Endocrine Abstracts

Prohormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones such as pro-opiomelanocortin, proinsulin, proglucagon into biologically active peptides. Inherited genomic mutations of PCSK1 present with malabsorptive diarrhoea, hyperinsulinemic hypoglycaemia, central adrenal and thyroid defects and severe obesity. Somatic mutations of insulinomas are associated with genetic defects interfering with insulin secretion from pancreatic beta-cells. However, somatic mutations in proinsulinomas have not been described. We report a case of a 70-year old woman with a 20-years history of frequent ‘blackout’ episodes. These episodes of syncope were manifestations of severe hypoglycaemia, caused by proinsulinomas in the head and tail of the pancreas. The diagnosis was initially missed as insulin levels were appropriately low in the presence of hypoglycaemia. A 72-hour fast was conducted and the blood glucose dropped to 1.9 mmol/l 24 h into the fast. Once again, plasma insulin and C-peptide levels were suppressed, but plasma proinsulin levels were measured and raised at 37 pmol/l (<10 pmol/l). CT imaging and endoscopic ultrasound revealed three distinct lesions in the pancreas which were found to be DOTATATE-avid. A laparoscopic spleen-preserving distal pancreatomy was performed without any postoperative complications. Immunohistochemistry was positive for insulin. More than 6 years later, the patient remains very well without any episodes of hypoglycaemia. This case highlights the investigative challenge of patients harbouring a proinsulinoma. Appropriately suppressed insulin levels in the context of hypoglycaemia do not always indicate absence of a neuroendocrine islet cell tumour and measurement of proinsulin levels is indicated to solidify the diagnosis. If proinsulin levels are elevated, low insulin and C-peptide levels might be explained by absent PC1/3 activity. Whilst our patient’s molecular analysis results are currently still pending, variants in the PCSK1 gene encoding PC1/3 expression causing hyperproinsulinemia need to be considered as a possible pathomechamism.