Hyperinsulinism (HI) is the most common cause of persistent hypoglycemia across the life span. In children, HI is more commonly congenital due to genetic defects in the insulin secretory pathway, while in adults, HI is typically due to an insulin-secreting tumor. There are multiple genetic forms of HI, but the most common and severe form is due to inactivating mutations of the beta cell KATP channels. This form of hyperinsulinism can be diffuse or focal. Focal hyperinsulinism can be cured by surgical removal of the lesion. The diagnosis of HI is established by the demonstration that insulin secretion/actions are not appropriately turned off during hypoglycemia, however, one must be aware that during evaluation and diagnoses plasma insulin concentrations are not always elevated in hyperinsulinism.
The first line of therapy for HI is diazoxide, a KATP channel opener. Lack of responsiveness to diazoxide suggest that the hyperinsulinism is due to a KATP channel mutation, and therefore, the possibility of focal hyperinsulinism should be considered and genetic testing should be promptly obtained. The finding of a recessive paternally inherited mutation in either one of the two genes encoding the KATP channel has a sensitivity of 97% for focal hyperinsulinism. When focal hyperinsulinism is suspected, specialized imaging with 18FDOPA PET for lesion localization and surgical resection is indicated. For diffuse diazoxide-unresponsive cases, somatostatin analogues are the second line of therapy and when this fails, a pancreatectomy may be required. Multiple new therapies for HI are under development and promise to make possible a personalized approach to treatment to improve long-term outcome.