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Severe Diabetes Induction as a Generational Model for Growth Restriction of Rat

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Abstract

We used uncontrolled maternal diabetes as a model to provoke fetal growth restriction in the female in the first generation (F1) and to evaluate reproductive outcomes and the possible changes in metabolic systems during pregnancy, as well as the repercussions at birth in the second generation (F2). For this, nondiabetic and streptozotocin-induced severely diabetic Sprague-Dawley rats were mated to obtain female pups (F1), which were classified as adequate (AGA) or small (SGA) for gestational weight. Afterward, we composed two groups: F1 AGA from nondiabetic dams (Control) and F1 SGA from severely diabetic dams (Restricted) (n minimum = 10 animals/groups). At adulthood, these rats were submitted to the oral glucose tolerance test, mated, and at day 17 of pregnancy, blood samples were collected to determine glucose and insulin levels for assessment of insulin resistance. At the end of the pregnancy, the blood and liver samples were collected to evaluate redox status markers, and reproductive, fetal, and placental outcomes were analyzed. Maternal diabetes was responsible for increased SGA rates and a lower percentage of AGA fetuses (F1 generation). The restricted female pups from severely diabetic dams presented rapid neonatal catch-up growth, glucose intolerance, and insulin resistance status before and during pregnancy. At term pregnancy of F1 generation, oxidative stress status was observed in the maternal liver and blood samples. In addition, their offspring (F2 generation) had lower fetal weight and placental efficiency, regardless of gender, which caused fetal growth restriction and confirmed the fetal programming influence.

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Acknowledgments

The authors are thankful to the research team, Mr. Danilo Chaguri and Mr. Jurandir Antonio for laboratory assistance and animal care.

Funding

This study was supported by the by the São Paulo Research Foundation (FAPESP), under the coordination of Dr. Débora Cristina Damasceno (grant no. 2016/25207-5); and Coordination of Superior Level Staff Improvement—CAPES/Brazil (L.L.C., Finance Code 001).

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Authors and Affiliations

  1. Postgraduate Course on Tocogynecology, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, São Paulo State, Brazil

    Larissa Lopes da Cruz, Vinícius Soares Barco, Verônyca Gonçalves Paula, Franciane Quintanilha Gallego, Maysa Rocha Souza & Débora Cristina Damasceno

  2. Institute of Biological and Health Sciences, Laboratory of System Physiology and Reproductive Toxicology, Federal University of Mato Grosso (UFMT), Barra do Garças, Mato Grosso State, Brazil

    Larissa Lopes da Cruz, Verônyca Gonçalves Paula, Maysa Rocha Souza & Gustavo Tadeu Volpato

  3. Research Support Office, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil

    José Eduardo Corrente

  4. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Department of Reproductive Biology, Mexico City, Mexico

    Elena Zambrano

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  1. Larissa Lopes da Cruz
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Contributions

LLC, GTV and DCD designed the study. LLC, VSB, VGP, FQG, JEC, GTV, and DCD collected the data and interpreted the results. LLC, MRS, EZ, GTV, and DCD drafted the work and performed the final revision of the intellectual content. All authors were responsible for critical revisions of the paper. All authors approved the final version of the manuscript.

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Correspondence to Débora Cristina Damasceno.

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The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national Guide for Care and Use of Experimental Animals and have been approved by the Committee on Ethics in the Use of Animals of Botucatu Medical School—São Paulo State University (UNESP) (CEUA Number: 1341/2019).

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da Cruz, L.L., Barco, V.S., Paula, V.G. et al. Severe Diabetes Induction as a Generational Model for Growth Restriction of Rat. Reprod. Sci. 30, 2416–2428 (2023). https://doi.org/10.1007/s43032-023-01198-9

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