Decreased Risk of Type I Diabetes in Offspring of Mothers Who Acquire Diabetes During Adrenarchy

Abstract

Fathers with type I diabetes transmit diabetes to their offspring 2–3 times more frequently than mothers with type I diabetes. This phenomenon has provoked both genetic and nongenetic hypotheses, but the mechanism remains obscure. We find that mothers who develop diabetes before age 8 transmit diabetes at the same rate as diabetic fathers, and that the sex difference in diabetes transmission is explained by a decreased transmission rate in mothers who acquired diabetes after age 8. We constructed a data base containing 2156 nondiabetic and diabetic offspring of parents with type I diabetes. Families were selected from our main data base, which contains demographic information and diabetes autoantibody test results on >8000 first-degree relatives of patients with type I diabetes and diabetic probands. Identification of offspring was made through diabetic parents who had participated in our autoantibody screening program at the Joslin Diabetes Center between 1983 and 1990. Questionnaires were sent to all other family members to determine the number of diabetic and nondiabetic offspring in each family. The 20-yr life-table risk of diabetes in offspring of diabetic fathers and mothers is 8.9 ± 1.0 and 3.4 ± 0.6%, respectively. For mothers acquiring diabetes before or after age 8, the risk of diabetes in offspring is 13.9 ± 4.4 and 2.4 ± 0.6% at 20 yr of age, respectively. Furthermore, we find that duration of diabetes in mothers before pregnancy has no effect on the risk of diabetes in their offspring. The increased transmission rate of diabetes in diabetic fathers is explained by a decreased transmission rate of diabetes in mothers who acquire diabetes after age 8. Because women acquiring diabetes after age 8 transmit less diabetes to their offspring, we propose that adrenarchy may have an apparent protective effect on diabetes transmission. We speculate that mothers who acquire diabetes after age 8 are more susceptible to this disorder (similar to susceptibility to other organ-specific autoimmune diseases) and may possess and transmit fewer genetic susceptibility determinants to their offspring.