THERAPY FOR PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA OF INFANCY - UNDERSTANDING THE RESPONSIVENESS OF BETA-CELLS TO DIAZOXIDE AND SOMATOSTATIN

The neonatal disorder persistent hyperinsulinemic hypoglycemia of infa ncy (PHHI) arises as the result of mutations in the subunits that form the ATP-sensitive potassium (K-ATP) channel in pancreatic beta cells, leading to insulin hypersecretion, Diazoxide (a specific K-ATP channe l agonist in normal beta cells) and somatostatin (octreotide) are the mainstay of medical treatment for the condition, To investigate the me chanism of action of these agents in PHHI beta cells that lack K-ATP c urrents, we applied patch clamp techniques to insulin-secreting cells isolated from seven patients with PHHI. Five patients showed favorable responses to medical therapy, and two were refractory. Our data revea l, in drug-responsive patients, that a novel ion channel is modulated by diazoxide and somatostatin, leading to termination of the spontaneo us electrical events that underlie insulin hypersecretion. The drug-re sistant patients, both of whom carried a mutation in one of the genes that encode K-ATP channel subunits, also lacked this novel K+ channel. There were no effects of diazoxide and somatostatin on beta cell func tion in vitro. These findings elucidate for the first time the mechani sms of action of diazoxide and somatostatin in infants with PHHI in wh om K-ATP channels are absent, and provide a rationale for development of new therapeutic opportunities by K+ channel manipulation in PHHI tr eatment.