Abstract
Exposure to maternal diabetes during pregnancy results in diabetes in offspring, but its underlying mechanisms are unclear. Here, we investigated the phenotype and molecular defects of the offspring of poorly controlled diabetic female mice generated by streptozotocin (STZ) administration. Offspring was exposed to maternal diabetes during pregnancy and lactation. The body weight of STZ offspring was lower than that of control offspring at birth and in adulthood, and glucose tolerance was impaired in adult STZ offspring. Interestingly, the phenotype was more pronounced in male offspring. We next investigated the morphology of islets and expression of β cell-related genes, but no significant changes were observed. However, transcriptome analysis of the liver revealed activation of the fork head box protein O1 (Foxo1) pathway in STZ male offspring. Notably, two key gluconeogenesis enzyme genes, glucose 6 phosphatase catalytic subunit (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1), were upregulated. Consistent with this finding, phosphorylation of Foxo1 was decreased in the liver of STZ male offspring. These changes were not obvious in female offspring. The activation of Foxo1 and gluconeogenesis in the liver may have contributed to the impaired glucose tolerance of STZ male offspring.
Highlights
Type 2 diabetes has strong familial aggregation, and genetic studies have identified genes responsible for the increased risk of the disease
The body weight of STZ offspring was clearly lower at birth (Fig. 1B), and it persisted to adulthood in both male and female offspring, the difference was larger in males (Fig. 1C,D)
When we investigated the mRNA-seq results in greater detail, several genes known to be upregulated by Foxo[1] (G6pc, Pdk[4], Cdkn1a, Gadd45a, Igfbp[1], and Hmox1)[19,20,22,23,24,25,26,27,28,29,30] were upregulated, and a gene known to be downregulated by Foxo[1] (Srebf1)[31] was downregulated in STZ male offspring (Fig. 5A)
Summary
Type 2 diabetes has strong familial aggregation, and genetic studies have identified genes responsible for the increased risk of the disease. Early life environment is implicated in disease development during adulthood[2], and recent studies suggest an important role of intrauterine exposure to diabetes in the pathogenesis of type 2 diabetes[3,4,5,6,7,8]. Www.nature.com/scientificreports leptin receptor show that the diabetic condition during pregnancy leads to impaired glucose tolerance (IGT), impaired insulin secretion, and/or increased insulin resistance in adult offspring[9,10,11,12,13,14]. The animal studies support the results of human studies and indicate an effect of the intrauterine diabetic environment on the risk of developing type 2 diabetes. Dysregulation of Foxo[1] target genes in the liver may contribute to increased gluconeogenesis in the liver, eventually leading to IGT
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