Prenatal dexamethasone exposure induced pancreatic ß-cell dysfunction and glucose intolerance of male offspring rats: Role of the epigenetic repression of ACE2.

The prevalence of diabetes in children and adolescents has been rising gradually, which is relevant to adverse environment during development, especially prepartum. We aimed to explore the effects of prenatal dexamethasone exposure (PDE) on ß-cell function and glucose homeostasis in juvenile offspring rats. Pregnant Wistar rats were subcutaneously administered with dexamethasone [0.1, 0.2, 0.4mg/(kg.d)] from gestational day 9 to 20. PDE impaired glucose tolerance in the male offspring rather than the females. In male offspring, PDE impaired the development and function of ß-cells, accompanied with lower H3K9ac, H3K14ac and H3K27ac levels in the promoter region of angiotensin-converting enzyme 2 (ACE2) as well as suppressed ACE2 expression. Meanwhile, PDE increased expression of glucocorticoid receptor (GR) and histone deacetylase 3 (HDAC3) in fetal pancreas. Dexamethasone also inhibited ACE2 expression and insulin production in vitro. Recombinant expression of ACE2 restored insulin production inhibited by dexamethasone. In addition, dexamethasone activated GR and HDAC3, increased protein interaction of GR with HDAC3, and promoted the binding of GR-HDAC3 complex to ACE2 promoter region. Both RU486 and TSA abolished dexamethasone-induced decline of histone acetylation and ACE2 expression. In summary, suppression of ACE2 is involved in PDE induced ß-cell dysfunction and glucose intolerance in juvenile male offspring rats.

Epigenetic repression of AT2 receptor is involved in ß cell dysfunction and glucose intolerance of adult female offspring rats exposed to dexamethasone prenatally.

Prenatal exposure to dexamethasone (PDE) impairs pancreatic ß cell development and glucose homeostasis in offspring especially females. To explore the underlying intrauterine programming mechanism, pregnant Wistar rats were subcutaneously administered with dexamethasone (0, 0.2 and 0.8 mg/kg·d) from gestational days (GD) 9 to 20. Female offspring were collected on GD20 (fetus) and in postnatal week 28 (adult), respectively. PDE reduced the serum insulin levels, ß cell mass, and pancreatic insulin expressions in fetuses and adults, causing glucose intolerance after maturity. The persistent suppression of pancreatic angiotensin II receptor type 2 (AT2R) expression before and after birth could be observed in the PDE females, which is accompanied with decreased histone 3 lysine 14 acetylation (H3K14ac) and H3K27ac levels in AT2R promoter. PDE increased the gene expressions of glucocorticoid receptor (GR) and histone deacetylase 2 (HDAC2) in fetal pancreas. Furthermore, dexamethasone inhibited insulin biosynthesis while activated GR and HDAC2 expression in the rat INS-1 cells. The AT2R expression was repressed by dexamethasone in vitro but only H3K27ac levels in AT2R promoter were lowered. Dexamethasone enhanced the interaction between GR and HDAC2 proteins as well as the binding of GR/HDAC2 complex to AT2R promoter. Moreover, overexpression of AT2R could restore the suppressed insulin biosynthesis induced by dexamethasone in vitro, and both GR antagonist and histone deacetylase abolished the decreased H3K27ac level and gene expression of AT2R. In conclusion, continuous epigenetic repression of AT2R before and after birth may be involved in ß cell dysfunction and glucose intolerance of the PDE adult female offspring.

Age-Characteristic Changes of Glucose Metabolism, Pancreatic Morphology and Function in Male Offspring Rats Induced by Prenatal Ethanol Exposure.

Intrauterine growth restricted offspring suffer from abnormal glucose homeostasis and ß cell dysfunction. In this study, we observed the dynamic changes of glucose metabolic phenotype, pancreatic morphology, and insulin synthesis in prenatal ethanol exposure (PEE) male offspring rats, and to explore the potential intrauterine programming mechanism of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis. Ethanol (4 g/kg·d) was administered through oral gavage during gestational day (GD) 9-20. Serum glucose and insulin levels, pancreatic ß cell mass, and expression of glucocorticoid receptor (GR), IGF1 and insulin were determined on GD20, postnatal week (PW) 6, PW12 with/without chronic stress (CS), and PW24, respectively. Both intraperitoneal glucose and insulin tolerance tests were conducted at PW12 and PW24. Results showed that the serum glucose and insulin levels as well as pancreatic ß cell mass were reduced on GD20 in PEE males compared with the controls, while pancreatic GR expression was enhanced but IGF1 and INS1/2 expression were suppressed. After birth, compared with the controls, ß cell mass in the PEE males was initially decreased at PW6 and gradually recovered from PW12 to PW24, which was accompanied by increased serum glucose/insulin levels and insulin resistance index (IRI) at PW6 and decreased serum glucose contents at PW12, as well as unchanged serum glucose/insulin concentrations at PW24. In addition, both improved glucose tolerance and impaired insulin sensitivity of the PEE males at PW12 were inversed at PW24. Moreover, at PW6 and PW12, pancreatic GR expression in the PEE group was decreased, while IGF1 expression was reversely increased, resulting in a compensatory increase of insulin expression. Moreover, CS induced pancreatic GR activation and inhibited IGF1 expression, resulting in impaired insulin biosynthesis. Conclusively, the above changes were associated with age and the intrauterine programming alteration of GC-IGF1 axis may be involved in prenatal and postnatal pancreatic dysplasia and impaired insulin biosynthesis in PEE male offspring.