Hyperinsulinism in Infancy (HI) is the most common cause of recurrent or persistent hypoglycaemia in early childhood, and manifests as either diffuse abnormalities of pancreatic beta-cell function (Di-HI), or focal adenomatous hyperplasia of beta-cells (Fo-HI). Di-HI is caused by defects in KATP channel genes ABCC8 (SUR1) or KCNJ11 (Kir6.2). Fo-HI arises from somatic loss of maternal heterozygosity resulting in the expression of paternally-derived mutation(s) in SUR1 or Kir6.2, and the loss of genes responsible for controlled cell growth and proliferation (i.e. H19 and p57kip2). By contrast, little is known about the molecular pathogenesis of beta-cell adenomas. We isolated tissue from 4 patients with adenoma (AD) following surgery and from 7 patients with Fo-HI. AD subjects were aged 1 month, 8.5 years, 14 years, and 79 years at the time of surgery and we have used patch-clamp techniques, immunofluorescence, RT-PCR and genetic studies to document the pathogenesis of this condition with reference to Fo-HI. All patients with AD were consistently found to possess KATP channels in beta-cells (n=36) and these responded to nucleotides, sulphonylureas and diazoxide in the normal manner. The expression of SUR1 and Kir6.2 was also confirmed by RT-PCR. By contrast, peak KATP channel values were reduced to zero in 3 patients with Fo-HI and to an average of <9% of control values in 4 others (n=20, 4/7 patients). In the AD pancreas we also confirmed the expression of p57kip2 in both the adenoma and non-adenoma portions of the pancreas.
Summary: These data document that hyperinsulinism as a consequence of adenoma has a different aetiology to that observed in Fo-HI which is due to abnormalities in the beta-cell KATP channel and beta-cell proliferation.
08 - 11 Apr 2002
British Endocrine Societies