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Late Cognitive Consequences of Gestational Diabetes to the Offspring, in a New Mouse Model

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Abstract

Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during gestation, which affects approximately 10% of pregnant women. Although previously considered a transient condition with few long-term consequences, growing evidence suggest that GD may be linked to permanent metabolic and neurologic changes in the offspring. Currently available GD models fail to recapitulate the full spectrum of this disease, thus providing limited information about the true burden of this condition. Here, we describe a new mouse model of GD, based on the administration of an insulin receptor antagonist (S961, 30 nmol/kg s.c. daily) during pregnancy. Pregnant mice developed increased fasting glycemia and glucose intolerance in the absence of maternal obesity, with a return to normoglycemia shortly after parturition. Moreover, we showed that the adult offspring of GD dams presented pronounced metabolic and cognitive dysfunction when exposed to short-term high-fat diet (HFD). Our data demonstrate that S961 administration to pregnant mice comprises a valuable approach to study the complex pathophysiology of GD, as well as strategies focused on prevention and treatment of both the mother and the offspring. Our findings suggest that the offspring of GD mothers are more susceptible to metabolic and cognitive impairments when exposed to high-fat diet later in life, thus indicating that approaches to prevent and treat these late effects should be pursued.

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Abbreviations

GD:

Gestational diabetes

GTT:

Glucose tolerance test

HFD:

High-fat diet

i.p.:

Intraperitoneal

ND:

Normal diet

NOR:

Novel object recognition

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Acknowledgments

We thank Melissa Florence, Jadilma Ferreira, and Ana Claudia Rangel.

Funding Sources

This work was supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (E.V.L., C.P.F., G.F.P., J.R.C.), Conselho Nacional de Desenvolvimento Científico e Tecnológico (C.P.F., J.R.C.), Institutos Nacionais de Pesquisa - Inovação em Medicamentos e Identificação de Novos Alvos Terapêuticos (C.P.F., G.F.P.), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (R.A.L.).

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  1. School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil

    Ricardo A. L. de Sousa, Emanuelle V. de Lima, Tamara P. da Silva, Renata V. de Souza, Claudia P. Figueiredo, Giselle F. Passos & Julia R. Clarke

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de Sousa, R.A., de Lima, E.V., da Silva, T.P. et al. Late Cognitive Consequences of Gestational Diabetes to the Offspring, in a New Mouse Model. Mol Neurobiol 56, 7754–7764 (2019). https://doi.org/10.1007/s12035-019-1624-0

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