[p57.sup.KIP2] 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.sup.+] channel Kir6.2, two subunits of the [beta]-cell ATP-sensitive [K.sup.+] channel ([K.sub.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 germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including [p57.sup.KIP2] and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined [p57.sup.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.sup.KIP2] was specifically localized to the endocrine portion. [beta]-Cells demonstrated the highest frequency of expression (34.9 [+ or -] 2.7%) compared with ~1-3% in other cell types. The fraction of [beta]-cells expressing [p57.sup.KIP2] did not vary significantly during development. [beta]-cells within the focal lesions did not express [p57.sup.KIP2], whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that [p57.sup.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.sup.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.