p57KIP2 expression in normal islet cells and in hyperinsulinism of infancy

Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K+ channel Kir6.2, two subunits of the beta -cell ATP-sensitive K+ channel (K-ATP channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta -cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta -cell precursor carrying a germline mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, :some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta -cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta -Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with similar to1-3% in other cell types. The fraction of beta -cells expressing p57(KIP2) did not vary significantly during development. beta -Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta -cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression In beta -cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta -cell failure observed in diabetes.