Endocrine Abstracts

Understanding how fate choices are made by multipotent progenitors during pancreas development is valuable information in the quest for regenerative medicine and cell therapy to treat diabetes mellitus. Pancreatic differentiation is well defined and understood in rodents however, human data are comparably scarce. Specifically, when human pancreatic progenitors are multipotent is unknown as are the epigenetic changes that these cells undergo during their differentiation to beta...

The last couple of years have seen an advance in generating human β-cells from pluripotent stem cells. It is now clear that cells of greatly increased maturity can be obtained from robust protocols. In addition to improving the prospects of cell replacement therapy, these developments allied to greater understanding of how human β-cells are first generated in the body are allowing development of more complex model systems. These model systems are likely to be importa...

The replacement or regeneration of functional insulin-secreting beta cells is an exciting prospect for the treatment of Type 1 diabetes. Research aimed at this goal must be conducted in a responsible, measured manner in order to maintain public consent and to manage the expectations of patients.My research group couples investigations of pluripotent stem cell biology with studies of the formation and function of the human endocrine organs during early de...

This is the case of a now 37 years old female. She was diagnosed with classical salt wasting congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency at 1 week after birth. She highlights the challenges of living with CAH. She struggled all through her childhood and adolescence with the burden of treatment, difficulties with compliance and the effects of the inadequate control of hyperandrogenism. In adulthood supraphysiological doses of exogenous steroids lead to...

Background/aims: The transcription factor neurogenin 3 (NGN3) is required for pancreatic islet cell specification from multipotent progenitor cells; yet we have limited understanding of the downstream genetic program it directly initiates. A 3 Mb centromeric region on chromosome 20p contains a number of genes activated downstream of NGN3 including INSM1 and NKX2.2. We proposed that NGN3 alters the expression of other genes within this region as poten...

Mammalian differentiation of the external genitalia must be strictly dimorphic for reproductive success. In humans, this is established by a complex interplay of genetic and hormonal factors during 7–12 weeks post-conception (wpc). Despite being fundamental to normal human biology, understanding of human sexual differentiation remains limited. Our objective was to define the onset and regulation of androgen biosynthesis in the human fetal testis and correlate this to diff...

The incretin hormone glucagon-like peptide-1 (GLP-1) has been proposed to increase beta cell mass, via effects on proliferation, apoptosis and neogenesis. However, the role of GLP-1 during normal human development is unclear. We have addressed this in human fetuses by quantifying GLP-1 secretion during fetal development and determining how GLP-1 signalling impacts on early human fetal pancreas in explant culture.GLP-1 is first secreted by the stomach, du...

Background: Lifelong surveillance should be offered to people with hereditary phaeochromocytoma and paraganglioma (PPGL), including asymptomatic carriers of pathogenic gene variants. Regular biochemical and radiological surveillance aims to improve disease detection and prognosis. During the COVID-19 pandemic, outpatient appointments were cancelled or postponed. Departments continue to face large backlogs of work. Clinicians in the USA reported 15% PPGL patients missing at lea...

Recent genome-wide association studies (GWAS) implicate the CYP17A1 locus in human blood pressure regulation. This gene is important in steroidogenesis, regulating both glucocorticoid and androgen synthesis through catalysis of 17α-hydroxylation and 17,20 lyase reactions. We hypothesised that functional CYP17A1 polymorphisms linked to those identified by GWAS influence blood pressure levels. We therefore screened the entire CYP17A1 locus by dire...

Congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) results in disordered sex development (DSD) in individuals of both sexes. POR provides electrons to CYP17A1 thereby facilitating synthesis of the major androgen precursor dehydroepiandrosterone (DHEA). ORD disrupts this enzymatic step, resulting in deficient synthesis of 5α-dihydrotestosterone (DHT) via DHEA, readily explaining undervirilisation (46,XY DSD) in male ORD neonates. Female virili...