Regulation of hepatic pyruvate dehydrogenase phosphorylation in offspring glucose intolerance induced by intrauterine hyperglycemia

Oncotarget. 2017 Feb 28;8(9):15205-15212. doi: 10.18632/oncotarget.14837.

Abstract

Aim: Gestational diabetes mellitus (GDM) has been shown to be associated with a high risk of diabetes in offspring. In mitochondria, the inhibition of pyruvate dehydrogenase (PDH) activity by PDH phosphorylation is involved in the development of diabetes. We aimed to determine the role of PDH phosphorylation in the liver in GDM-induced offspring glucose intolerance.

Results: PDH phosphorylation was increased in lymphocytes from the umbilical cord blood of the GDM patients and in high glucose-treated hepatic cells. Both the male and female offspring from GDM mice had elevated liver weights and glucose intolerance. Further, PDH phosphorylation was increased in the livers of both the male and female offspring from GDM mice, and elevated acetylation may have contributed to this increased phosphorylation.

Materials and methods: We obtained lymphocytes from umbilical cord blood collected from both normal and GDM pregnant women. In addition, we obtained the offspring of streptozotocin-induced GDM female pregnant mice. The glucose tolerance test was performed to assess glucose tolerance in the offspring. Further, Western blotting was conducted to detect changes in protein levels.

Conclusions: Intrauterine hyperglycemia induced offspring glucose intolerance by inhibiting PDH activity, along with increased PDH phosphorylation in the liver, and this effect might be mediated by enhanced mitochondrial protein acetylation.

Keywords: gestational diabetes mellitus; glucose intolerance; offspring; phosphorylation; pyruvate dehydrogenase.

MeSH terms

  • Animals
  • Animals, Newborn
  • Blood Glucose / metabolism
  • Diabetes, Gestational / physiopathology*
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Glucose Intolerance / enzymology
  • Glucose Intolerance / etiology*
  • Glucose Intolerance / pathology
  • Glucose Tolerance Test
  • Humans
  • Hyperglycemia / complications*
  • Ketone Oxidoreductases / metabolism*
  • Male
  • Mice
  • Phosphorylation
  • Pregnancy
  • Pyruvates / metabolism

Substances

  • Blood Glucose
  • Pyruvates
  • Ketone Oxidoreductases
  • pyruvate dehydrogenase (NADP+)