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In this volume of'Frontiers in Diabetes'dealing with the molecular basis of monogenic disease of beta-cell insulin regulation, world-renowned experts provide in-depth descriptions of the many recent advances in genetic defects that cause hyperinsulinemic hypoglycemia. These disorders comprise the most important form of hypoglycemia in infants and children and are associated with a high risk of morbidity, including seizures and severe brain injury. The discovery of eight different genetic loci involved in congenital hyperinsulinism has led to greatly improved methods of diagnosis and treatment. New approaches to diagnosis are highlighted, such as 18F-DOPA PET scans for preoperative localization of focal hyperinsulinism, as well as potential new treatments, such as green tea polyphenols for GDH-HI and GLP-receptor antagonists for SUR1 and Kir6.2 hyperinsulinism. Practitioners, including pediatricians and specialists in endocrinology, surgery, genetics, pathology, and radiology, will find important up-to-date information for clinical diagnosis, management, and new treatments for infants and children with congenital hyperinsulinism. Researchers will discover how genetic hyperinsulinism disorders provide novel insights into the basic mechanisms regulating insulin secretion not only in diabetics, but also in healthy humans.