Hyperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder that occurs in ~1 of 50,000 live births. Histologically, pancreases from HI patients can be divided into 2 major groups. In the first, diffuse HI, ␤-cell distribution is similar to that seen in normal neonatal pancreas, whereas in the second, focal HI, there is a discrete region of ␤-cell adenomatous hyperplasia. In most patients, the clinical course of the disease suggests a slow progressive loss of ␤-cell function. Using double immunostaining, we examined the proportion of ␤-cells undergoing proliferation and apoptosis during the development of the normal human pancreas and in pancreases from diffuse and focal HI patients. In the control samples, our findings show a progressive decrease in ␤-cell proliferation from 3.2 ± 0.5% between 17 and 32 weeks of gestation to 0.13 ± 0.08% after 6 months of age. In contrast, frequency of apoptosis is low (0.6 ± 0.2%) in weeks 17-32 of gestation, elevated (1.3 ± 0.3%) during the perinatal period, and again low (0.08 ± 0.3%) after 6 months of age. HI ␤-cells showed an increased frequency of proliferation, with focal lesions showing particularly high levels. Similarly, the proportion of apoptotic cells was increased in HI, although this reached statistical significance only after 3 months of age. In conclusion, we demonstrated that islet remodeling normally seen in the neonatal period may be primarily due to a wave of ␤-cell apoptosis that occurs at that time. In HI, our findings of persistently increased ␤-cell proliferation and apoptosis provide a possible mechanism to explain the histologic picture seen in diffuse disease. The slow progressive decrease in insulin secretion seen clinically in these patients suggests that the net effect of these phenomena may be loss of ␤-cell mass. Diabetes 49: 1325-1333, 2000 H yperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder, the molecular basis of which was recently elucidated. Most cases are caused by mutations in either the sulfonylurea receptor (SUR1) or the inward rectifying potassium channel (Kir6.2), 2 subunits of the ␤-cell K ATP channel (1-5). A minority of patients have glucokinase or glutamate dehydrogenase mutations, whereas in 40-50% of the patients, the genetic cause of the disease is still not known (4-7).The histologic appearance of the pancreases from affected children can be subdivided into 2 major forms: diffuse HI and focal HI (8-10). The former is more common and bears some characteristics of nesidioblastosis, a phenomenon observed in the healthy fetus and newborn but which normally evolves during the first year of life into the adult-type architecture (9,11,12). In diffuse HI, the neonatal-type ␤-cell distribution persists (8,13).Focal HI is generally easily recognized as a discrete region of adenomatous hyperplasia (8), whereas the rest of the pancreas appears normal for its age. Focal HI is caused by the somatic l...

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Type 1 diabetes is an incurable disease that is currently treated by insulin injections or in rare cases by islet transplantation. We have recently shown that NKp46, a major killer receptor expressed by NK cells, recognizes an unknown ligand expressed by β cells and that in the absence of NKp46, or when its activity is blocked, diabetes development is inhibited. In this study, we investigate whether NKp46 is involved in the killing of human β cells that are intended to be used for transplantation, and we also thoroughly characterize the interaction between NKp46 and its human and mouse β cell ligands. We show that human β cells express an unknown ligand for NKp46 and are killed in an NKp46-dependent manner. We further demonstrate that the expression of the NKp46 ligand is detected on human β cells already at the embryonic stage and that it appears on murine β cells only following birth. Because the NKp46 ligand is detected on healthy β cells, we wondered why type 1 diabetes does not develop in all individuals and show that NK cells are absent from the vicinity of islets of healthy mice and are detected in situ in proximity with β cells in NOD mice. We also investigate the molecular mechanisms controlling NKp46 interactions with its β cell ligand and demonstrate that the recognition is confined to the membrane proximal domain and stalk region of NKp46 and that two glycosylated residues of NKp46, Thr125 and Asn216, are critical for this recognition.

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 ␤-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 ␤-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 ␤-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 ␤-cells from patients with focal HI (n ‫؍‬ 8). Within the pancreas, p57 KIP2 was specifically localized to the endocrine portion. ␤-Cells demonstrated the highest frequency of expression (34.9 ؎ 2.7%) compared with ϳ1-3% in other cell types. The fraction of ␤-cells expressing p57 KIP2 did not vary significantly during development. ␤-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 ␤-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 ␤-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the ␤-cell failure observed in diabetes.

In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.