Ghrelin responses to oral glucose and reactive hypoglycemia across BMI categories

Background Reactive hypoglycemia (RH) is increasingly recognized across the spectrum of adiposity; however, little is known about whether ghrelin changes measured during an OGTT differ across BMI categories in individuals with RH. Ghrelin is a key regulator of energy homeostasis, yet its behavior during the hypoglycemic phase of the oral glucose tolerance test (OGTT) remains poorly characterized. Methods A total of 150 adults were enrolled and stratified by BMI into normal-weight (<25 kg/m²), overweight (25–29.9 kg/m²), and obese (≥30 kg/m²) groups. Each category included participants with and without RH, defined as symptomatic criteria of RH and plasma glucose <70 mg/dL concentration during OGTT. Anthropometric, biochemical, and hormonal parameters were assessed, including glucose, insulin, HOMA-IR, lipid profile, 25(OH) vitamin D, and body composition (InBody 220). Serum ghrelin concentrations were measured at fasting (0′), 60 minutes, and during the hypoglycemic phase using enzyme-linked immunosorbent assay (ELISA). Statistical analyses included between-group comparisons, correlation analyses, correction for multiple testing using the Holm method, and linear mixed-effects modeling to evaluate repeated ghrelin measurements during OGTT. Results Ghrelin concentrations decreased from fasting baseline to 60 minutes in both RH and control participants across BMI categories. Pairwise RH–control comparisons at either time point were not significant after Holm correction. In the mixed-effects model, ghrelin concentrations were lower in the RH group (β = −522.11, 95% CI −994.40 to −49.81, p = 0.030), but the time × RH interaction was not significant, indicating no detected difference in the early change between RH and control participants. The early ghrelin response differed across BMI categories (time × BMI-category interaction: p = 0.021), with a significant ordered trend ( p = 0.044). Across all participants, the signed change from baseline to 60 minutes correlated negatively with BMI ( r = −0.33, p = 0.002), WHR ( r = −0.232, p = 0.006), fasting insulin ( r = −0.28, p = 0.01), HOMA-IR ( r = −0.31, p = 0.003), and triglycerides ( r = −0.27, p = 0.02). Among participants with RH, ghrelin was higher at the documented hypoglycemic time point than at 60 minutes. In unadjusted analyses, the 60-minute-to-hypoglycemia change ( p = 0.042) and relative late increase ( p = 0.046) differed across BMI categories, with the smallest changes observed in participants with obesity. However, after accounting for the variable timing of hypoglycemia, the association between BMI category and ΔGhrelin (Hypo–60′) was no longer statistically significant ( p = 0.054). Conclusions The early ghrelin response to oral glucose differed across BMI categories, whereas no difference in the early response was detected between participants with and without RH. The observed BMI-related differences in the later change among participants with RH were not maintained after accounting for the timing of hypoglycemia. Because late ghrelin was not measured in controls, the increase observed at the hypoglycemic time point cannot be attributed specifically to hypoglycemia.