Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channel
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 studied wider abnormalities in the β-cell and other pancreatic lineages. Islets were disorganized in CHI-D c...
| Hoofdauteurs: | , , , , , , , , , , , , , , , |
|---|---|
| Formaat: | Journal article |
| Taal: | English |
| Gepubliceerd in: |
American Diabetes Association
2015
|
| _version_ | 1826256916985151488 |
|---|---|
| author | Salisbury, R Han, B Jennings, R Berry, A Stevens, A Mohamed, Z Sugden, S De Krijger, R Cross, S Johnson, P Newbould, M Cosgrove, K Hanley, K Banerjee, I Dunne, M Hanley, N |
| author_facet | Salisbury, R Han, B Jennings, R Berry, A Stevens, A Mohamed, Z Sugden, S De Krijger, R Cross, S Johnson, P Newbould, M Cosgrove, K Hanley, K Banerjee, I Dunne, M Hanley, N |
| author_sort | Salisbury, R |
| collection | OXFORD |
| description | 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 studied wider abnormalities in the β-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared with controls. PAX4 and ARX expression was decreased. A tendency toward increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas, and implied immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. In CHI-D, increased proliferation was most elevated in duct (5- to 11-fold) and acinar (7- to 47-fold) lineages. Increased β-cell proliferation observed in some cases was offset by an increase in apoptosis; this is 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 with 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. |
| first_indexed | 2024-03-06T18:09:52Z |
| format | Journal article |
| id | oxford-uuid:02a39e05-5d8d-44de-b769-c10e01010375 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:09:52Z |
| publishDate | 2015 |
| publisher | American Diabetes Association |
| record_format | dspace |
| spelling | oxford-uuid:02a39e05-5d8d-44de-b769-c10e010103752022-03-26T08:41:52ZAltered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channelJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:02a39e05-5d8d-44de-b769-c10e01010375EnglishSymplectic Elements at OxfordAmerican Diabetes Association2015Salisbury, RHan, BJennings, RBerry, AStevens, AMohamed, ZSugden, SDe Krijger, RCross, SJohnson, PNewbould, MCosgrove, KHanley, KBanerjee, IDunne, MHanley, NDiffuse 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 studied wider abnormalities in the β-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared with controls. PAX4 and ARX expression was decreased. A tendency toward increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas, and implied immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. In CHI-D, increased proliferation was most elevated in duct (5- to 11-fold) and acinar (7- to 47-fold) lineages. Increased β-cell proliferation observed in some cases was offset by an increase in apoptosis; this is 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 with 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. |
| spellingShingle | Salisbury, R Han, B Jennings, R Berry, A Stevens, A Mohamed, Z Sugden, S De Krijger, R Cross, S Johnson, P Newbould, M Cosgrove, K Hanley, K Banerjee, I Dunne, M Hanley, N Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channel |
| title | Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channel |
| title_full | Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channel |
| title_fullStr | Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channel |
| title_full_unstemmed | Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channel |
| title_short | Altered phenotype of β-cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the ATP-sensitive K-channel |
| title_sort | altered phenotype of β cells and other pancreatic cell lineages in patients with diffuse congenital hyperinsulinism in infancy caused by mutations in the atp sensitive k channel |
| work_keys_str_mv | AT salisburyr alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT hanb alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT jenningsr alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT berrya alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT stevensa alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT mohamedz alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT sugdens alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT dekrijgerr alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT crosss alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT johnsonp alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT newbouldm alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT cosgrovek alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT hanleyk alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT banerjeei alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT dunnem alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel AT hanleyn alteredphenotypeofbcellsandotherpancreaticcelllineagesinpatientswithdiffusecongenitalhyperinsulinismininfancycausedbymutationsintheatpsensitivekchannel |