Gene expression and cell cycle regulation in human pancreas development and congenital hyperinsulinism

  • Rachel Salisbury

    Student thesis: Unknown


    The dynamics of β-cell mass are at the focus of an extensive international effort to develop β-cell replacement therapies for type 1 diabetes. During normal fetal development endocrine cells emerge from a pool of PDX1+/SOX9+ multipotent progenitors that transiently express the proendocrine gene NGN3. These cells become hormone-positive and are seen to bud from the ductal structures and aggregate into islet clusters. Congenital hyperinsulinism in its diffuse form (CHI-D) is characterised by an increase in hormone-positive cells associated with ducts and diffuse patterns of insulin expression. CHI-D arises from mutations inactivating the KATP channel and is diagnosed following persistent episodes of hypoglycaemia caused by an inappropriate secretion of insulin. Whilst existing knowledge has focused on the β-cell, we have explored the histology of CHI-D across multiple pancreatic cell lineages. The starting hypothesis considered CHI-D as an over-exuberance of endocrine differentiation with a progenitor population underlying this process. We suggest CHI-D is not simply an excessive proliferation of pre-existing β-cells. Expression of many transcription factors involved in endocrine differentiation were unchanged in CHI-D, NKX2.2 was increased and persisted in delta-cells. The incidence of nucleomegaly was also confirmed in CHI-D samples, predominantly in the β- and delta-cell lineages. Whilst increases in endocrine cell proliferation were subtle, the ductal and acinar cell lineages had significantly elevated proliferation correlating with changes in cell cycle regulation. The expression of NGN3 was profiled in a range of human fetal samples to determine whether a competence window for endocrine differentiation exists during development. Peak expression was observed between 10-17 wpc whilst protein and transcript expression were both reduced by birth and postnatally. Combined with the data in CHI-D and postnatal controls, it is likely that endocrine commitment ceases in human towards the end of gestation and that further increases in β-cell mass rely on proliferation or NGN3-independent pathways.These data provide new clues for the pathological mechanisms of CHI-D and the establishment and maintenance of the β-cell mass in the human pancreas. We have shown an altered potential for cell proliferation in CHI-D in previously unappreciated ways and provide a rationale for studying molecular components of the β-cell to help unlock β-cell proliferation as a therapeutic option in diabetes.
    Date of Award1 Aug 2015
    Original languageEnglish
    Awarding Institution
    • The University of Manchester
    SupervisorNeil Hanley (Supervisor), Mark Dunne (Supervisor) & Karen Piper Hanley (Supervisor)


    • Transcription Factor
    • Cell Cycle
    • Endocrine
    • Neurogenin3
    • Proliferation
    • Islets
    • Gene
    • Hyperinsulinism
    • Beta Cell
    • Human Development
    • Pancreas
    • Differentiation
    • Fetal
    • Congenital Hyperinsulinism Infancy

    Cite this