Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

Abstract

Aims/hypothesis Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism. Materials and Methods The pancreatic phenotype of GR null/null mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week. Results E18 GR null/null fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR null/null mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR null/null pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR null/null pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR +/null mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion. Conclusions/interpretation Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.

Genetic evidence of the programming of beta cell mass and function by glucocorticoids in mice

“…Moreover, the effects seen with GR PdxCr but not GR RIPCre indicate that GR signalling is important between progenitors and insulin-positive cells, though the precise stage at which this occurs is not yet clear. The data from the GFR model showing decreased Ngn3 expression and increased exocrine markers suggest that it could be earlier than endocrine commitment, but the normal pancreas development seen at E15.5 in GR −/− mutants [21] makes this hypothesis rather unlikely and places the glucocorticoidsensitive period between E15.5 and E18.5 in the mouse. Interestingly, undernutrition reduced fetal body weight in all groups of fetuses, irrespective of their genotype, underlining that suppression of glucocorticoid signalling in pancreatic precursor cells may protect and enhance beta cell mass but not fetal body weight during GFR, a result that was expected as the deletion of glucocorticoid signalling is pancreas specific.…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…Nutritional insults that occur during early life may result Age-dependent changes in islet morphology in non-human primates Old age • Islet amyloidosis plays a role in beta cell death in the Celebes crested macaque (Macaca nigra) and rhesus monkeys • Progressive islet amyloidosis is associated not only with increased beta cell apoptosis (reduced relative beta cell volume), but also with increased alpha cell replication and hypertrophy (increased relative alpha cell volume) in baboons in decreased beta cell mass and function that persist in adulthood to promote increased risk of glucose intolerance and type 2 diabetes [34]. Maternal restricted energy intake during parturition and the consequent increased levels of glucocorticoids [35] have been reported to decrease fetal beta cell mass as a result of reduced differentiation and decreased beta cell expression of the key transcription factors pancreatic and duodenal homeobox 1 (PDX1), paired box protein 4 (PAX4) and NK6 homeobox 1 (NKX6.1). A maternal diet low in protein content causes intrauterine growth retardation, and the newborn rodents exhibit underdeveloped beta cell mass owing to reduced proliferation and increased apoptosis associated with reduced levels of growth factors [36].…”

Antenatal Treatment with Glucocorticoids and the Hypotalamic-Pituitary-Adrenal Axis

“…To achieve this, glucocorticoids influence the timely differentiation of vital organ systems, including the central nervous system, gastrointestinal system, as well as other endocrine axes and tissue hormones sensitivity. Fetal lung maturation and surfactant production, enhancement of gluconeogenic enzyme activities in the liver and glycogen deposition, as well as adaptive thermogenesis in brown adipose tissue are also controlled by glucocorticoid action (12)(13)(14).…”

“…To achieve this, glucocorticoids influence the timely differentiation of vital organ systems, including the central nervous system, gastrointestinal system, as well as other endocrine axes and tissue hormones sensitivity. Fetal lung maturation and surfactant production, enhancement of gluconeogenic enzyme activities in the liver and glycogen deposition, as well as adaptive thermogenesis in brown adipose tissue are also controlled by glucocorticoid action (12)(13)(14).Like in adults, where stress implicates an HPA axis response, adverse intrauterine conditions in fetuses also provoke fetal HPA axis activation (15). For example, fetal hypoxemia leads to an increase in the fetal ACTH concentration with up-regulation of mRNAs of the ACTH receptor and steroid-synthesizing enzymes in the adrenals that result in selective increase of cortisol synthesis in fetal sheep (16).…”