Background: Hyperglycemia in diabetic mothers enhances the risk of fetal cardiac hypertrophy during gestation.However, the mechanism of high glucose-induced cardiac hypertrophy is not largely understood.This study aims to demonstrate the potential cellular and molecular biological pathogenesis of cardiac hypertrophy induced by diabetic pregnancy.Methods and results: In this study, we demonstrated that the incidence rate of cardiac hypertrophy dramatically increased in the fetuses of diabetic mothers using color ultrasound examination.In addition, human fetal cardiac hypertrophy was successfully mimicked in a streptozotocin (STZ)-induced diabetes mouse model, in which mouse cardiac hypertrophy was diagnosed using type-M ultrasound and a histological assay.The PH3 immunofluorescent staining of mouse fetal hearts indicated that cell proliferation decreased in diabetic mice, and cell apoptosis in H9c2 cells increased in the presence of high glucose in a dose-dependent manner.Next, we found that the individual cardiomyocyte size increased in pre-gestational diabetes mellitus mice and in response to high glucose exposure.Meanwhile, the expression of β-MHC and BMP10 was up-regulated.The expression of Nkx2.5, a crucial cardiac transcription factor, was suppressed in diabetic mouse hearts and cultured H9c2 cells exposed to high glucose, and the expression of KCNE1 and Cx43 was also restricted.Conclusions: Taken together, cell size alteration rather than cell proliferation or apoptosis is responsible for hyperglycemia-induced fetal cardiac hypertrophy.The aberrant expression of Nkx2.5 and its regulated genes in the presence of high glucose could be a principal pathogenesis in the development of fetal cardiac hypertrophy.