Clinical and Biochemical Characteristics of Non-Diabetic Hypoglycemia in a Tertiary Care Cohort

Non-diabetic hypoglycemia is a heterogeneous condition with diverse etiologies and remains a diagnostic challenge in clinical practice. This study aimed to characterize the clinical and biochemical features of patients evaluated for non-diabetic hypoglycemia and to assess the diagnostic utility of the supervised prolonged fasting test in distinguishing reactive hypoglycemia from endogenous hyperinsulinemic conditions. This retrospective observational study included 92 non-diabetic adults evaluated for suspected hypoglycemia at a tertiary referral center between 2020 and 2023. Demographic, clinical, laboratory, and fasting test data were reviewed. All patients underwent a standardized supervised prolonged fasting test, and biochemical parameters were analyzed according to final etiological diagnosis. Reactive hypoglycemia was diagnosed in 80 patients (87.0%), while insulinoma or other neuroendocrine tumors (NETs) were identified in 12 patients (13.0%). Compared with reactive hypoglycemia, patients with insulinoma/NET had significantly lower plasma glucose levels (39.73 ± 9.74 vs. 55.38 ± 9.69 mg/dL, p < 0.001), higher insulin levels (6.17 vs. 2.57 μIU/mL, p = 0.010), and higher C-peptide concentrations (2.50 vs. 0.88 ng/mL, p = 0.006). The median time to hypoglycemia during fasting was shorter in the insulinoma/NET group (47 vs. 72 hours, p < 0.001). No significant differences were observed in HbA1c, HOMA-IR, vitamin D, or hematological indices. The supervised prolonged fasting test, combined with glucose, insulin, and C-peptide measurements, effectively differentiated endogenous hyperinsulinemic hypoglycemia from reactive hypoglycemia. Earlier onset of hypoglycemia during fasting provided additional diagnostic value beyond standard biochemical parameters. Prospective studies with larger cohorts are needed to confirm these findings.