Intrauterine Hyperglycemia Is Associated With an Earlier Diagnosis of Diabetes in HNF-1α Gene Mutation Carriers

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Abstract
OBJECTIVE —In animals, experimentally induced maternal hyperglycemia during pregnancy results in hyperglycemic offspring. Similarly, Pima Indian offspring with mothers who are diabetic at the time of pregnancy have increased risk of early-onset diabetes. We hypothesized that exposure to hyperglycemia in utero would decrease the age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY) due to a mutation in the hepatocyte nuclear factor 1α (HNF-1α) gene. RESEARCH DESIGN AND METHODS —We analyzed the affect of maternal diabetes on age at diagnosis of diabetes in 150 HNF-1α gene mutation carriers from 55 families. RESULTS —Age at diagnosis in HNF-1α mutation carriers was younger when the mother was diagnosed before pregnancy compared with when the mother was diagnosed after pregnancy (15.5 ± 5.4 vs. 27.5 ± 13.1 years, P < 0.0001). This is unlikely to represent a generalized familial decrease in age at diagnosis due to a more severe mutation, because no difference was seen in age of the offspring at diagnosis of diabetes when the father was diagnosed at a young age, and a similar trend was seen when only the single common mutation, P291fsinsC, was analyzed. CONCLUSIONS —We conclude that maternal hyperglycemia during pregnancy probably increases the penetrance of HNF-1α mutations. The potential role of exposure to hyperglycemia in utero in a monogenic diabetic subgroup warrants prospective study.