Poorly controlled diabetes during pregnancy and lactation activates the Foxo1 pathway and causes glucose intolerance in adult offspring

Yukihiro Inoguchi, Kenji Ichiyanagi, Hiroaki Ohishi, Yasutaka Maeda, Noriyuki Sonoda, Yoshihiro Ogawa, Toyoshi Inoguchi, Hiroyuki Sasaki

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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.

Original languageEnglish
Article number10181
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Glucose Intolerance
Streptozocin
Lactation
Pregnancy
Gluconeogenesis
Liver
Pregnancy in Diabetics
Phenotype
Maternal Exposure
Glucose-6-Phosphatase
Phosphoenolpyruvate
Gene Expression Profiling
Islets of Langerhans
Genes
Catalytic Domain
Head
Body Weight
Phosphorylation
Mothers
Parturition

All Science Journal Classification (ASJC) codes

  • General

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Poorly controlled diabetes during pregnancy and lactation activates the Foxo1 pathway and causes glucose intolerance in adult offspring. / Inoguchi, Yukihiro; Ichiyanagi, Kenji; Ohishi, Hiroaki; Maeda, Yasutaka; Sonoda, Noriyuki; Ogawa, Yoshihiro; Inoguchi, Toyoshi; Sasaki, Hiroyuki.

In: Scientific reports, Vol. 9, No. 1, 10181, 01.12.2019.

Research output: Contribution to journalArticle

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