Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade.

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.

The role of potassium and other ions in the control of aldosterone synthesis.

Fast and slow K+ efflux components, independently regulated by angiotensin II (AII), have been identified in bovine adrenocortical cells. We have further investigated the role of potassium in the control of aldosterone synthesis in two ways. Firstly, isotopic tracers, in conjunction with channel modulators, have been used to study the interrelationship of K+ and Ca2+ in the control of AII-stimulated aldosterone synthesis. Secondly, electron probe X-ray microanalysis (EPXMA) was used to quantify potassium, sodium, chlorine and phosphorous in control and AII-stimulated cells. The effects of verapamil on 43K efflux were measured at two stages during AII stimulation. During the first ten minutes of treatment, when efflux via the fast component predominates, AII and verapamil both slowed efflux and their effects were additive. If verapamil was added later, at the time when efflux by the fast component appeared exhausted and the stimulatory effect of AII on the slow efflux component was apparent, it again slowed efflux. These data suggest that verapamil prevents calcium-gated K+ channels from opening by blocking Ca2+ channels. However, verapamil had no effect on AII-stimulated calcium efflux. In addition to blocking Ca2+ channels, verapamil may directly inhibit potassium efflux. EPXMA showed a bimodal distribution of potassium concentrations in control cells. However, in cells stimulated with AII for five minutes, the mean potassium content was less than in controls and was not bimodally distributed. Sodium content was increased by AII-treatment, chlorine was lowered and phosphorus remained unchanged. The data confirm previous observations that AII inhibits Na+/K+ ATPase activity.