Therapy for Persistent Hyperinsulinemic Hypoglycemia of Infancy

The neonatal disorder persistent hyperinsulinemic hypoglycemia of infancy (PHHI) arises as the result of mutations in the subunits that form the ATP-sensitive potassium (K ATP ) channel in pancreatic b cells, leading to insulin hypersecretion. Diazoxide (a specific K ATP channel agonist in normal b cells) and somatostatin (octreotide) are the mainstay of medical treatment for the condition. To investigate the mechanism of action of these agents in PHHI b cells that lack K ATP currents, 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 reveal, in drugresponsive patients, that a novel ion channel is modulated by diazoxide and somatostatin, leading to termination of the spontaneous electrical events that underlie insulin hypersecretion. The drug-resistant patients, both of whom carried a mutation in one of the genes that encode K ATP channel subunits, also lacked this novel K 1 channel. There were no effects of diazoxide and somatostatin on b cell function in vitro. These findings elucidate for the first time the mechanisms of action of diazoxide and somatostatin in infants with PHHI in whom K ATP channels are absent, and provide a rationale for development of new therapeutic opportunities by K 1 channel manipulation in PHHI treatment. ( J. Clin. Invest. 1997. 100:1888–1893.)