excess.

Perhaps the most mechanistically intriguing component of the study was an exploratory mediation analysis. The team asked whether measurable metabolic traits, specifically waist circumference, uric acid, and the liver enzyme alanine aminotransferase, might explain the statistical link between the skin sign and hyperinsulinemia. Together, these three factors accounted for a substantial proportion of the association. Waist circumference is the classic anthropometric proxy for visceral adiposity, the metabolically active fat depot most tightly coupled to insulin resistance. Uric acid has been repeatedly linked to hyperinsulinemia and metabolic syndrome, while elevated alanine aminotransferase reflects hepatic steatosis, the fatty infiltration of the liver that both drives and responds to insulin excess. That these mediators soak up much of the association suggests that acanthosis nigricans sits at the convergence of visceral obesity, fatty liver, and hyperuricemia, a cluster of interlocking abnormalities that all feed the same compensatory physiology.

The authors are candid about the limits of their design. This was a clinic-based cohort of adults attending an obesity and endocrinology service in Shanghai, so the participants carry a high baseline burden of adiposity and metabolic risk; the prevalence figures would very likely differ in a general population sample. The cross-sectional structure captures a single moment in time and cannot prove that hyperinsulinemia causes the skin changes, only that the two travel together in this population. The mediation analysis, by the authors’ own framing, is exploratory and does not establish causal pathways. Longitudinal follow-up would be needed to determine whether the appearance of acanthosis nigricans predicts progression from the hyperinsulinemic stage to prediabetes and diabetes, and whether treating the underlying insulin excess causes the plaques to fade.

Even with those caveats, the clinical takeaway is unusually actionable for a marker that costs nothing to detect. The hyperinsulinemic stage, the one most tightly bound to the skin sign, is precisely the window in which intervention has the greatest chance of preventing progression. Lifestyle change, weight reduction, and pharmacologic agents that lower insulin demand are all most effective before beta-cell function falters and glucose begins to climb. Yet this stage is also the one least likely to be caught by routine screening, because fasting glucose and even glycated hemoglobin, measured as HbA1c, remain normal while insulin surges unseen. The study therefore supports treating acanthosis nigricans as an adjunctive clinical sign, in the authors’ phrase, rather than a standalone screening tool, one that should prompt a clinician to order fasting insulin, C-peptide, an oral glucose tolerance test with insulin curves, and assessment of waist circumference and liver enzymes in high-risk individuals. A dark patch of skin that patients often hide or ignore may, on closer inspection, be the body’s earliest visible cry that its metabolic budget is being spent faster than it can be replenished, and recognizing it could buy years of prevention that blood tests alone would miss.

Subject of Research: Acanthosis nigricans as a cutaneous marker of compensatory hyperinsulinemia across metabolic stages

Article Title: Acanthosis nigricans as a cutaneous marker of compensatory hyperinsulinemia with preserved glycemia: a cross-sectional study

Article References: Mutailipu, K., Zha, X., Yin, J., Xin, J., Sun, H., Ren, T., Zhao, Y., Qu, S., & Bu, L. (2026). Acanthosis nigricans as a cutaneous marker of compensatory hyperinsulinemia with preserved glycemia: a cross-sectional study. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02630-2

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02630-2

Keywords: acanthosis nigricans, hyperinsulinemia, insulin resistance, prediabetes, type 2 diabetes, metabolic syndrome, obesity, C-peptide, waist circumference, fatty liver, uric acid, cross-sectional study

The study followed 97 children, adolescents, and young adults aged 1 to 25 years who attended routine follow-up at the BADAS Paediatric Diabetes Care and Research Centre at BIRDEM in Dhaka between March and November 2024. Each participant wore a blinded professional continuous glucose monitor, the Abbott FreeStyle Libre Pro iQ, on the upper arm for 14 days. Unlike the consumer devices increasingly common in high-income countries, the blinded sensor recorded interstitial glucose every 15 minutes without displaying any readings to the wearer. That design choice matters scientifically: when patients can see their glucose in real time, they tend to correct with extra insulin, adjust meals, or change activity, which artificially smooths the very fluctuations researchers want to measure. By keeping the sensor invisible, the team captured a less confounded estimate of true day-to-day glycaemic instability.

The central measure was the coefficient of variation, calculated as the standard deviation of glucose readings divided by the mean glucose and expressed as a percentage. International consensus guidelines, including those from the International Society for Paediatric and Adolescent Diabetes, recommend keeping this value at or below 36 percent, because higher variability is linked to more hypoglycaemic episodes, particularly dangerous overnight drops in blood sugar. In the Dhaka cohort, the mean coefficient of variation was 39.4 percent, with individual values ranging from 19.3 to 59.1 percent. Nearly 61 percent of participants exceeded the recommended threshold, meaning suboptimal variability was the norm rather than the exception. That mean is substantially above the 32 to 37 percent range typically reported in well-resourced paediatric cohorts, and because those comparison studies mostly used real-time devices that tend to lower observed variability, the true gap is likely even wider.

The contrast between diabetes types was stark. Participants with Type 1 diabetes, who made up just over 70 percent of the cohort, had a mean coefficient of variation of 41.9 percent, compared with 33.3 percent among those with Type 2 diabetes, a difference of 8.6 percentage points. More than three-quarters of the Type 1 group exceeded the variability target, against roughly a quarter of the Type 2 group. Time-in-range, the proportion of readings between 70 and 180 milligrams per decilitre, averaged just 52.5 percent in the Type 1 group versus 70.3 percent in the Type 2 group. Notably, time spent below range, which captures hypoglycaemia, was statistically similar between the two groups, at around 10 to 11 percent each, indicating that dangerous low blood sugar is not a concern confined to Type 1 diabetes in this population.

The study’s most intriguing finding concerns C-peptide, a byproduct of insulin production that serves as a marker of residual beta-cell function. When insulin-producing cells in the pancreas are destroyed, as in Type 1 diabetes, C-peptide falls to undetectable levels; when they survive, as in Type 2 diabetes or early Type 1 disease, measurable amounts persist. Fasting C-peptide was available for 46 of the 97 participants, and its relationship with glucose stability was striking. Higher C-peptide correlated strongly with lower variability, and in a multivariable regression adjusting for diabetes type, age, and insulin dose, each additional nanogram per millilitre of C-peptide was associated with a 1.94 percentage point reduction in the coefficient of variation.

Stratifying participants into three C-peptide categories revealed a clear dose-response pattern. The 20 participants with near-complete beta-cell depletion, defined as C-peptide below 0.2 nanograms per millilitre, had a mean coefficient of variation of 44.8 percent, time-in-range of only 42.1 percent, and time below range of 13.6 percent. The 13 participants with the best-preserved beta-cell function, above 1.0 nanograms per millilitre, achieved a mean variability of 32.2 percent and time-in-range of 65.8 percent, approaching international targets despite having no access to advanced insulin delivery technology. Time below range was nearly doubled in the lowest category compared with the highest, showing that hypoglycaemia risk, not just hyperglycaemia, tracks inversely with residual insulin secretion. The statistical trend across categories was significant for variability, time-in-range, time below range, and mean glucose.

The biology behind this relationship is coherent. Preserved endogenous insulin secretion provides meal-responsive, physiologically titrated insulin delivery that no injection regimen fully replicates, buffering the post-meal spikes that drive variability upward. Intact beta cells also support counter-regulatory glucagon responses that restrain hypoglycaemic swings. What makes the finding clinically important is its practicality: a single fasting C-peptide measurement costs roughly 5 to 10 US dollars in Bangladesh and can be run in ordinary hospital biochemistry laboratories, without the stimulation protocols or antibody assays that are often unavailable in low-resource settings. If confirmed in larger samples, the authors suggest, the test could help clinicians identify children who need prioritised access to glucose monitoring, more frequent clinical contact, or structured hypoglycaemia counselling.

The researchers are careful to frame the C-peptide results as hypothesis-generating. Because diabetes type was itself classified partly using fasting C-peptide, the two variables are partially collinear, and the association is best interpreted as a gradient of residual beta-cell function rather than a fully independent effect. Sensitivity analyses restricted to participants with Type 1 diabetes alone, and to those with at least 10 days of valid sensor data, produced consistent results, but C-peptide was missing for more than half the cohort, and although those with and without measurements differed on no measured baseline characteristic, residual selection bias cannot be excluded. The study was also single-centre, conducted at a tertiary referral facility where patients receive specialist care and may not represent all children with diabetes in Bangladesh. The 14-day monitoring window cannot capture seasonal or illness-related patterns, and the cross-sectional design precludes conclusions about cause and effect.

Even so, the findings carry weight for a region where diabetes in young people is rising and monitoring technology remains scarce and unevenly distributed. The authors point out that the elevated variability likely reflects a combination of resource-limited care realities: limited access to rapid-acting and long-acting analogue insulins, inconsistent meal timing, infrequent clinical contact, and practical barriers to rapid dose adjustment. Notably, even the Type 2 subgroup, which retained meaningful insulin secretion, showed variability exceeding values reported in comparably managed high-income country cohorts, suggesting the resource environment imposes a burden that operates across diabetes types. The team calls for multicentre studies across South Asia and sub-Saharan Africa to establish regionally appropriate benchmarks, for intervention trials testing whether variability-focused protocols reduce both high and low glucose excursions, and for cost-effectiveness analyses comparing professional glucose monitoring against standard HbA1c-only care. In the meantime, they argue, reducing variability, not merely lowering average HbA1c, should become an explicit treatment goal for young people with diabetes of both types in resource-limited settings.

Subject of Research: Glycaemic variability and residual beta-cell function in young people with Type 1 and Type 2 diabetes in Bangladesh

Article Title: Glycaemic Variability and C‐Peptide in Bangladeshi Children, Adolescents, and Young Adults With Diabetes: A Prospective Study

Article References: Flabe, A. H., Zabeen, B., Amirat, S., & Luo, J. (2026). Glycaemic Variability and C‐Peptide in Bangladeshi Children, Adolescents, and Young Adults With Diabetes: A Prospective Study. Endocrinology, Diabetes & Metabolism, 9(6), Article e70347. https://doi.org/10.1002/edm2.70347

Image Credits: AI Generated

DOI: 10.1002/edm2.70347

Keywords: continuous glucose monitoring, glycaemic variability, C-peptide, Type 1 diabetes, Type 2 diabetes, paediatric diabetes, hypoglycaemia, time-in-range, Bangladesh, low- and middle-income countries, beta-cell function, HbA1c

At the heart of DOHaD lies the concept of developmental plasticity. A single genotype, the theory holds, can produce different phenotypes—distinct physiological states and behaviors—depending on the environmental conditions encountered during critical windows of development. In evolutionary terms, this flexibility is meant to be adaptive: a fetus sensing its future environment calibrates its biology accordingly, in principle increasing fitness under anticipated conditions. But when the prenatal environment misrepresents the world the child will actually inhabit, the calibration can go awry, setting the stage for chronic disease. The mechanisms are thought to involve a complex interplay of genetic, epigenetic, and environmental factors that alter gene expression and, through it, physiological processes—changes that can, in some cases, be transmitted across generations.

Among the prenatal exposures now under intense scrutiny is maternal metabolic dysregulation, particularly hyperglycemia. Gestational diabetes mellitus, a form of glucose intolerance first recognized during pregnancy, affects a substantial and growing share of expectant mothers worldwide, and evidence suggests that intrauterine exposure to elevated maternal glucose, alongside an excessive or deficient nutritional environment, can influence both metabolic and neurodevelopmental trajectories across the offspring’s life course. Some studies point to intergenerational transmission through epigenetic mechanisms, raising the possibility that the metabolic storms of one pregnancy may leave molecular marks that surface in children and even grandchildren. The developing brain, with its precisely choreographed sequence of proliferation, migration, and synapse formation, is considered especially vulnerable to these metabolic perturbations.

Against this backdrop, a new study by Yin and colleagues, published in Pediatric Research and accompanied by a commentary from Ali H. Ziyab of Kuwait University, asks a deceptively simple question: could a single, easily modifiable nutrient—vitamin D—alter the neurological risks that gestational diabetes poses to the developing fetus? The question matters because vitamin D is no ordinary vitamin. Its active form functions as a secosteroid hormone, binding to the vitamin D receptor present in numerous tissues, including the placenta and the brain. During pregnancy, the placenta takes up and metabolizes circulating 25-hydroxyvitamin D, the standard blood marker of vitamin D status, determining how much of the hormone’s activity reaches the fetoplacental unit. Maternal vitamin D deficiency has previously been linked in the DOHaD literature to a range of adverse offspring outcomes, and prior birth cohort work has suggested that vitamin D status can even modulate the effect of pre-pregnancy obesity on gestational diabetes risk itself.

To interrogate the interplay between vitamin D and gestational diabetes, the researchers drew on a large prospective birth cohort of 7,438 pregnant women—an unusually robust sample for developmental research, where loss to follow-up and small numbers often blunt statistical power. The design was carefully sequenced in time. Maternal vitamin D status was measured by serum concentrations of 25-hydroxyvitamin D at 16 to 23 weeks of gestation, capturing the nutrient’s availability during a critical window of fetal brain development. Gestational diabetes was then ascertained at 24 to 28 weeks, the standard period for screening. By establishing the exposure timeline in this way, the investigators could examine whether a mother’s vitamin D status before the onset of detectable glucose intolerance modified the association between the condition and her child’s later neurodevelopment.

The assessment of the children was equally rigorous. Offspring neurodevelopment was evaluated at three ages—5 to 7 months, 11 to 13 months, and 24 to 36 months—using a two-step screening and confirmation approach. Children were first screened with the Denver Developmental Screening Test-II, a widely used instrument that surveys gross motor, fine motor, language, and personal-social skills, and those flagged by the screen underwent confirmatory assessment with the Gesell Developmental Schedules, a more detailed standardized evaluation. This dual-gate design reduces the false positives that plague single-screen studies, lending weight to any association that survives it. Few cohort studies of metabolic pregnancy complications can claim developmental outcomes measured this carefully and this repeatedly across infancy and toddlerhood.

Crucially, the team also probed the potential mechanistic pathway connecting maternal metabolism to the fetal brain. At the time of gestational diabetes diagnosis, the researchers quantified maternal insulin resistance using the homeostatic model assessment of insulin resistance, or HOMA-IR, a standard index derived from fasting glucose and insulin values. Then, at delivery, they measured C-peptide in umbilical cord blood—a fragment cleaved from proinsulin that serves as a surrogate marker of the fetus’s own endogenous insulin production. Because fetal insulin secretion responds to the glucose crossing the placenta, cord-blood C-peptide offers a window into how intensely the fetal pancreas was stimulated in the final weeks of gestation. Together, these two measures sketch a plausible biological chain: maternal insulin resistance, fetal hyperinsulinemia, and downstream effects on the developing nervous system, with vitamin D positioned as a potential modifier somewhere along that chain.

The plausibility of such a role is grounded in biology rather than speculation. Vitamin D deficiency during pregnancy has been associated in animal and human studies with altered placental function, inflammation, and fetal programming of multiple organ systems, and the vitamin D receptor is expressed in brain regions central to learning and motor control. If gestational diabetes harms fetal neurodevelopment partly through oxidative stress, inflammation, or impaired nutrient and oxygen delivery, then adequate vitamin D status could plausibly buffer some of those insults—either by supporting placental metabolism of the hormone, by modulating immune and inflammatory pathways, or by influencing gene expression through epigenetic mechanisms. The DOHaD framework itself predicts exactly this kind of gene–environment interplay, in which a nutritional exposure modifies how a metabolic stressor is translated into developmental outcomes.

For clinicians and public health practitioners, the implications are tantalizing but must be handled with care. Vitamin D supplementation is inexpensive, widely available, and already recommended in various forms during pregnancy, yet the field is littered with nutrients that looked protective in observational cohorts but failed in randomized trials. Prospective cohort designs, however large and well-measured, can control for confounding only to the extent that the confounders are known and captured—socioeconomic status, diet, sunlight exposure, adiposity, and ethnicity all intertwine with both vitamin D levels and child development. The value of the Yin et al. study lies in its scale, its temporal sequencing of exposures, its two-step developmental assessments, and its attempt to trace a mechanistic pathway through insulin biology; together these features elevate it well above typical associations. Whether correcting maternal vitamin D deficiency can genuinely attenuate the neurodevelopmental consequences of gestational diabetes is a question that will ultimately demand intervention trials. Until then, the study adds to a growing body of evidence that the fetal brain is not merely a passive target of maternal metabolic disease, but an organ whose fate may be partly negotiable—with the right nutrient, at the right time, in the right mother.

Subject of Research: The modifying role of maternal vitamin D status in the association between gestational diabetes mellitus and offspring neurodevelopment

Article Title: Shielding the fetal brain: maternal vitamin D attenuates the neurodevelopmental consequences of gestational diabetes mellitus

Article References: Ziyab, A. H. (2026). Shielding the fetal brain: maternal vitamin D attenuates the neurodevelopmental consequences of gestational diabetes mellitus. Pediatric Research. https://doi.org/10.1038/s41390-026-05522-2

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05522-2

Keywords: vitamin D, gestational diabetes, neurodevelopment, DOHaD, fetal programming, birth cohort, 25-hydroxyvitamin D, insulin resistance, C-peptide, placenta, epigenetics, Pediatric Research

The embryology behind the condition is elegantly precise. The pancreas forms from two outgrowths of the primitive foregut: a ventral bud and a dorsal bud. The ventral bud gives rise to the head of the pancreas and its uncinate process, whereas the dorsal bud builds the majority of the organ, including the neck, body, and tail, along with the accessory duct of Santorini. When the dorsal bud never appears, the distal pancreas simply does not exist. The clinical consequences can range from complete silence, discovered only incidentally, to abdominal pain, acute or recurrent pancreatitis, exocrine pancreatic insufficiency, and diabetes mellitus. The diabetes is thought to follow directly from the missing tissue: a substantial fraction of the insulin-producing beta cells reside in the body and tail, so their congenital absence reduces endocrine reserve from the very start of life.

In the weeks before his emergency presentation, the young man had been losing weight, roughly four kilograms over eight weeks, and had developed the classic warning signs of rising blood sugar: excessive urination and unquenchable thirst. He had also noticed intermittent discomfort after meals. On the day of admission, the picture crystallized. His blood glucose measured an alarming 412 milligrams per deciliter, his urine tested strongly positive for ketones, and his venous pH of 7.31 with a bicarbonate of 17.2 milliequivalents per liter indicated mild metabolic acidosis, treated clinically as mild diabetic ketoacidosis. At the same time, his serum lipase of 486 units per liter and amylase of 312 units per liter both exceeded their upper reference limits more than threefold, and combined with his epigastric pain and imaging evidence of peripancreatic inflammation, this satisfied the standard diagnostic criteria for acute pancreatitis.

Contrast-enhanced computed tomography delivered the decisive finding. The scan showed complete absence of the pancreatic neck, body, and tail distal to the splenic vein, together with an enlarged pancreatic head measuring 4.1 centimeters in its anteroposterior diameter, minimal peripancreatic fat stranding, and no signs of necrosis, pseudocyst, or fluid collections. A subtle but diagnostically valuable clue, the dependent stomach sign, was also present: with the distal pancreas missing, the stomach settles into the space it would normally occupy. Magnetic resonance cholangiopancreatography, performed eight weeks after discharge, added ductal confirmation by demonstrating a preserved ventral pancreatic duct, the duct of Wirsung, and a completely absent dorsal pancreatic duct, the duct of Santorini. Together, the morphological and ductal evidence established the congenital nature of the defect beyond reasonable doubt.

Reaching that conclusion required excluding a long list of impostors. Pancreatic lipomatosis, in which functioning tissue is replaced by fat, can create the illusion of a missing gland. Chronic pancreatitis can cause distal atrophy and ductal changes, but this patient had no history of chronic inflammation. Prior trauma, necrotizing pancreatitis, or surgery were ruled out by his history. A pancreatic tumor was considered unlikely given his age and the absence of any discrete mass or obstructive lesion on imaging. The etiological workup for pancreatitis also came back clean: triglycerides of 184 milligrams per deciliter and calcium of 9.1 milligrams per deciliter excluded the two major metabolic causes, liver enzymes showed no evidence of biliary obstruction, no gallstones were seen, and the patient denied alcohol, tobacco, drugs, and relevant medications.

The diabetes workup proved equally revealing. Twelve weeks after admission, his fasting C-peptide level was just 0.31 nanograms per milliliter, confirming profoundly low insulin production, while tests for the GAD65, IA-2A, and ZnT8 autoantibodies, the immunological fingerprints of classic type 1 diabetes, were all negative. This combination, severe insulin deficiency without autoimmune markers, in the presence of a major structural pancreatic defect, points toward a structural rather than autoimmune explanation. The authors were careful, however, not to over-classify. Type 3c diabetes, or pancreatogenic diabetes, formally requires evidence of exocrine pancreatic insufficiency in addition to structural disease and absent autoimmunity. In this patient, fecal elastase measured 210 micrograms per gram, within acceptable range, and there was no steatorrhea or malabsorption, so the team preferred the more cautious description of diabetes associated with dorsal pancreatic agenesis and severe insulin deficiency.

Treatment followed established pathways for both conditions simultaneously. The patient received intravenous fluid resuscitation, insulin infusion, analgesia, electrolyte monitoring, and a gradual reintroduction of oral feeding, and his abdominal symptoms resolved without any surgical intervention. Because his admission potassium of 4.3 milliequivalents per liter was normal, no supplementation was needed before starting insulin. He was discharged on a basal-bolus regimen combining once-nightly glargine insulin with pre-meal lispro. Pancreatic enzyme replacement was deliberately withheld given his preserved exocrine function. By week twelve, his fasting glucose ranged from 110 to 140 milligrams per deciliter and postprandial values from 140 to 180, his HbA1c had fallen from 9.73 percent to 7.1 percent, and he had experienced no hypoglycemic episodes, no recurrence of abdominal pain, and no further attacks of pancreatitis.

The case also carries an instructive lesson about the limits of diagnostic imaging. An initial ultrasound described the pancreatic body and tail as normal, but retrospective review showed this reflected inadequate visualization rather than genuine confirmation, a discrepancy fully explained by the well-known difficulty of imaging the distal pancreas through the stomach. The authors were similarly transparent about their own limitations: the only archived CT images were labeled as plain scans, preventing independent verification of the contrast phase, β-hydroxybutyrate levels were never measured, the paired glucose reference for the C-peptide test was not recorded, genetic testing was not performed, and follow-up lasted only twelve weeks. These caveats matter, because they remind readers that even striking case reports rest on imperfect data, and that the enlarged pancreatic head seen during active pancreatitis could reflect inflammatory edema rather than true compensatory hypertrophy.

What makes this report resonate beyond its rarity is the diagnostic challenge it poses to routine thinking. Diabetes in an 18-year-old is usually presumed to be autoimmune type 1 disease, and most of the time that presumption is correct. But this case demonstrates why severe new-onset diabetes deserves a structural look at the pancreas itself. Dorsal pancreatic agenesis has been linked to mutations in developmental genes such as GATA6, a recognized cause of human pancreatic agenesis, and recessive regulatory mutations in PTF1A have been described in isolated pancreatic agenesis, although no molecular mechanism could be attributed in this patient without genetic testing. Compared with previously published cases, including a systematic review of 53 patients and individual reports of DPA with diabetes or ketoacidosis, this patient stands out for the simultaneous occurrence of complete dorsal agenesis, acute pancreatitis, and antibody-negative severe insulin deficiency in one young man. The message for clinicians is clear: when the pancreas is missing half of itself, the diagnosis of diabetes should rest on imaging, C-peptide levels, and antibody studies together, not on age or assumption alone.

Subject of Research: Dorsal pancreatic agenesis presenting with new-onset diabetes and acute pancreatitis

Article Title: Dorsal Pancreatic Agenesis Associated With New‐Onset Diabetes Mellitus and Acute Pancreatitis in an 18‐Year‐Old Man: A Case Report

Article References: Rab, M., Javaid, M. H., Numani, R. N., Khanam, F., Khalid, M., & Segawa, F. (2026). Dorsal Pancreatic Agenesis Associated With New‐Onset Diabetes Mellitus and Acute Pancreatitis in an 18‐Year‐Old Man: A Case Report. Clinical Case Reports, 14(10), Article e73606. https://doi.org/10.1002/ccr3.73606

Image Credits: AI Generated

DOI: 10.1002/ccr3.73606

Keywords: dorsal pancreatic agenesis, pancreatitis, diabetes mellitus, diabetic ketoacidosis, C-peptide, MRCP, congenital anomaly, pancreatic imaging, type 3c diabetes, GATA6, insulin deficiency, case report