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Exercise during pregnancy improve organ development in offspring with gestational diabetes mellitus Shengju Chen, Hangming Fan, Yu Chen Abstract In this commentary, we discuss the study by Tang et al., “Effect of exercise during pregnancy on offspring development through ameliorating high glucose and hypoxia in gestational diabetes mellitus”. Gestational diabetes mellitus (GDM), defined as ‘glucose intolerance with onset or first recognition during pregnancy’, impacts millions of women worldwide and poses significant health risks. Exercise during pregnancy has been shown to improve offspring health outcomes in obese mothers, potentially reducing epigenetic changes associated with maternal high-fat diets and minimizing abnormalities in lipid and glucose metabolism. However, while prenatal exercise’s impact on metabolic disorders in GDM offspring has been explored, its effects on organ growth remain insufficiently understood. Tang et al. identified GLUT1 and HIF1 as key regulators influencing the development of the heart, liver, and kidney in GDM offspring. Their study demonstrates that exercise during pregnancy supports organ development by inhibiting placental GLUT1 and HIF1 expression in GDM. This work contributes to understanding the role of GLUT1 and HIF1 in moderating the effects of prenatal exercise on organ development in GDM-affected offspring, supporting the idea that maternal exercise is an important intervention for improving offspring outcomes in GDM pregnancies and warrants further investigation in future epigenetic research. Introduction Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications, affecting approximately 20.9 million pregnant women and their newborns worldwide as of 2020. GDM is associated with a range of adverse pregnancy outcomes, including preeclampsia, polyhydramnios, and fetal organomegaly (Pettitt et al., 1980). Additionally, GDM poses several short-term risks to offspring, such as neonatal respiratory distress, metabolic complications (Ferrara et al., 2007), and increased perinatal mortality rates. The GDM quintet management model recommends five core interventions to mitigate these risks, exercise, dietary regulation, maternal education, pharmacological treatment, and fetal health evaluation (Association, 2003). Pathophysiologically, GDM is characterized by hyperglycemia, glucose intolerance, and insulin resistance, typically manifesting in the late second to early third trimester of pregnancy (Buchanan et al., 2012, Jovanovic and Pettitt, 2001, Pereira et al., 2015). Several mechanisms have been proposed to explain these outcomes, including chronic fetal hyperinsulinemia, impaired oxygenation due to elevated metabolic rates, and metabolic acidosis (Freinkel, 1980). In this commentary, we discuss the article by Tang et al., recently published in the recent issue of the World Journal of Diabetes, which explores the impact of maternal exercise during pregnancy on organ development in offspring of mothers with GDM. Risks and complications associated with GDM In a healthy pregnancy, insulin sensitivity decreases to allow more glucose availability for the fetus; however, normoglycemia is typically maintained through increased insulin production by pancreatic β-cells. In cases of GDM, the pancreas may fail to produce sufficient insulin, resulting in elevated blood glucose levels and the onset of GDM (Freinkel, 1980). GDM pregnancies can lead to additional complications that negatively impact maternal and fetal health (Poston et al., 2011). Immediate complications in offspring of overweight women with GDM include macrosomia, the most severe of which is shoulder dystocia; other neonatal complications such as hypoglycemia and hyperbilirubinemia have also been reported (Kaaja and Rönnemaa, 2008, Lecomte et al., 2017). Long-term exposure to GDM increases the risk of obesity, type 2 diabetes, and cardiovascular diseases (CVD) as offspring age (Capobianco et al., 2016). Epigenetic studies indicate that the intrauterine environment significantly influences offspring organ development, and exposure to elevated maternal blood levels can impair fetal health. Maintaining a healthy uterine environment is thus essential to promoting favorable health outcomes in offspring. Exercise, as a non-pharmacological intervention without side effects, is widely used in diabetes prevention and management. Given that pregnancy is a period when non-pharmacological interventions are especially favored by medical staff and patients, exercise is particularly promising for managing GDM. Benefits of exercise during pregnancy Eight national guidelines on exercise during pregnancy recommend 60-150 minutes of aerobic exercise per week for healthy pregnant women (Savvaki et al., 2018). The benefits of exercise for pregnant women include improved overall health, better weight management, reduced risk of GDM and gestational hypertension (Davenport et al., 2018, Yu et al., 2018). For women with GDM, moderate aerobic or combined exercise has been shown to enhance postprandial blood glucose control (Walter and Klaus, 2014), although the optimal duration and intensity remain unclear. Moderate exercise during pregnancy can improve maternal insulin sensitivity, reduce placental lipid accumulation in both male and female fetuses, and alleviate hypoxia, positively influencing the intrauterine environment and fetal growth (Laker et al., 2014). Exercise during pregnancy also promotes healthier liver glucose production, helps maintain liver triglycerides levels, and prevents the expression of liver enzymes and genes in offspring caused by maternal high-fat diet, thereby improving the offspring’s metabolic profile. These findings suggest that maternal exercise can mitigate modifications linked to a high-fat diet, protecting offspring from future metabolic diseases. Regulation of GLUT1 by maternal exercise and offspring health outcomes in GDM The placenta is responsible for transporting essential nutrients and oxygen from maternal to fetal circulation, as fetal gluconeogenesis is minimal (Kalhan and Parimi, 2000). GDM disrupts placental function, leading to various morphological (Treesh and Khair, 2015) and vascular changes (Aldahmash et al., 2022, El Sawy et al., 2018) and including fetal vascular changes and DNA methylation (Song et al., 2022). Placental transport proteins, such as glucose transporters, facilitate nutrient transfer from the mother to the fetus. Glucose is the primary energy source for both placental and fetal growth (Stanirowski et al., 2017), with GLUT1 and GLUT3 serving as the main placental glucose transport proteins in humans. GLUT1 is expressed in syncytiotrophoblast microvilli and the basal membrane, as well as in vascular endothelium and cell layers (Brown et al., 2011, Jansson et al., 1993). Research on GDM in humans and mice shows increased placental GLUT1 expression, likely due to increased glucose availability in maternal circulation, which enhances placental glucose consumption (Muralimanoharan et al., 2016). This increase in GLUT1 may contribute to the higher rates of macrosomia observed in GDM pregnancies (Stanirowski et al., 2022). Moreover, GDM leads to placental hypoxia, elevated hypoxia-inducible (HIF) levels, and glial cell missing 1 degradation, inhibiting trophoblast migration and invasion. Exercise during pregnancy can significantly reduce placental GLUT1 expression and alleviate hypoxia. Silencing GLUT1 can partially counteract the reduced trophoblast migration caused by hyperglycemia and hypoxia. Beyond energy metabolism, GLUT1 is also related to the development of the heart, liver, and kidneys. Zhang et al. investigated the relationship between GLUT1 expression in these organs and their structural and pathological changes, examining how exercise influences growth and development in offspring with GDM. In a neonatal GLUT1 transgenic heart model, increased glucose metabolism can stimulate hyperplastic growth after cardiac injury (Fajardo et al., 2021). Maternal exercise during pregnancy has been shown to lower hepatic GLUT1 expression, reduce inflammatory infiltration, and decrease the risk of liver disease in adult offspring (Baker and Friedman, 2018). In the kidney, GLUT1 functions vary by cell type; elevated GLUT1 in mesangial cells can impair kidney structure, while in podocytes, it may reduce mesangial expansion and fibronectin accumulation (Chen et al., 2024). Future research is recommended to clarify the specific mechanisms by which exercise benefits renal structure and function in GDM offspring. Directions for future studies The specific mechanisms by which maternal exercise during pregnancy improves health outcomes in diabetic offspring remain under investigation, with multiple synergistic pathways likely involved. Given its role in glucose metabolism, GLUT1 is of particular interest as a regulatory factor in mitigating adverse outcomes in offspring of mothers with GDM through exercise. This underscores the significant influence of exercise on glucose metabolism, which enhances the intrauterine environment and supports offspring health. Improved placental GLUT1 expression appears to regulate the GLUT1 levels in offspring organs, positively impacting organ development. These findings extend our understanding of exercise-related epigenetics modifications, yet further research is essential to clarify the pathways through which maternal exercise regulates placental GLUT1, thereby promoting healthy organ development in offspring and underscoring the benefits of prenatal exercise. Conclusion GDM can lead to adverse outcomes for both the mother and their offspring. Maternal exercise during pregnancy improves the intrauterine environment and enhances offspring health. Elevated maternal blood glucose can cause fetal hyperinsulinemia, hypoxia, and metabolic acidosis. Exercise enhances glucose metabolism, reduces high blood sugar levels, and supports a healthier intrauterine environment, thereby decreasing the risk of metabolic diseases in offspring. The study by Tang et al. confirms the association between elevated placental GLUT1 expression in GDM and abnormal offspring organ development related to hypoxia. Their research demonstrates that exercise during pregnancy can improve placental glucose transport and reduce hypoxia, mitigating adverse developmental outcomes in offspring organs at various stages. These findings validate, across human, animal, and cellular models, the molecular mechanisms through which maternal exercise enhances organ development in offspring affected by GDM. This contributes to clinical application and emphasizes the role of epigenetics in promoting offspring health. As research in epigenetic progresses, the pathways through exercise benefits GDM-affected offspring will become clearer, with GLUT1 as a central regulator of glucose metabolism. Further investigation into these mechanisms will advance our understanding of how maternal exercise supports healthier outcomes for GDM offspring. Aldahmash, W.M., Alwasel, S.H., Aljerian, K., 2022. Gestational diabetes mellitus induces placental vasculopathies. Environ Sci Pollut Res Int 29 (13), 19860-19868. Association, A.D., 2003. Gestational diabetes mellitus. Diabetes Care 26 Suppl 1, S103-105. Baker, P.R., 2nd, Friedman, J.E., 2018. Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease. J Clin Invest 128 (9), 3692-3703. Brown, K., Heller, D.S., Zamudio, S., Illsley, N.P., 2011. Glucose transporter 3 (GLUT3) protein expression in human placenta across gestation. Placenta 32 (12), 1041-1049. Buchanan, T.A., Xiang, A.H., Page, K.A., 2012. 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