Diabetes is a chronic disease characterized by a partial or absolute lack of insulin synthesis, secretion, and insulin resistance. In the last few decades, the prevalence of diabetes has increased, with approximately 422 million diabetic people worldwide, and about 1.5 million deaths every year (World Health Organization, 2023). Moreover, nearly 21.3 million births worldwide are affected yearly by high blood glucose levels during pregnancy (Cho et al., 2018). Exposure to a substandard uterine environment in early life and childhood increases the risk of metabolic dysregulation in the offspring in adulthood. Fetal programming is related to developmental plasticity in response to the environment, nutritional signals, and potential metabolic disorders (risk of cardiovascular, type 2 diabetes, metabolic and behavioral diseases) in adulthood, as well as health (Gluckman and Hanson, 2007). Over the past decades, our research group and others have dedicated efforts to understanding the influence of maternal diabetes on rat offspring. Our previous studies have shown that an unfavorable intrauterine environment induced by maternal hyperglycemia leads to alterations in pre-embryos (Bueno et al., 2020), fetuses, newborns (Araujo-Silva et al., 2021), and adult female offspring (Paula et al., 2022). Yet, maternal hyperglycemia-induced pancreatic islet damage leads to impaired insulin, glucagon, and somatostatin synthesis/secretion homeostasis, which causes hyperglycemia in the offspring at birth (Iessi et al., 2016). In addition, female rats exposed to hyperglycemia during pregnancy present pancreatic β-cell dysfunction and dyslipidemia, contributing to a glucose intolerant status (Paula et al., 2022) and hypertrophied adipose tissue (Saullo et al., 2022).

The intrauterine exposition of fetuses to an energy unbalanced environment provided by a high fat diet, obesity, dyslipidemia, hyperglycemia, insulin resistance, and Diabetes mellitus results in epigenetic alterations and metabolic reprogramming (Sinha et al., 2021). As a central hub in metabolism, mitochondria play a central role in this adaptive process in response to the intracellular environment. However, abnormal mitochondrial functioning might impair oxidative phosphorylation, decreasing energetic efficiency and increasing oxidative stress, which can be harmful to the cells, especially those with high-energy requirements (Bansal et al., 2019), such as skeletal muscle. Under such stressful conditions, atypical nuclear positioning is often observed, indicating muscle dysfunction (Metzger et al., 2012; Auld and Folker, 2016). In this regard, it was shown that type 2 diabetes affects muscle morphology and architecture in rats (Murakami et al., 2012). Then, considering its high-energy consumption associated with high metabolic activity, the soleus muscle constitutes a valuable model to investigate diabetes-induced mitochondrial damages. Alterations in mitochondrial metabolism and dynamics have been implicated as an emerging mechanistic framework involved in the etiology and pathophysiological progression of insulin resistance and diabetes (Rovira-Llopis et al., 2017; Jheng et al., 2012). Abnormal expression of proteins related to mitochondrial fusion and fission machinery and its control by adenosine monophosphate-activated protein kinase (AMPK) has been proposed (Tilokani et al., 2018; Vásquez-Trincado et al., 2016; Chan, 2020; Skuratovskaia et al., 2020). AMPK is a well-known energy sensor that regulates many biological processes, such as oxidative stress, mitochondrial function, and cell survival (Zhang et al., 2017). Its downstream target PI3K (phosphatidylinositol 3-kinase) is a critical effector of the actions of insulin, playing an essential regulatory function on cell metabolism and insulin signaling (Taniguchi et al., 2006). Additionally, insulin resistance might affect downstream substrates involved in cell survival and proliferation, as the MAPK/ERK signaling pathway (Cobb, 1999), which is directly involved with mitochondrial dynamics regulation, since the activation of ERK promotes mitochondrial fission due to the direct phosphorylation and activation of DRP1 (Kashatus et al., 2015a).

All these findings demonstrate that the maternal environment influences fetal plasticity and causes changes in the metabolism and vasculature of different tissues and organs of fetuses and infants, leading to impaired glucose metabolism, β-cell dysfunction, insulin resistance, obesity, and diabetes (Ozanne and Constância, 2007). However, molecular alterations of these outcomes are not entirely elucidated. Therefore, this study aimed to verify whether exposure to a hyperglycemic intrauterine environment during pregnancy induces systemic insulin resistance and alterations in the skeletal muscle of adult rat offspring (150 days of life), and the underlying mechanisms were also investigated.