Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy due to mutations in the ATP-sensitive K-channel.Citation formats

  • External authors:
  • Rachel Salisbury
  • Bing Han
  • Andrew A Berry
  • Z Mohamed
  • Krijger R De
  • SE Cross
  • PP Johnson
  • M Newbould
  • Indi Banerjee
  • Mark J Dunne
  • Neil Hanley

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Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy due to mutations in the ATP-sensitive K-channel. / Salisbury, Rachel; Han, Bing; Jennings, Rachel E; Berry, Andrew A; Stevens, Adam; Mohamed, Z; Sugden, Sarah; De, Krijger R; Cross, SE; Johnson, PP; Newbould, M; Cosgrove, Karen E; Piper Hanley, Karen; Banerjee, Indi; Dunne, Mark J; Hanley, Neil.

In: Diabetes, Vol. 64, No. 9, 01.09.2015, p. 3182-3188.

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@article{2a9df1361ba8409a983e3e1eaef17beb,
title = "Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy due to mutations in the ATP-sensitive K-channel.",
abstract = "Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel, however, the phenotype is difficult to explain from electrophysiology alone. Here we have studied wider abnormalities in the β-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared to control. PAX4 and ARX expression was decreased. A tendency to increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas and implying immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. Increased proliferation in CHI-D was most elevated in duct (5-11 fold) and acinar (7-47 fold) lineages. Increased β-cell proliferation observed in some cases was offset by an increase in apoptosis; in keeping with no difference in INSULIN expression or surface area stained for insulin between CHI-D and control pancreas. However, nuclear localization of CDK6 and P27 was markedly enhanced in CHI-D β-cells compared to cytoplasmic localization in control cells. These combined data support normal β-cell mass in CHI-D, but with G1/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in δ-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a β-cell disorder.",
author = "Rachel Salisbury and Bing Han and Jennings, {Rachel E} and Berry, {Andrew A} and Adam Stevens and Z Mohamed and Sarah Sugden and De, {Krijger R} and SE Cross and PP Johnson and M Newbould and Cosgrove, {Karen E} and {Piper Hanley}, Karen and Indi Banerjee and Dunne, {Mark J} and Neil Hanley",
note = "This work was supported by the Wellcome Trust (NAH, WT088566MA and WT097820MF), the Medical Research Council (RJS, PhD student, and REJ, clinical fellow), and the National Institute for Health Research (MJD, IB, KEC).",
year = "2015",
month = sep,
day = "1",
doi = "10.2337/db14-1202",
language = "English",
volume = "64",
pages = "3182--3188",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association ",
number = "9",

}

RIS

TY - JOUR

T1 - Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy due to mutations in the ATP-sensitive K-channel.

AU - Salisbury, Rachel

AU - Han, Bing

AU - Jennings, Rachel E

AU - Berry, Andrew A

AU - Stevens, Adam

AU - Mohamed, Z

AU - Sugden, Sarah

AU - De, Krijger R

AU - Cross, SE

AU - Johnson, PP

AU - Newbould, M

AU - Cosgrove, Karen E

AU - Piper Hanley, Karen

AU - Banerjee, Indi

AU - Dunne, Mark J

AU - Hanley, Neil

N1 - This work was supported by the Wellcome Trust (NAH, WT088566MA and WT097820MF), the Medical Research Council (RJS, PhD student, and REJ, clinical fellow), and the National Institute for Health Research (MJD, IB, KEC).

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel, however, the phenotype is difficult to explain from electrophysiology alone. Here we have studied wider abnormalities in the β-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared to control. PAX4 and ARX expression was decreased. A tendency to increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas and implying immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. Increased proliferation in CHI-D was most elevated in duct (5-11 fold) and acinar (7-47 fold) lineages. Increased β-cell proliferation observed in some cases was offset by an increase in apoptosis; in keeping with no difference in INSULIN expression or surface area stained for insulin between CHI-D and control pancreas. However, nuclear localization of CDK6 and P27 was markedly enhanced in CHI-D β-cells compared to cytoplasmic localization in control cells. These combined data support normal β-cell mass in CHI-D, but with G1/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in δ-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a β-cell disorder.

AB - Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel, however, the phenotype is difficult to explain from electrophysiology alone. Here we have studied wider abnormalities in the β-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared to control. PAX4 and ARX expression was decreased. A tendency to increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas and implying immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. Increased proliferation in CHI-D was most elevated in duct (5-11 fold) and acinar (7-47 fold) lineages. Increased β-cell proliferation observed in some cases was offset by an increase in apoptosis; in keeping with no difference in INSULIN expression or surface area stained for insulin between CHI-D and control pancreas. However, nuclear localization of CDK6 and P27 was markedly enhanced in CHI-D β-cells compared to cytoplasmic localization in control cells. These combined data support normal β-cell mass in CHI-D, but with G1/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in δ-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a β-cell disorder.

U2 - 10.2337/db14-1202

DO - 10.2337/db14-1202

M3 - Article

C2 - 25931474

VL - 64

SP - 3182

EP - 3188

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -