p57KIP2 Expression in Normal Islet Cells and in Hyperinsulinism of Infancy
- S. A. Kassem1,
- I. Ariel2,
- P. S. Thornton3,
- K. Hussain4,
- V. Smith4,
- K. J. Lindley4,
- A. Aynsley-Green4 and
- B. Glaser1
- 1Department of Endocrinology and Metabolism, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
- 2Department of Pathology, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
- 3Division of Endocrinology/Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
- 4London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children National Health Service Trust and the Institute of Child Health, University College London, U.K.
Abstract
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 β-cell ATP-sensitive K+ channel (KATP channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all β-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 β-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 p57KIP2 and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57KIP2 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 β-cells from patients with focal HI (n = 8). Within the pancreas, p57KIP2 was specifically localized to the endocrine portion. β-Cells demonstrated the highest frequency of expression (34.9 ± 2.7%) compared with ∼1–3% in other cell types. The fraction of β-cells expressing p57KIP2 did not vary significantly during development. β-Cells within the focal lesions did not express p57KIP2, whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57KIP2 is expressed and is paternally imprinted in human pancreatic β-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57KIP2 expression in β-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the β-cell failure observed in diabetes.
Footnotes
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Address correspondence and reprint requests to Benjamin Glaser, Director, Endocrinology and Metabolism Service, Hebrew University, Hadassah Medical Center, POB 12000, 91120 Jerusalem, Israel. E-mail: beng{at}cc.huji.ac.il.
Received for publication 11 May 2001 and accepted in revised form 17 September 2001.
Cdk, cyclin-dependent kinase; HI, hyperinsulinism of infancy; IOD, integrated optical density; KATP, ATP-sensitive K+ channel; LOH, loss of heterozygosity; SUR1, sulfonylurea receptor-1.
