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9 May 2017 Antenatal blockade of n-methyl-d-aspartate receptors by memantine reduces the susceptibility to diabetes induced by a high-fat diet in rats with intrauterine growth restriction
Xiao-Ting Huang, Shao-Jie Yue, Chen Li, Jia Guo, Yan-Hong Huang, Jian-Zhong Han, Dan-Dan Feng, Zi-Qiang Luo
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Abstract

Intrauterine growth retardation (IUGR) is closely related to the later development of type 2 diabetes in adulthood. Excessive activation of N-methly-D-aspartate receptors (NMDARs) causes excitatory neurotoxicity, resulting in neuronal injury or death. Inhibition of NMDARs enhances the glucose-stimulated insulin secretion and survival of islet cells in type 2 diabetic mouse and human islets. Here, we examined whether antenatal blockade of NMDARs by Memantine could decrease the risk of diabetes induced by a high-fat (HF) diet at adulthood in IUGR rats. Pregnant SD rats were assigned to four groups: control, IUGR, Memantine, and Memantine IUGR. The pregnant rats were exposed to hypoxic conditions (FiO2 = 0.105) for 8 h/day (IUGR group) or given a daily Memantine injection (5 mg/kg, i.p.) before hypoxia exposure from embryonic day (E) 14.5 to E 20.5 (Memantine IUGR). The offspring were fed an HF diet with 60% of the calories from age 4 to 12 weeks. We found that NMDAR mRNAs were expressed in the fetal rat pancreas. An HF diet resulted in a high rate of diabetes at adulthood in the IUGR group. Antenatal Memantine treatment decreased the risk of diabetes at adulthood of rats with IUGR, which was associated with rescued glucose tolerance, increased insulin release, improved the insulin sensitivity, and increased expression of genes related to beta-cell function in the pancreas. Together, our results suggest that antenatal blockade of NMDARs by Memantine in pregnant rats improves fetal development and reduces the susceptibility to diabetes at adulthood in offspring.

Summary Sentence

The excessive activation of NMDARs is involved in the restriction of fetal pancreas development induced by intrauterine hypoxia, and antenatal Memantine treatment attenuates the susceptibility to diabetes induced by an HF diet in IUGR rats.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Xiao-Ting Huang, Shao-Jie Yue, Chen Li, Jia Guo, Yan-Hong Huang, Jian-Zhong Han, Dan-Dan Feng, and Zi-Qiang Luo "Antenatal blockade of n-methyl-d-aspartate receptors by memantine reduces the susceptibility to diabetes induced by a high-fat diet in rats with intrauterine growth restriction," Biology of Reproduction 96(5), 960-970, (9 May 2017). https://doi.org/10.1095/biolreprod.116.145011
Received: 11 November 2016; Accepted: 10 January 2017; Published: 9 May 2017
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