Type 2 diabetes mellitus - genes or intrauterine environment? An embryo transfer paradigm in rats

Aims/hypothesis. The familial predisposition to Type 2 diabetes mellitus is mediated by both genetic and intrauterine environmental factors. In the normal course of events, maternal genes always develop in the same uterus, thus restricting studies aimed at investigating the relative contribution of these factors. We have developed an embryo transfer paradigm in rats to overcome this difficulty. Methods. Euglycaemic female Wistar rats were superovulated and mated with male Wistar rats. The following day, fertilised eggs were transferred into pseudo-pregnant female Wistar rats or hyperglycaemic Goto Kakizaki (GK) rats. Pregnancies were allowed to go to term. Offspring were weighed at 6 weeks, 3 months and 6 months of age and an intravenous glucose tolerance test was carried out at 6 months of age. Results. Offspring from Wistar into Wistar embryo transfers (n=20) were not significantly hyperglycaemic compared to the non-manipulated Wistar stock colony (n=26). However, offspring from Wistar gametes reared in hyperglycaemic GK mothers (n=51) were significantly lighter at 6 weeks of age (156+/-4.1 g vs 180+/-6.1 g [mean +/- SEM], p<0.01) and significantly more hyperglycaemic at 6 months of age (fasting glucose 6.6+/-0.18 mmol/l vs 4.8+/-0.21 mmol/l, mean blood glucose during glucose tolerance test 14.3+/-0.31 mmol/l vs 11.1+/-0.28 mmol/l, p<0.01) than Wistar gametes transferred back into euglycaemic Wistar mothers. When GK rats were superovulated and mated together, transfer of 1-day-old embryos into pseudo-pregnant Wistar dams did not alleviate hyperglycaemia in adult offspring. Conclusions/interpretation. In GK rats, a euglycaemic intrauterine environment cannot overcome the strong genetic predisposition to diabetes. However, in Wistar rats with a low genetic risk of diabetes, exposure to hyperglycaemia in utero significantly increases the risk of diabetes in adult life.