Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.

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We examined the effects of removing extracellular Ca2+ (Ca2+e), depleting intracellular Ca2+ (Ca2+i), inhibiting Ca2(+)-dependent calmodulin, blocking voltage-sensitive Ca2+ channels, and combining Ca2+i depletion with exposure to glucocorticoid on the secretion of ACTH by perifused dispersed rat anterior pituitary cells stimulated with ovine CRF and 8-bromo-cAMP (8-Br-cAMP). A time-course analysis of the effect of perifusing the cells for 60 min with Ca2(+)-free medium on 10 nM CRF-stimulated ACTH release revealed that inhibition required about 3 min to begin and about 40 min to reach maximal effect. Within 2 min of restoring Ca2+ to the medium, ACTH secretion rebounded for about 5 min before falling to the pre-Ca2+e removal rate. A similar pattern and time course were observed when Ca2+e was more completely removed by perifusing the cells with Ca2(+)-free medium containing 2 mM EGTA, except that greater suppression was observed. Removing Ca2+e reduced CRF- and 5 mM 8-Br-cAMP-induced ACTH release by 54% and 49%, respectively, and delayed by 1 min the response to 8-Br-cAMP, but not that to CRF. Perifusing 0.2 mM nimodipine, a dihydropyridine Ca2+ channel blocker, before and after restoration of Ca2+ to the Ca2(+)-free medium inhibited ACTH release by 40-48%, and the blockade persisted for at least 70 min after nimodipine was removed from the medium. When intracellular Ca2+ was depleted by perifusing the cells with Ca2(+)-free/EGTA medium containing the Ca2+ ionophore A23187 to facilitate the efflux of Ca2+i, CRF- and 8-Br-cAMP-stimulated ACTH release were reduced by 70% and 71%, respectively, and the responses to both agents were delayed by 1 min. Preperifusion of the cells with 5 microM penfluridol, a calmodulin inhibitor, reduced CRF- and 8-Br-cAMP-induced ACTH release by 54% and 41%, respectively. The combination of Ca2+i depletion and perifusion with 100 nM dexamethasone, a maximally inhibitory concentration, inhibited CRF- and 8-Br-cAMP-stimulated ACTH release by 82% and 83%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)