المؤلفون: Zhao, Allan, Jiang, Hong, Palomares, Arturo Reyes, Larsson, Alice, He, Wenteng, Grünler, Jacob, Zheng, Xiaowei, Rodriguez Wallberg, Kenny A, Catrina, Sergiu-Bogdan, Deng, Qiaolin

المصدر: EMBO Reports; Apr2024, Vol. 25 Issue 4, p1752-1772, 21p

مستخلص: Emerging evidence indicates that parental diseases can impact the health of subsequent generations through epigenetic inheritance. Recently, it was shown that maternal diabetes alters the metaphase II oocyte transcriptome, causing metabolic dysfunction in offspring. However, type 1 diabetes (T1D) mouse models frequently utilized in previous studies may be subject to several confounding factors due to severe hyperglycemia. This limits clinical translatability given improvements in glycemic control for T1D subjects. Here, we optimize a T1D mouse model to investigate the effects of appropriately managed maternal glycemic levels on oocytes and intrauterine development. We show that diabetic mice with appropriate glycemic control exhibit better long-term health, including maintenance of the oocyte transcriptome and chromatin accessibility. We further show that human oocytes undergoing in vitro maturation challenged with mildly increased levels of glucose, reflecting appropriate glycemic management, also retain their transcriptome. However, fetal growth and placental function are affected in mice despite appropriate glycemic control, suggesting the uterine environment rather than the germline as a pathological factor in developmental programming in appropriately managed diabetes. Synopsis: Appropriate glycemic management in diabetes protects the female germline from hyperglycemia-induced molecular alterations. It is not sufficient though to protect the uterine environment and affects fetal development, suggesting that the uterine environment might be a potential therapeutic target. Improved treatment for patients with type 1 diabetes (T1D) has led to appropriate glycemic management for patients but effects on offspring development persist. Glycemic levels reflecting appropriate glycemic management safeguard the molecular signatures of oocytes from both T1D model mice and human donors. Glycemic levels reflecting appropriate glycemic management fail to protect fetal development from an adverse uterine environment and placental hypoxia. Appropriate glycemic management in diabetes protects the female germline from hyperglycemia-induced molecular alterations. It is not sufficient though to protect the uterine environment and affects fetal development, suggesting that the uterine environment might be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

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المؤلفون: Zheng, Xiaowei, Narayanan, Sampath, Xu, Cheng, Eliasson Angelstig, Sofie, Grunler, Jacob, Zhao, Allan, Di Toro, Alessandro, Bernardi, Luciano, Mazzone, Massimiliano, Carmeliet, Peter, Del Sole, Marianna, Solaini, Giancarlo, Forsberg, Elisabete A., Zhang, Ao, Brismar, Kerstin, Schiffer, Tomas A., Rajamand Ekberg, Neda, Botusan, Ileana Ruxandra, Palm, Fredrik, Catrina, Sergiu-Bogdan

مصطلحات موضوعية: diabetes, hypoxia, hypoxia-inducible factor-1, reactive oxygen species, mitochondria, diabetic complications, Human, Mouse, Endocrinology and Diabetes, Endokrinologi och diabetes

الوصف: Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, ...

وصف الملف: application/pdf

العلاقة: eLIFE, 2022, 11; orcid:0000-0001-7625-1103; orcid:0000-0001-7961-1821; orcid:0000-0002-0127-3348; http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469764Test; PMID 35164902; ISI:000760317000001

الإتاحة: https://doi.org/10.7554/eLife.70714Test
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469764Test