ESPE Abstracts

Congenital Hyperinsulinism (CHI) is primarily associated with defects in the regulated release of insulin from ß-cells but little information is available about the role of other islet cell types. Pancreatic polypeptide (PP) cells represent a minor component of the islet endocrine cell population. PP causes satiety, decreases gastrointestinal tract motility and suppresses glucagon release. Since CHI is associated with feeding problems and loss of glucagon-mediated counter-regulatory responses to hypoglycaemia, we hypothesised the involvement of PP in the pathophysiology of CHI and investigated the expression of PP cells in pancreatic tissue.

Methods: We analysed tissue from 28 patients with either focal (CHI-F) (n = 17) or diffuse (CHI-D) (n = 11) CHI. All patients had confirmed mutations in either KCNJ11 or ABCC8. Gene expression studies were performed using Affymetrix Human Transcriptome Arrays (HTA 2.0) and protein expression was assessed by immunohistochemistry and electron microscopy.

Results: All patients experienced feeding problems during the early stages of diagnosis and treatment of CHI. These were identified as difficulty with sucking, swallowing, vomiting, and feed aversion (or a combination). In 82% of CHI-F cases, feeding problems ameliorated within 4-8 weeks following surgery. By contrast 80% of patients with CHI-D continued to experience feeding difficulties for more than 2 years after surgery. In CHI-D patients with genomic defects in all islet cells in the pancreas, we found no alteration in either the expression of PPY, the incidence of PP cells within islets (<1% of cells, n = 46,960) or the fraction of islet cells expressing pancreatic polypeptide (33 ± 5%, n = 8 cases, n = 425 islets) compared to age-matched control tissue. In marked contrast, in CHI-F lesions (resulting from somatic events that cause expansion of ß-cells and the paternal inheritance of ABCC8/KCNJ11) defects trigger a marked increase in PPY expression (P < 0.0001) and a greater than 30-fold increase in the population of PP cells. We found no evidence from gene transcript profiling for the loss of ß-cell identity and PP secretory granules were not seen in other populations of islet cells by electron microscopy.

Conclusion: We conclude that increased islet PP cell frequency is not directly and causally correlated to ABCC8/KCNJ11 defects. The consistent association of increased islet PP with CHI-F may indicate that inappropriate endocrine signalling has a significant impact upon the phenotype of disease and may prove valuable in diagnosing CHI-F.