We provide an exhaustive dissection of the endocrine mechanisms driving ketogenesis, challenging the canonical "insulin-deficiency" model by integrating novel data on human pancreatic α-cell SGLT1 expression, renal sodium-monocarboxylate transporter (SMCT) upregulation, and the newly elucidated arginine vasopressin (AVP)-V1b receptor axis which mechanistically links dehydration to hyperglucagonemia. This evidence concerns the gene SLC5A8 and hyperinsulinemic hypoglycemia, familial, 4.