Proinsulinoma Unmasked by Intermittent Fasting: A Case of Endogenous Proinsulinaemic Hypoglycaemia

We report a 45-year-old man with recurrent fasting and post-prandial hypoglycaemia due to a proinsulin (PI)-secreting pancreatic neuroendocrine tumour (NET). During a supervised fast, plasma glucose fell to 1.8 mmol/L with detectable but low insulin (0.6 μU/L) and C-peptide (range 0.3-0.6 nmol/L). These concentrations did not meet diagnostic thresholds for endogenous hyperinsulinaemia proposed by the Endocrine Society, The North American Neuroendocrine Tumor Society (NANETS), or European Neuroendocrine Tumor Society (ENETS). In contrast, PI was markedly elevated at 33 pmol/L, exceeding all guideline cut-offs (≥5 pmol/L) and establishing PI-mediated hypoglycaemia. Cross-sectional imaging demonstrated a 16-mm arterially enhancing lesion in the pancreatic body, with intense somatostatin receptor expression on DOTATATE PET (SUVmax 18.0) and no evidence of metastatic disease. Histopathology confirmed a Grade 1 pancreatic NET, consistent with a localised proinsulinoma. This case highlights a diagnostic pitfall associated with contemporary insulin immunoassays, which have limited cross-reactivity with PI and may yield deceptively low insulin levels despite clinically significant endogenous hyperinsulinism. Routine measurement of PI during fasting evaluation is essential, particularly when insulin or C-peptide results appear discordant with the clinical phenotype, to avoid delayed diagnosis and facilitate timely curative intervention.