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Synergistic effects of genetic beta cell dysfunction and maternal glucose intolerance on offspring metabolic phenotype in mice


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 (betaArnt) mice develop GDM from beta cell dysfunction. betaArnt 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 betaArnt GDM offspring than in GDM offspring of control genotype, demonstrating an interaction between genotype and pregnancy exposure. betaArnt 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 betaArnt 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 betaArnt 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.

Authors Lau, S. M.; Lin, S.; Stokes, R. A.; Cheng, K.; Baldock, P. A.; Enriquez, R. F.; McLean, M.; Cheung, N. W.; Sainsbury, A.; Gonzalez, F. J.; Herzog, H.; Gunton, J. E.
Published Date 2011-03-01
Published Volume 54
Published Issue 4
Published Pages 910-21
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version