Differential timing for programming of glucose homoeostasis, sensitivity to insulin and blood pressure by in utero exposure to dexamethasone in sheep

Numerous epidemiological studies have related an increased risk of adult-on set cardiovascular and metabolic disease to an adverse intra-uterine enviro nment at critical periods. We have shown that fetal sheep exposed to dexame thasone for only 2 days at 27 days of gestation (term 150 days) became hype rtensive adults, whereas those exposed at 64 days of gestation remained nor motensive, as did controls. In the same sheep, now nearly 5 years old, we p erformed glucose tolerance tests and hyperinsulinaemic euglycaemic damps to study the insulin sensitivity of glucose, amino acid and non-esterified fa tty acid metabolism. Glucose tolerance, calculated as the area under the cu rve, after intravenous administration of bolus glucose and insulin secretio n in response to a glucose challenge were not altered in any group. There w ere no significant differences in the insulin sensitivity of net whole-body glucose or amino acid uptake. However, suppression of lipolysis by insulin , measured as the proportional decrease in the circulating concentration of non-esterified fatty acids during the hyperinsulinaemic clamp, was 69+/-1. 2% at steady-state plasma insulin levels(approximate to 1000 m-units/l) in the group exposed to dexamethasone at 27 days of gestation, but only 50.8+/ -6.5% in the controls (P < 0.05). In the group exposed to dexamethasone at 64 days of gestation, the decrease was 66.4+/-5.1%, which did not reach sig nificance compared with the controls (P = 0.10). Thus brief dexamethasone e xposure during early gestation programmed hypertension independently of ins ulin resistance of glucose or amino acid metabolism; however, it did lead t o increased insulin sensitivity of the inhibition of lipolysis, which may i ncrease susceptibility to the development of obesity postnatally.