O R I G I N A L A R T I C L E
High Prevalence of Type 2 Diabetes and Pre-Diabetes in Adult Offspring of Women With Gestational Diabetes Mellitus or Type 1 Diabetes
The role of intrauterine hyperglycemia
TINE D. CLAUSEN, MD1 ELISABETH R. MATHIESEN, MD, DMSC2 TORBEN HANSEN, MD, PHD3 OLUF PEDERSEN, MD, DMSC3 DORTE M. JENSEN, MD, PHD4 JEANNET LAUENBORG, MD,PHD1 PETER DAMM, MD, DMSC1 possible role of intrauterine hyperglycemia in the pathogenesis of type 2 diabetes (1). Maternal glucose crosses placenta easily, and maternal hyperglycemia leads to intrauterine hyperglycemia, fetal hyperinsulinemia, and possible modiﬁcation of growth and development of the fetus (2). Pronounced hyperglycemia in relation to pregnancies of women with type 1 diabetes as wellas mild hyperglycemia, as seen among women with gestational diabetes mellitus (GDM), are both associated with increased fetal growth and perinatal morbidity (3,4). Also, less severe forms of glucose intolerance are associated with increased feto-maternal morbidity (5). In animal studies, intrauterine hyperglycemia increases the risk of abnormal glucose tolerance, diabetes, overweight, and insulinresistance in offspring (6 – 10). Despite very convincing animal studies, questions still exist concerning the long-term impact of intrauterine hyperglycemia in humans, especially regarding the impact in adult Caucasians. Observational and prospective studies among the Pima Indians and from the Chicago group support the ﬁndings of animal studies (11–18). The studies of the Pima Indians examinechildren and adult offspring in contrast to the majority of the other studies, in which offspring before the end of puberty are investigated (14 –16,18). Because of the very speciﬁc genetics of the Pima Indians, the results are not directly applicable to other populations (11– 13,19). Furthermore, some of the other studies have limitations: small number of participants (17), high number of dropoutsduring follow-up (14,15), and analyses including maternal type 1 and type 2 diabetes together (16). Only one follow-up study of children from a small randomized trial in women with GDM has been performed—without deﬁnitive conclusions (20). Thus, in the present paper we aimed to evaluate the prevalence of type 2 dia-
OBJECTIVE — The role of intrauterine hyperglycemia and future risk of type 2diabetes in human offspring is debated. We studied glucose tolerance in adult offspring of women with either gestational diabetes mellitus (GDM) or type 1 diabetes, taking the impact of both intrauterine hyperglycemia and genetic predisposition to type 2 diabetes into account. RESEARCH DESIGN AND METHODS — The glucose tolerance status following a 2-h 75-g oral glucose tolerance test (OGTT) wasevaluated in 597 subjects, primarily Caucasians, aged 18 –27 years. They were subdivided into four groups according to maternal glucose metabolism during pregnancy and genetic predisposition to type 2 diabetes: 1) offspring of women with diet-treated GDM (O-GDM), 2) offspring of genetically predisposed women with a normal OGTT (O-NoGDM), 3) offspring of women with type 1 diabetes (O-type 1), and 4)offspring of women from the background population (O-BP). RESULTS — The prevalence of type 2 diabetes and pre-diabetes (impaired glucose tolerance or impaired fasting glucose) in the four groups was 21, 12, 11, and 4%, respectively. In multiple logistic regression analysis, the adjusted odds ratios (ORs) for type 2 diabetes/pre-diabetes were 7.76 (95% CI 2.58 –23.39) in O-GDM and 4.02 (1.31–12.33) inO-type 1 compared with O-BP. In O-type 1, the risk of type 2 diabetes/pre-diabetes was signiﬁcantly associated with elevated maternal blood glucose in late pregnancy: OR 1.41 (1.04 –1.91) per mmol/l. CONCLUSIONS — A hyperglycemic intrauterine environment appears to be involved in the pathogenesis of type 2 diabetes/pre-diabetes in adult offspring of primarily Caucasian women with either...