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 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.
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, U.K.
Rachel J
RJ
Salisbury
Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
Bing
B
Han
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, U.K. Department of Endocrinology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, U.K.
Rachel E
RE
Jennings
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, U.K.
Andrew A
AA
Berry
Faculty of Life Sciences, The University of Manchester, Manchester, U.K. Department of Paediatric Endocrinology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, U.K.
Adam
A
Stevens
Faculty of Life Sciences, The University of Manchester, Manchester, U.K. Department of Paediatric Endocrinology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, U.K.
Zainab
Z
Mohamed
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, U.K.
Sarah A
SA
Sugden
Erasmus MC, Rotterdam, the Netherlands Department of Pathology, Reinier de Graaf Hospital, Delft, the Netherlands.
Ronald
R
De Krijger
Diabetes Research & Wellness Foundation Human Islet Isolation Facility, Nuffield Department of Surgical Sciences and Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
Sarah E
SE
Cross
Diabetes Research & Wellness Foundation Human Islet Isolation Facility, Nuffield Department of Surgical Sciences and Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
Paul P V
PP
Johnson
Department of Paediatric Histopathology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, U.K.
Melanie
M
Newbould
Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
Karen E
KE
Cosgrove
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, U.K.
Karen Piper
KP
Hanley
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, U.K. Department of Paediatric Endocrinology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, U.K.
Indraneel
I
Banerjee
Faculty of Life Sciences, The University of Manchester, Manchester, U.K. neil.hanley@manchester.ac.uk mark.dunne@manchester.ac.uk.
Mark J
MJ
Dunne
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, U.K. Department of Endocrinology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, U.K. neil.hanley@manchester.ac.uk mark.dunne@manchester.ac.uk.
Neil A
NA
Hanley
D016022:Case-Control Studies; D019070:Cell Lineage; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000235:genetics* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005333:Fetus / Q000166:cytology; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D019864:Somatostatin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D064233:Sulfonylurea Receptors / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D029961:Zebrafish Proteins; D000099161:Kcnj11 Channel
D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007328:Insulin; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human; C469264:ARX protein, human; C436291:CDKN1B protein, human; C000715631:NKX2-2 protein, human; C491709:PAX4 protein, human; C000715630:nkx2.2b protein, zebrafish; C495911:CDK6 protein, human