Synergistic Effects of Genetic Beta Cell Dysfunction and Maternal Glucose Intolerance on Offspring Metabolic Phenotype in Mice

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2010 Dec 25

PMID 21181398

Citations 11

Authors

S M Lau

S Lin

R A Stokes

K Cheng

P A Baldock

R F Enriquez

M McLean

N W Cheung

A Sainsbury

F J Gonzalez

H Herzog

J E Gunton

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: Diabetes in pregnancy is linked to development of obesity in the offspring, but the mechanisms are not fully understood. Gestational diabetes mellitus (GDM) occurs when beta cells are unable to compensate for the normal insulin resistance of late pregnancy. In this study, we used a murine model of beta cell dysfunction to examine the effects of maternal GDM on phenotype in male offspring with and without an inherited predisposition for beta cell dysfunction.

Methods: Beta cell-specific aryl-hydrocarbon receptor nuclear translocator-null (βArnt) mice develop GDM from beta cell dysfunction. βArnt and control female mice were used to induce GDM and non-diabetic pregnancies, respectively.

Results: Offspring from GDM pregnancies became spontaneously obese on a normal-chow diet. They were heavier than offspring from non-diabetic pregnancies, with increased body fat. Respiratory exchange ratio (RER) was higher, indicating decreased capacity to switch to lipid oxidation. Metabolic rate in GDM offspring was decreased prior to onset of obesity. The phenotype was more pronounced in βArnt GDM offspring than in GDM offspring of control genotype, demonstrating an interaction between genotype and pregnancy exposure. βArnt GDM offspring had increased hypothalamic neuropeptide Y (Npy) and decreased pro-opiomelanocortin (Pomc) expression. Weight, body fat, insulin sensitivity and RER in all mice, and hypothalamic Npy in βArnt mice were significantly correlated with AUC of maternal late pregnancy glucose tolerance tests (p < 0.01), but not with litter size, maternal weight, triacylglycerol or pre-pregnancy glycaemia.

Conclusions/interpretation: In βArnt mice, exposure to GDM and inheritance of genetic beta cell dysfunction had additive effects on male offspring obesity; severity of the offspring phenotype correlated with maternal glycaemia.

Citing Articles

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Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis.

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Supplementation with a prebiotic (polydextrose) in obese mouse pregnancy improves maternal glucose homeostasis and protects against offspring obesity.

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Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function.

Girgis C, Cha K, So B, Tsang M, Chen J, Houweling P J Cachexia Sarcopenia Muscle. 2019; 10(6):1228-1240.

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Hepatic Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) regulates metabolism in mice.

Scott C, Cha K, Ngai J, Jiang C, Cheng K, Stokes R PLoS One. 2017; 12(11):e0186543.

PMID: 29190746 PMC: 5708799. DOI: 10.1371/journal.pone.0186543.

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