PCSK2 (proprotein convertase subtilisin/kexin type 2) is a serine endopeptidase that processes prohormone precursors at basic amino acid residue sites, with primary roles in insulin and glucagon biosynthesis 1. The enzyme processes proinsulin into mature insulin and is expressed in pancreatic beta cells where it contributes to insulin secretion 2. PCSK2 is also widely expressed in hypothalamic POMC neurons (84% of hindbrain POMC neurons express PCSK1, PCSK2, or both) where it processes neuropeptide precursors including proenkephalin and POMC, with expression regulated by CREB in response to dietary nutrients 34. The gene is additionally expressed in neuroendocrine tumors of midgut, pulmonary, and pheochromocytoma-paraganglioma origins, serving as a diagnostic marker for primary tumor location 5. Genetic variants in PCSK2 associate with type 2 diabetes and gestational diabetes mellitus susceptibility across multiple populations 167. Polymorphisms including rs2269023 and rs2021785 correlate with altered fasting glucose, insulin levels, HOMA-IR, and impaired proinsulin conversion 167. PCSK2 is expressed throughout human brain regions including the hypothalamus, consistent with neuropeptide production roles 8. This enzyme represents a pleiotropic susceptibility factor affecting glucose homeostasis and energy balance regulation.