Glucocorticoids and foetal programming of adult hyperglycaemia: dissecting the fundamental molecular mechanisms
Lead Research Organisation:
University of Edinburgh
Department Name: Endocrinology
Abstract
Low birth weight is associated with increased risk of diabetes in adulthood. Exposure of the foetus in the womb to excess ‘stress‘ steroid hormones called glucocorticoids has been suggested as a potential cause. In animals and humans prenatal glucocorticoid treatment reduces birth weight and permanently elevates blood glucose (hyperglycaemia) and blood pressure. These effects are passed onto future generations without further glucocorticoid treatment. Stressful events/illnesses during pregnancy increase glucocorticoid levels, and may have similar long-term effects. We have shown in rat liver that these effects might be mediated by changes in expression of two genes called GR and HNF4a. We now wish to prove this notion. Additionally, because these genes are also present in the pancreas where they control insulin secretion, we will determine whether their expression is also deranged in this organ and whether this causes disturbed insulin secretion. We also wish to elucidate the mechanisms through which the changes in these genes are inherited across generations. These studies may provide new insights into causes of diabetes, and its link with low birth weight. They may also indicate ways of preventing or ameliorating diabetes, as well as inform the therapeutic use of glucocorticoids in pregnant mothers and young babies.
Technical Summary
Numerous epidemiological studies have shown that low birth weight is associated with increased prevalence of cardiometabolic disorders, including type 2 diabetes. Recent studies have shown that prenatal exposure to glucocorticoid ‘stress‘ hormones might underpin this association; treating pregnant rats with the glucocorticoid dexamethasone reduces birth weight, and causes lifelong hypertension and hyperglycaemia in the adult offspring. Intriguingly, these phenotypes are transmitted into subsequent generations without further dexamethasone treatment, suggesting glucocorticoids may induce epigenetic changes. Our recent studies on the liver show that prenatal dexamethasone associates with early-onset and lifelong overexpression of two key transcription factors that regulate metabolism, namely the glucocorticoid receptor GR and hepatocyte nuclear factor 4 alpha (HNF4a). This may be of functional significance since hepatic expression of PEPCK, the rate-limiting step of gluconeogenesis and an important target of both GR and HNF4a, is also permanently increased. Hepatic GR and PEPCK expression is increased in other animal models of foetal programming of hyperglycaemia (maternal protein restriction or uterine artery ligation), suggesting that GR and/or HNF4a may mediate effects of various early environmental insults on subsequent hyperglycaemia.
GR and HNF4a are also particularly important for development and function of the endocrine pancreas - where glucocorticoids inhibit insulin secretion from ß-cells and mutations of the HNF4a gene cause maturity-onset diabetes of the young1 (MODY1). Deranged expression of these genes in the pancreas would therefore have significant pathophysiological consequences and may contribute to hyperglycaemia in this model.
The main aim of the proposed research is to elucidate the fundamental molecular mechanisms through which prenatal glucocorticoid exposure causes permanent hyperglycaemia. Specifically we will: 1) use a transgenic approach to test whether hepatic HNF4a over-expression is sufficient to induce PEPCK expression and hyperglycaemia; 2) examine whether prenatal dexamethasone alters GR and HNF4a expression in pancreatic beta-cells and determine whether changes affect long term beta-cell function (insulin secretion); 3) determine the methylation status of the GR and HNF4a promoters in order to elucidate the mechanisms through which dexamethasone increases expression of these genes and how this is transmitted across generations.
These studies may provide new insights into the pathogenesis of type 2 diabetes and its relationship with birth weight, as well as indicate targets for prevention and/or therapy. If the epigenetic changes could easily be determined with a blood sample, it would allow early testing (before disease manifestation) in children with low birth weight or those treated with glucocorticoids perinatally to accelerate lung maturity in cases of premature labour.
GR and HNF4a are also particularly important for development and function of the endocrine pancreas - where glucocorticoids inhibit insulin secretion from ß-cells and mutations of the HNF4a gene cause maturity-onset diabetes of the young1 (MODY1). Deranged expression of these genes in the pancreas would therefore have significant pathophysiological consequences and may contribute to hyperglycaemia in this model.
The main aim of the proposed research is to elucidate the fundamental molecular mechanisms through which prenatal glucocorticoid exposure causes permanent hyperglycaemia. Specifically we will: 1) use a transgenic approach to test whether hepatic HNF4a over-expression is sufficient to induce PEPCK expression and hyperglycaemia; 2) examine whether prenatal dexamethasone alters GR and HNF4a expression in pancreatic beta-cells and determine whether changes affect long term beta-cell function (insulin secretion); 3) determine the methylation status of the GR and HNF4a promoters in order to elucidate the mechanisms through which dexamethasone increases expression of these genes and how this is transmitted across generations.
These studies may provide new insights into the pathogenesis of type 2 diabetes and its relationship with birth weight, as well as indicate targets for prevention and/or therapy. If the epigenetic changes could easily be determined with a blood sample, it would allow early testing (before disease manifestation) in children with low birth weight or those treated with glucocorticoids perinatally to accelerate lung maturity in cases of premature labour.
