Abstract
Aim/HypothesisMaternal diabetes and high-fat feeding during pregnancy have been linked to later life outcomes in offspring. To investigate the effects of both maternal and paternal hyperglycemia on offspring phenotypes, we utilized an autosomal dominant mouse model of diabetes (hypoinsulinemic hyperglycemia in Akita mice). We determined metabolic and skeletal phenotypes in wildtype offspring of Akita mothers and fathers.ResultsBoth maternal and paternal diabetes resulted in phenotypic changes in wildtype offspring. Phenotypic changes were more pronounced in male offspring than in female offspring. Maternal hyperglycemia resulted in metabolic and skeletal phenotypes in male wildtype offspring. Decreased bodyweight and impaired glucose tolerance were observed as were reduced whole body bone mineral density and reduced trabecular bone mass.Phenotypic changes in offspring of diabetic fathers differed in effect size from changes in offspring of diabetic mothers. Male wildtype offspring developed a milder metabolic phenotype, but a more severe skeletal phenotype. Female wildtype offspring of diabetic fathers were least affected.ConclusionsBoth maternal and paternal diabetes led to the development of metabolic and skeletal changes in wildtype offspring, with a greater effect of maternal diabetes on metabolic parameters and of paternal diabetes on skeletal development. The observed changes are unlikely to derive from Mendelian inheritance, since the investigated offspring did not inherit the Akita mutation. While fetal programming may explain the phenotypic changes in offspring exposed to maternal diabetes in-utero, the mechanism underlying the effect of paternal diabetes on wildtype offspring is unclear.
Highlights
In data from a human cohort from the early 20th century, Barker observed that infants with the lowest birth weight had the highest risk of developing cardiovascular disease
Offspring of diabetic mothers seem to carry a risk for the development of obesity and diabetes, as shown in population studies in Pima Indians, American youth with Type 2 Diabetes, and children of mothers affected by gestational diabetes [2], [3]
Our results suggest that the Akita mouse is likely to be a useful model for investigating the phenotypic spectrum and bases of maternal and paternal diabetes effects on offspring
Summary
In data from a human cohort from the early 20th century, Barker observed that infants with the lowest birth weight had the highest risk of developing cardiovascular disease. This observation formed the basis for the hypothesis that an adverse in-utero environment could have a programming effect on the developing fetus, resulting in lifelong effects [1]. Offspring of diabetic mothers seem to carry a risk for the development of obesity and diabetes, as shown in population studies in Pima Indians, American youth with Type 2 Diabetes, and children of mothers affected by gestational diabetes [2], [3] While part of this risk is likely due to the transmission of DNA sequence variants (Mendelian inheritance), fetal programming appears to be an additional factor. Recent data suggest a programming effect by higher glucose concentration during pregnancy [4]
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