De Blasio M J, Dodic M, Jefferies A J, Moritz K M, Wintour E M, Owens J A
Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide SA 5005, Australia.
Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E75-82. doi: 10.1152/ajpendo.00689.2006. Epub 2007 Mar 13.
An adverse intrauterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring. However, male offspring are often more susceptible to early life "programming". Pregnant sheep were infused intravenously with saline (0.19 ml/h), dexamethasone (0.48 mg/h), or cortisol (5 mg/h), for 2 days from 26 to 28 days of gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance [intravenous glucose tolerance test (IVGTT)], insulin secretion, and insulin sensitivity of glucose, alpha-amino nitrogen, and free fatty acid metabolism were assessed at 4 yr of age. We show that cortisol, but not dexamethasone, treatment of mothers causes fasting hyperglycemia in adult male offspring. Maternal cortisol induced a second-phase hyperinsulinemia during IVGTT, whereas maternal dexamethasone induced a first-phase hyperinsulinemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinemia in adult male offspring, but in a glucocorticoid-specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans.
不良的子宫内环境会增加患各种成年期疾病的风险，这些疾病的性质随暴露时间的不同而有所变化。人类母体营养不良会增加肥胖风险，以及成年后患冠心病和糖耐量受损的风险，这可能部分由母体或胎儿的内分泌应激反应介导。在绵羊中，孕早期使用地塞米松会损害成年雌性后代的心血管功能，但不会影响其葡萄糖稳态。然而，雄性后代往往更容易受到早期生活“编程”的影响。在妊娠第26至28天，给怀孕的绵羊静脉输注生理盐水（0.19毫升/小时）、地塞米松（0.48毫克/小时）或皮质醇（5毫克/小时），持续2天。对雄性后代测量出生时的大小和出生后的生长情况，并在4岁时评估其葡萄糖耐量[静脉葡萄糖耐量试验（IVGTT）]、胰岛素分泌以及葡萄糖、α-氨基氮和游离脂肪酸代谢的胰岛素敏感性。我们发现，母亲接受皮质醇而非地塞米松治疗会导致成年雄性后代出现空腹高血糖。母体皮质醇在IVGTT期间诱导第二相高胰岛素血症，而母体地塞米松诱导第一相高胰岛素血症。地塞米松改善了葡萄糖耐量，而皮质醇没有影响，两者均未影响胰岛素敏感性。这表明孕早期母体暴露于糖皮质激素会改变成年雄性后代的葡萄糖稳态并诱导高胰岛素血症，但方式具有糖皮质激素特异性。孕早期暴露于糖皮质激素的这些后果可能会长期导致胰腺功能衰竭和糖尿病，这与孕早期的应激导致人类出现此类结果是一致的。
