|
1
|
Tang D, Wang CF, Wang J, Jing XT, Ma J. Mechanism of the epidermal growth factor receptor in promoting endothelial cell dysfunction in gestational diabetes mellitus. World J Diabetes 2025; 16:105173. [DOI: 10.4239/wjd.v16.i6.105173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/29/2025] [Accepted: 05/08/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is a transmembrane protein that is differentially expressed in gestational diabetes mellitus (GDM). Endothelial dysfunction is a hallmark of GDM and plays a key role in its pathogenesis. EGFR is associated with endothelial dysfunction in the context of various diseases. However, the exact mechanism by which EGFR causes endothelial dysfunction in GDM is unknown, particularly its regulation at the transcriptional and protein levels.
AIM To explore the molecular mechanism by which EGFR influences endothelial cell dysfunction in GDM at the transcriptional and protein levels.
METHODS Quantitative real-time polymerase chain reaction was used to detect the expression of EGFR and H19. Western blotting was used to detect the expression of endothelial cell dysfunction markers. A cell counting kit 8 assay was used to assess cell viability, flow cytometry was used to assess apoptosis, scratch and Transwell assays were used to assess cell migration, and a tube formation assay was used to assess cell vascular formation. Hematoxylin-eosin staining was used to observe histopathological changes in the placentas of the mice.
RESULTS In this study, EGFR was upregulated in clinical samples, GDM animal models and GDM cell models, and the knockdown of EGFR could mitigate the effect of streptozotocin (STZ) and high glucose (HG); promoted the proliferation, migration and vascularization of human umbilical vein endothelial cells (HUVECs); inhibited cell apoptosis and the expression of endothelial cell dysfunction markers (vascular cell adhesion molecule-1, tumor necrosis factor-α, vascular endothelial growth factor-A, and intercellular cell adhesion molecule-1); and alleviated the process of GDM in vivo. Mechanistically, EIF4A3 binding to long noncoding RNA H19 increased the stability of EGFR messenger RNA, thereby promoting HG-induced HUVECs dysfunction or STZ-induced endothelial cell dysfunction in GDM mice. In addition, ERRFI1 also regulated the expression of EGFR, and ERRFI1 inhibited EGFR activity by binding to EGFR, thereby inhibiting HG-induced HUVECs dysfunction.
CONCLUSION Our study revealed that EGFR can accelerate the development of GDM by promoting endothelial cell dysfunction.
Collapse
Affiliation(s)
- Dan Tang
- Department of Obstetrics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Cheng-Fen Wang
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jue Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Xiao-Tao Jing
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing Ma
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| |
Collapse
|
|
2
|
Li L, Wu YQ, Yang JE. Stress-Related LncRNAs and Their Roles in Diabetes and Diabetic Complications. Int J Mol Sci 2025; 26:2194. [PMID: 40076814 PMCID: PMC11900361 DOI: 10.3390/ijms26052194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/23/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder and one of the most significant global health burdens worldwide. Key pathophysiological mechanisms underlying its onset and associated complications include hyperglycemia-related stresses, such as oxidative stress and endoplasmic reticulum stress (ER stress). Long non-coding RNAs (lncRNAs), defined as RNA transcripts longer than 200 nucleotides and lacking protein-coding capacity, play crucial roles in various biological processes and have emerged as crucial regulators in the pathogenesis of diabetes. This review provides a comprehensive overview of lncRNA biogenesis and its functional roles, emphasizing recent findings that link stress-related lncRNAs to diabetic pathology and complications. Also, we discuss how lncRNAs influence diabetes and its complications by modulating pathways involved in cell death, proliferation, inflammation, and fibrosis, which contribute to pancreatic β cell dysfunction, insulin resistance, diabetic nephropathy, and retinopathy. By analyzing current research, we aim to enhance understanding of lncRNA involvement in diabetes while identifying potential therapeutic targets and guiding future research directions to elucidate the complex mechanisms underlying this pervasive condition.
Collapse
Affiliation(s)
| | | | - Jin-E Yang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, China; (L.L.); (Y.-Q.W.)
| |
Collapse
|
|
3
|
Guo HY, Tang SB, Li LJ, Lin J, Zhang TT, Chao S, Jin XW, Xu KP, Su XF, Yin S, Zhao MH, Huang GA, Yang LJ, Shen W, Zhang L, Zhang CL, Sun QY, Ge ZJ. Gestational diabetes mellitus causes genome hyper-methylation of oocyte via increased EZH2. Nat Commun 2025; 16:127. [PMID: 39747080 PMCID: PMC11696910 DOI: 10.1038/s41467-024-55499-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 12/13/2024] [Indexed: 01/04/2025] Open
Abstract
Gestational diabetes mellitus (GDM), a common pregnancy disease, has long-term negative effects on offspring health. Epigenetic changes may have important contributions to that, but the underlying mechanisms are not well understood. Here, we report the influence of GDM on DNA methylation of offspring (GDF1) oocytes and the possible mechanisms. Our results show that GDM induces genomic hyper-methylation of offspring oocytes, and at least a part of the altered methylation is inherited by F2 oocytes, which may be a reason for the inheritance of metabolic disorders. We further find that GDM exposure increases the expression of Ezh2 in oocytes. Ezh2 regulates DNA methylation via DNMT1, and Ezh2 knockdown reduces the genomic methylation level of GDF1 oocytes. These results suggest that GDM may induce oocyte genomic hyper-methylation of offspring via enhancing the Ezh2 expression recruiting more DNMT1 into nucleus.
Collapse
Affiliation(s)
- Hong-Yan Guo
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Shou-Bin Tang
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
- Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
| | - Li-Jun Li
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Jing Lin
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
- College of Horticulture, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Ting-Ting Zhang
- Reproductive Medicine Center, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, 450003, People's Republic of China
| | - Shuo Chao
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Xiao-Wen Jin
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Kui-Peng Xu
- College of Horticulture, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Xiao-Feng Su
- College of Horticulture, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Shen Yin
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Ming-Hui Zhao
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Gui-An Huang
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Li-Jia Yang
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Wei Shen
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China
| | - Lei Zhang
- Department of Obstetrics and Gynecology, School of Clinical Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, People's Republic of China
| | - Cui-Lian Zhang
- Reproductive Medicine Center, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, 450003, People's Republic of China.
| | - Qing-Yuan Sun
- Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health and Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, 510317, People's Republic of China.
- Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, People's Republic of China.
| | - Zhao-Jia Ge
- College of Life Sciences, Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China.
| |
Collapse
|
|
4
|
Huang D, Li M, Qiao Z, Zhou H, Zhang Z, Zhou J. Quetiapine Reverses the Behavior and Myelination in Alcohol-Exposed Gestational Diabetes Mellitus Offspring Mice via ERK1/2 Signaling. Biol Pharm Bull 2025; 48:323-335. [PMID: 40159228 DOI: 10.1248/bpb.b24-00642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Gestational diabetes mellitus (GDM) is a glucose metabolism abnormality that first emerges during pregnancy and may negatively affect the behavioral and neurodevelopmental outcomes of offspring. Quetiapine (QUE) has been shown to promote differentiation of oligodendrocyte precursor cells (OPCs) and protect oligodendrocytes and myelination. To explore the effects of QUE on improving the expression of conditioned place preference (CPP) and myelination in the infralimbic cortex (IL) of the medial prefrontal cortex in alcohol-exposed GDM offspring mice, we evaluated CPP expression in 5-week-old alcohol-exposed GDM offspring and treated them with QUE and the extracellular-regulated protein kinase (ERK) inhibitor U0126. Immunohistochemical staining compared the numbers of mature oligodendrocytes, OPCs, and myelin expression levels. Immunofluorescence staining was employed to examine OPC differentiation and the activation of the ERK1/2 signaling pathway. In GDM offspring, CPP expression increased considerably following alcohol exposure, whereas early treatment with QUE or U0126 significantly decreased CPP expression. Meanwhile, alcohol exposure resulted in substantial activation of the ERK1/2 signaling pathway within OPCs in the IL region, as well as a substantial reduction in OPC differentiation, mature oligodendrocyte count, and myelin expression. QUE or U0126 inhibited the activation of the ERK1/2 signaling pathway within OPCs in the IL region of alcohol-exposed GDM offspring and markedly restored OPC differentiation, mature oligodendrocyte numbers, and myelin expression. Collectively, QUE enhanced the differentiation of OPCs in the IL region of GDM offspring after alcohol exposure by regulating the overactivation of the ERK1/2 signaling pathway, thus partially reversing myelination loss and ultimately improving CPP expression.
Collapse
Affiliation(s)
- Dong Huang
- Clinical Research Center, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
| | - Maolin Li
- Clinical Research Center, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
| | - Zhifei Qiao
- Clinical Research Center, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
| | - Hongli Zhou
- Clinical Research Center, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
| | - Zuo Zhang
- Clinical Research Center, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
| | - Jiyin Zhou
- Clinical Research Center, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China
| |
Collapse
|
|
5
|
Shi Y, Ma J, Li S, Liu C, Liu Y, Chen J, Liu N, Liu S, Huang H. Sex difference in human diseases: mechanistic insights and clinical implications. Signal Transduct Target Ther 2024; 9:238. [PMID: 39256355 PMCID: PMC11387494 DOI: 10.1038/s41392-024-01929-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 06/26/2024] [Accepted: 07/23/2024] [Indexed: 09/12/2024] Open
Abstract
Sex characteristics exhibit significant disparities in various human diseases, including prevalent cardiovascular diseases, cancers, metabolic disorders, autoimmune diseases, and neurodegenerative diseases. Risk profiles and pathological manifestations of these diseases exhibit notable variations between sexes. The underlying reasons for these sex disparities encompass multifactorial elements, such as physiology, genetics, and environment. Recent studies have shown that human body systems demonstrate sex-specific gene expression during critical developmental stages and gene editing processes. These genes, differentially expressed based on different sex, may be regulated by androgen or estrogen-responsive elements, thereby influencing the incidence and presentation of cardiovascular, oncological, metabolic, immune, and neurological diseases across sexes. However, despite the existence of sex differences in patients with human diseases, treatment guidelines predominantly rely on male data due to the underrepresentation of women in clinical trials. At present, there exists a substantial knowledge gap concerning sex-specific mechanisms and clinical treatments for diverse diseases. Therefore, this review aims to elucidate the advances of sex differences on human diseases by examining epidemiological factors, pathogenesis, and innovative progress of clinical treatments in accordance with the distinctive risk characteristics of each disease and provide a new theoretical and practical basis for further optimizing individualized treatment and improving patient prognosis.
Collapse
Affiliation(s)
- Yuncong Shi
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Jianshuai Ma
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Sijin Li
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Chao Liu
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Yuning Liu
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Jie Chen
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ningning Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shiming Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Hui Huang
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China.
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
| |
Collapse
|
|
6
|
Li N, Liu HY, Liu SM. Deciphering DNA Methylation in Gestational Diabetes Mellitus: Epigenetic Regulation and Potential Clinical Applications. Int J Mol Sci 2024; 25:9361. [PMID: 39273309 PMCID: PMC11394902 DOI: 10.3390/ijms25179361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/08/2024] [Accepted: 08/15/2024] [Indexed: 09/15/2024] Open
Abstract
Gestational diabetes mellitus (GDM) represents a prevalent complication during pregnancy, exerting both short-term and long-term impacts on maternal and offspring health. This review offers a comprehensive outline of DNA methylation modifications observed in various maternal and offspring tissues affected by GDM, emphasizing the intricate interplay between DNA methylation dynamics, gene expression, and the pathogenesis of GDM. Furthermore, it explores the influence of environmental pollutants, maternal nutritional supplementation, and prenatal gut microbiota on GDM development through alterations in DNA methylation profiles. Additionally, this review summarizes recent advancements in DNA methylation-based diagnostics and predictive models in early GDM detection and risk assessment for subsequent type 2 diabetes. These insights contribute significantly to our understanding of the epigenetic mechanisms underlying GDM development, thereby enhancing maternal and fetal health outcomes and advocating further efforts in this field.
Collapse
Affiliation(s)
- Nan Li
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, China
| | - Huan-Yu Liu
- Department of Obstetrics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, China
- Hubei Clinical Research Center for Prenatal Diagnosis and Birth Health, 169 Donghu Road, Wuhan 430071, China
| | - Song-Mei Liu
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, China
- Hubei Clinical Research Center for Prenatal Diagnosis and Birth Health, 169 Donghu Road, Wuhan 430071, China
| |
Collapse
|
|
7
|
Li X, Zhu W, Cheng Y, Ren Z, Liu X, Yang H, Ding G, Huang H. Intrauterine hyperglycemia induces SIRT3-mediated mitochondrial dysfunction: the fetal origin pathogenesis of precocious osteoarthritis. Osteoarthritis Cartilage 2024; 32:950-962. [PMID: 38782252 DOI: 10.1016/j.joca.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 04/06/2024] [Accepted: 05/01/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVE Diabetes and other metabolic and inflammatory comorbidities are highly associated with osteoarthritis (OA). However, whether early-life hyperglycemia exposure affects susceptibility to long-term OA is still unknown. The purpose of this study was to explore the fetal origins of OA and provide insights into early-life safeguarding for individual health. METHOD This study utilized streptozotocin to induce intrauterine hyperglycemia and performed destabilization of the medial meniscus surgery on the knee joints of the offspring mice to induce accelerated OA. Cartilage degeneration-related markers, as well as the expression levels of mitochondrial respiratory chain complexes and mitophagy genes in the adult offspring mice, were investigated. In vitro, mitochondrial function and mitophagy of chondrocyte C28/I2 cells stimulated under high glucose conditions were also evaluated. The methylation levels of the sirt3 gene promoter region in the articular cartilage of intrauterine hyperglycemia-exposed offspring mice were further analyzed. RESULTS In this study, we found that the intrauterine hyperglycemic environment could lead to an increase in individual susceptibility to OA in late adulthood, mainly due to persistently low levels of Sirt3 expression. Downregulation of Sirt3 causes impaired mitophagy in chondrocytes and abnormal mitochondrial respiratory function due to a failure to clear aged and damaged mitochondria in a timely manner. Overexpressing Sirt3 at the cellular level or using Sirt3 agonists like Honokiol in mouse models can partially rescue mitophagy disorders caused by the hyperglycemic environment and thus alleviate the progression of OA. CONCLUSION Our study revealed a significantly increased susceptibility to OA in the gestational diabetes mellitus offspring, which is partly attributed to exposure to adverse factors in utero and ultimately to the onset of disease via epigenetic modulation.
Collapse
Affiliation(s)
- Xinyuan Li
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Wanbo Zhu
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi Cheng
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Zhuoran Ren
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Xinmei Liu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Hongbo Yang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Guolian Ding
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Hefeng Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
| |
Collapse
|
|
8
|
Yan YS, Mo JY, Huang YT, Zhu H, Wu HY, Lin ZL, Liu R, Liu XQ, Lv PP, Feng C, Sheng JZ, Jin M, Huang HF. Intrauterine hyperglycaemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling. Nutr Diabetes 2024; 14:56. [PMID: 39043630 PMCID: PMC11266655 DOI: 10.1038/s41387-024-00299-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 05/03/2024] [Accepted: 05/29/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified. METHODS Pregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon. RESULTS Short-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation. CONCLUSIONS Short-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.
Collapse
Affiliation(s)
- Yi-Shang Yan
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
| | - Jia-Ying Mo
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
- The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Yu-Tong Huang
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China
| | - Hai-Yan Wu
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
| | - Zhong-Liang Lin
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
- The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Rui Liu
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
- The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Xuan-Qi Liu
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
| | - Ping-Ping Lv
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
| | - Chun Feng
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China
| | - Jian-Zhong Sheng
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China.
- The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China.
| | - Min Jin
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China.
| | - He-Feng Huang
- Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, China.
- The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China.
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.
| |
Collapse
|
|
9
|
Ghasemi Gojani E, Rai S, Norouzkhani F, Shujat S, Wang B, Li D, Kovalchuk O, Kovalchuk I. Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment. Curr Issues Mol Biol 2024; 46:7621-7667. [PMID: 39057094 PMCID: PMC11275945 DOI: 10.3390/cimb46070453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
The β-cells within the pancreas play a pivotal role in insulin production and secretion, responding to fluctuations in blood glucose levels. However, factors like obesity, dietary habits, and prolonged insulin resistance can compromise β-cell function, contributing to the development of Type 2 Diabetes (T2D). A critical aspect of this dysfunction involves β-cell dedifferentiation and transdifferentiation, wherein these cells lose their specialized characteristics and adopt different identities, notably transitioning towards progenitor or other pancreatic cell types like α-cells. This process significantly contributes to β-cell malfunction and the progression of T2D, often surpassing the impact of outright β-cell loss. Alterations in the expressions of specific genes and transcription factors unique to β-cells, along with epigenetic modifications and environmental factors such as inflammation, oxidative stress, and mitochondrial dysfunction, underpin the occurrence of β-cell dedifferentiation and the onset of T2D. Recent research underscores the potential therapeutic value for targeting β-cell dedifferentiation to manage T2D effectively. In this review, we aim to dissect the intricate mechanisms governing β-cell dedifferentiation and explore the therapeutic avenues stemming from these insights.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (E.G.G.)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (E.G.G.)
| |
Collapse
|
|
10
|
Xiao Z, Liu X, Luan X, Duan R, Peng W, Tong C, Qiao J, Qi H. Glucose uptake in trophoblasts of GDM mice is regulated by the AMPK-CLUT3 signaling pathway. Sci Rep 2024; 14:12051. [PMID: 38802412 PMCID: PMC11130200 DOI: 10.1038/s41598-024-61719-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 05/08/2024] [Indexed: 05/29/2024] Open
Abstract
GDM, as a metabolic disease during pregnancy, regulates GLUT3 translocation by AMPK, thereby affecting glucose uptake in trophoblasts. It provides a new research idea and therapeutic target for alleviating intrauterine hyperglycemia in GDM. STZ was used to construct GDM mice, inject AICAR into pregnant mice, and observe fetal and placental weight; flow cytometry was employed for the detection of glucose uptake by primary trophoblast cells; immunofluorescence was applied to detect the localization of GLUT3 and AMPK in placental tissue; Cocofal microscope was used to detect the localization of GLUT3 in trophoblast cells;qRT-PCR and Western blot experiments were carried out to detect the expression levels of GLUT3 and AMPK in placental tissue; CO-IP was utilized to detect the interaction of GLUT3 and AMPK. Compared with the normal pregnancy group, the weight of the fetus and placenta of GDM mice increased (P < 0.001), and the ability of trophoblasts to take up glucose decreased (P < 0.001). In addition, AMPK activity in trophoblasts and membrane localization of GLUT3 in GDM mice were down-regulated compared with normal pregnant mice (P < 0.05). There is an interaction between GLUT3 and AMPK. Activating AMPK in trophoblasts can up-regulate the expression of GLUT3 membrane protein in trophoblasts of mice (P < 0.05) and increase the glucose uptake of trophoblasts (P < 0.05). We speculate that inhibition of AMPK activity in GDM mice results in aberrant localization of GLUT3, which in turn attenuates glucose uptake by placental trophoblast cells. AICAR activates AMPK to increase the membrane localization of GLUT3 and improve the glucose uptake capacity of trophoblasts.
Collapse
Affiliation(s)
- Zhenghua Xiao
- Department of Obstetrics, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, People's Republic of China
| | - Xue Liu
- Department of Obstetrics, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, People's Republic of China
| | - Xiaojin Luan
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Ran Duan
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Youyi Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Wei Peng
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Youyi Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Chao Tong
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Juan Qiao
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Youyi Road, Yuzhong District, Chongqing, 400016, People's Republic of China.
| | - Hongbo Qi
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
- Women and Children's Hospital of Chongqing Medical University, Chongqing, 401147, People's Republic of China.
| |
Collapse
|
|
11
|
Li X, Zhu W, Liu R, Ding G, Huang H. Cerium Oxide Nanozymes Improve Skeletal Muscle Function in Gestational Diabetic Offspring by Attenuating Mitochondrial Oxidative Stress. ACS OMEGA 2024; 9:21851-21863. [PMID: 38799328 PMCID: PMC11112706 DOI: 10.1021/acsomega.3c09025] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 04/14/2024] [Accepted: 04/30/2024] [Indexed: 05/29/2024]
Abstract
Gestational diabetes mellitus (GDM) is a significant complication during pregnancy that results in abnormalities in the function of multiple systems in the offspring, which include skeletal muscle dysfunction and reduced systemic metabolic capacity. One of the primary causes behind this intergenerational effect is the presence of mitochondrial dysfunction and oxidative stress in the skeletal muscle of the offspring due to exposure to a high-glucose environment in utero. Cerium oxide (CeO2) nanozymes are antioxidant agents with polymerase activity that have been widely used in the treatment of inflammatory and aging diseases. In this study, we synthesized ultrasmall particle size CeO2 nanozymes and applied them in GDM mouse offspring. The CeO2 nanozymes demonstrated an ability to increase insulin sensitivity and enhance skeletal muscle motility in GDM offspring by improving mitochondrial activity, increasing mitochondrial ATP synthesis function, and restoring abnormal mitochondrial morphology. Furthermore, at the cellular level, CeO2 nanozymes could ameliorate metabolic dysregulation and decrease cell differentiation in adult muscle cells induced by hyperglycemic stimuli. This was achieved through the elimination of endogenous reactive oxygen species (ROS) and an improvement in mitochondrial oxidative respiration function. In conclusion, CeO2 nanozymes play a crucial role in preserving muscle function and maintaining the metabolic stability of organisms. Consequently, they serve to reverse the negative effects of GDM on skeletal muscle physiology in the offspring.
Collapse
Affiliation(s)
- Xinyuan Li
- Obstetrics
and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai200433,China
- Research
Units of Embryo Original Diseases, Chinese
Academy of Medical Sciences (No. 2019RU056), Shanghai200011,China
- Key
Laboratory of Reproductive Genetics (Ministry of Education), Department
of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou310058,China
| | - Wanbo Zhu
- Department
of Orthopedics, Shanghai Sixth People’s Hospital Affiliated
to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai 200233, China
| | - Rui Liu
- Obstetrics
and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai200433,China
- Research
Units of Embryo Original Diseases, Chinese
Academy of Medical Sciences (No. 2019RU056), Shanghai200011,China
- Key
Laboratory of Reproductive Genetics (Ministry of Education), Department
of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou310058,China
- Reproductive
Medicine Center, International Institutes of Medicine, the Fourth
Affiliated Hospital, Zhejiang University
School of Medicine, Yiwu322000, China
| | - Guolian Ding
- Obstetrics
and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai200433,China
- Research
Units of Embryo Original Diseases, Chinese
Academy of Medical Sciences (No. 2019RU056), Shanghai200011,China
| | - Hefeng Huang
- Obstetrics
and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai200433,China
- Research
Units of Embryo Original Diseases, Chinese
Academy of Medical Sciences (No. 2019RU056), Shanghai200011,China
- Key
Laboratory of Reproductive Genetics (Ministry of Education), Department
of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou310058,China
| |
Collapse
|
|
12
|
Xu MT, Zhang M, Wang GL, Gong S, Luo MJ, Zhang J, Yuan HJ, Tan JH. Postovulatory Aging of Mouse Oocytes Impairs Offspring Behavior by Causing Oxidative Stress and Damaging Mitochondria. Cells 2024; 13:758. [PMID: 38727294 PMCID: PMC11083947 DOI: 10.3390/cells13090758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/25/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
Information on long-term effects of postovulatory oocyte aging (POA) on offspring is limited. Whether POA affects offspring by causing oxidative stress (OS) and mitochondrial damage is unknown. Here, in vivo-aged (IVA) mouse oocytes were collected 9 h after ovulation, while in vitro-aged (ITA) oocytes were obtained by culturing freshly ovulated oocytes for 9 h in media with low, moderate, or high antioxidant potential. Oocytes were fertilized in vitro and blastocysts transferred to produce F1 offspring. F1 mice were mated with naturally bred mice to generate F2 offspring. Both IVA and the ITA groups in low antioxidant medium showed significantly increased anxiety-like behavior and impaired spatial and fear learning/memory and hippocampal expression of anxiolytic and learning/memory-beneficial genes in both male and female F1 offspring. Furthermore, the aging in both groups increased OS and impaired mitochondrial function in oocytes, blastocysts, and hippocampus of F1 offspring; however, it did not affect the behavior of F2 offspring. It is concluded that POA caused OS and damaged mitochondria in aged oocytes, leading to defects in anxiety-like behavior and learning/memory of F1 offspring. Thus, POA is a crucial factor that causes psychological problems in offspring, and antioxidant measures may be taken to ameliorate the detrimental effects of POA on offspring.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Hong-Jie Yuan
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an 271018, China; (M.-T.X.); (M.Z.); (G.-L.W.); (S.G.); (M.-J.L.); (J.Z.)
| | - Jing-He Tan
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an 271018, China; (M.-T.X.); (M.Z.); (G.-L.W.); (S.G.); (M.-J.L.); (J.Z.)
| |
Collapse
|
|
13
|
Ren ZR, Luo SS, Qin XY, Huang HF, Ding GL. Sex-Specific Alterations in Placental Proteomics Induced by Intrauterine Hyperglycemia. J Proteome Res 2024; 23:1272-1284. [PMID: 38470452 DOI: 10.1021/acs.jproteome.3c00735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and the fetus. The aim of this study was to investigate the changes in the placenta in GDM and its gender differences. In this study, we established an intrauterine hyperglycemia model using ICR mice. We collected placental specimens from mice before birth for histological observation, along with tandem mass tag (TMT)-labeled proteomic analysis, which was stratified by sex. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratification by sex, the male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. Our study suggests that the observed sex differences in placental protein expression may explain the differential impact of GDM on offspring.
Collapse
Affiliation(s)
- Zhuo-Ran Ren
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Reproduction and Development, Shanghai 200032, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China
| | - Si-Si Luo
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China
- Shanghai First Maternity and Infant Hospital, Shanghai 201204, China
| | - Xue-Yun Qin
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Reproduction and Development, Shanghai 200032, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China
| | - He-Feng Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Reproduction and Development, Shanghai 200032, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China
- Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Guo-Lian Ding
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Reproduction and Development, Shanghai 200032, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China
| |
Collapse
|
|
14
|
da Silva LBG, Zajdenverg L, Keating E, Silvestre MPS, dos Santos BMB, Saunders C. Effect of Prenatal Care on Perinatal Outcomes of Pregnant Women with Diabetes Mellitus: A Systematic Review. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2024; 97:49-65. [PMID: 38559460 PMCID: PMC10964819 DOI: 10.59249/wpty4075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Objective: to evaluate the effect of prenatal care (PC) on perinatal outcomes of pregnant women with diabetes mellitus (DM). Methods: systematic review developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines and conducted through the population, intervention, control, and outcomes (PICO) strategy. Clinical trials and observational studies were selected, with adult pregnant women, single-fetus pregnancy, diagnosis of DM, or gestational DM and who had received PC and/or nutritional therapy (NT). The search was carried out in PubMed, Scopus, and BIREME databases. The quality of the studies was evaluated using the tools of the National Heart, Lung and Blood Institute-National Institutes of Health (NHLBI-NIH). Results: We identified 5972 records, of which 15 (n=47 420 pregnant women) met the eligibility criteria. The most recurrent outcomes were glycemic control (14 studies; n=9096 participants), hypertensive disorders of pregnancy (2; n=39 282), prematurity (6; n=40 163), large for gestational age newborns (4; n=1556), fetal macrosomia (birth weight >4kg) (6; n=2980) and intensive care unit admission (4; n=2022). Conclusions: The findings suggest that PC interferes with the perinatal outcome, being able to reduce the risks of complications associated with this comorbidity through early intervention, especially when the NT is an integral part of this assistance.
Collapse
Affiliation(s)
- Letícia B. G. da Silva
- Josué de Castro Institute of Nutrition, Federal
University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | | | - Elisa Keating
- Department of Biochemistry, Faculty of Medicine of
Porto, University of Porto, Porto, Portugal
| | | | - Beatriz M. B. dos Santos
- Multidisciplinary Residency Program at the Federal
University of Rio de Janeiro Maternity School, Rio de Janiero, RJ, Brazil
| | - Cláudia Saunders
- Josué de Castro Institute of Nutrition, Federal
University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
15
|
Meza-León A, Montoya-Estrada A, Reyes-Muñoz E, Romo-Yáñez J. Diabetes Mellitus and Pregnancy: An Insight into the Effects on the Epigenome. Biomedicines 2024; 12:351. [PMID: 38397953 PMCID: PMC10886464 DOI: 10.3390/biomedicines12020351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/17/2023] [Accepted: 01/08/2024] [Indexed: 02/25/2024] Open
Abstract
Worldwide, diabetes mellitus represents a growing health problem. If it occurs during pregnancy, it can increase the risk of various abnormalities in early and advanced life stages of exposed individuals due to fetal programming occurring in utero. Studies have determined that maternal conditions interfere with the genotypes and phenotypes of offspring. Researchers are now uncovering the mechanisms by which epigenetic alterations caused by diabetes affect the expression of genes and, therefore, the development of various diseases. Among the numerous possible epigenetic changes in this regard, the most studied to date are DNA methylation and hydroxymethylation, as well as histone acetylation and methylation. This review article addresses critical findings in epigenetic studies involving diabetes mellitus, including variations reported in the expression of specific genes and their transgenerational effects.
Collapse
Affiliation(s)
| | | | | | - José Romo-Yáñez
- Coordinación de Endocrinología Ginecológica y Perinatal, Instituto Nacional de Perinatología, Montes Urales 800, Lomas Virreyes, Mexico City 11000, Mexico
| |
Collapse
|
|
16
|
Wang S, Wu J, Chen Z, Wu W, Lu L, Cheng Y, Li S, Chen L, Tan X, Yang L, Wang C, Song Y. DNA methylation reprogramming mediates transgenerational diabetogenic effect induced by early-life p,p'-DDE exposure. CHEMOSPHERE 2024; 349:140907. [PMID: 38092165 DOI: 10.1016/j.chemosphere.2023.140907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/18/2023] [Accepted: 12/03/2023] [Indexed: 12/19/2023]
Abstract
Increasing evidence shows that an adverse environment during the early fetal development can affect the epigenetic modifications on a wide range of diabetes-related genes, leading to an increased diabetic susceptibility in adulthood or even in subsequent generations. p,p'-Dichlorodiphenoxydichloroethylene (p,p'-DDE) is a break-down product of the pesticide dichlorodiphenyltrichloroethane (DDT). p,p'-DDE has been associated with various health concerns, such as diabetogenic effect. However, the precise molecular mechanism remains unclear. In this study, p,p'-DDE was given by gavage to pregnant rat dams from gestational day (GD) 8 to GD15 to generate male germline to investiagate the transgenerational effects. We found that early-life p,p'-DDE exposure increased the transgenerational diabetic susceptibility through male germline inheritance. In utero exposure to p,p'-DDE altered the sperm DNA methylome in F1 progeny, and a significant number of those differentially methylated genes could be inherited by F2 progeny. Furthermore, early-life p,p'-DDE exposure altered DNA methylation in glucose metabolic genes Gck and G6pc in sperm and the methylation modification were also found in liver of the next generation. Our study demonstrate that DNA methylation plays a critical role in mediating transgenerational diabetogenic effect induced by early-life p,p'-DDE exposure.
Collapse
Affiliation(s)
- Shuo Wang
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Jingjing Wu
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Zhong Chen
- Center for Genomics, Loma Linda University School of Medicine, 11021 Campus Street, Loma Linda, CA, 92350, USA
| | - Wei Wu
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Liping Lu
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Yuzhou Cheng
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Shuqi Li
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Liangjing Chen
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Xiaohua Tan
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Lei Yang
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China
| | - Charles Wang
- Center for Genomics, Loma Linda University School of Medicine, 11021 Campus Street, Loma Linda, CA, 92350, USA
| | - Yang Song
- School of Public Health, Hangzhou Normal University, 2318 Yuhangtang Road, Hangzhou, China.
| |
Collapse
|
|
17
|
Govindarajah V, Sakabe M, Good S, Solomon M, Arasu A, Chen N, Zhang X, Grimes HL, Kendler A, Xin M, Reynaud D. Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring. J Clin Invest 2024; 134:e169730. [PMID: 37988162 PMCID: PMC10786695 DOI: 10.1172/jci169730] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 11/16/2023] [Indexed: 11/23/2023] Open
Abstract
Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the advanced glycation end product receptor (AGER) and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which lead to increased placental inflammation. In adult offspring, we find that this memory is associated with DNA methyltransferase 1 (DNMT1) upregulation and epigenetic changes in hematopoietic progenitors. Together, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes and that this memory constitutes a pathway connecting gestational health to adult pathologies.
Collapse
Affiliation(s)
| | | | - Samantha Good
- Division of Experimental Hematology and Cancer Biology and
| | | | - Ashok Arasu
- Division of Experimental Hematology and Cancer Biology and
| | - Nong Chen
- Division of Experimental Hematology and Cancer Biology and
| | - Xuan Zhang
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA
| | - H. Leighton Grimes
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA
- Department of Pediatrics and
| | - Ady Kendler
- Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Mei Xin
- Division of Experimental Hematology and Cancer Biology and
- Department of Pediatrics and
| | - Damien Reynaud
- Division of Experimental Hematology and Cancer Biology and
- Department of Pediatrics and
| |
Collapse
|
|
18
|
Thornton JM, Shah NM, Lillycrop KA, Cui W, Johnson MR, Singh N. Multigenerational diabetes mellitus. Front Endocrinol (Lausanne) 2024; 14:1245899. [PMID: 38288471 PMCID: PMC10822950 DOI: 10.3389/fendo.2023.1245899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 12/27/2023] [Indexed: 02/01/2024] Open
Abstract
Gestational diabetes (GDM) changes the maternal metabolic and uterine environment, thus increasing the risk of short- and long-term adverse outcomes for both mother and child. Children of mothers who have GDM during their pregnancy are more likely to develop Type 2 Diabetes (T2D), early-onset cardiovascular disease and GDM when they themselves become pregnant, perpetuating a multigenerational increased risk of metabolic disease. The negative effect of GDM is exacerbated by maternal obesity, which induces a greater derangement of fetal adipogenesis and growth. Multiple factors, including genetic, epigenetic and metabolic, which interact with lifestyle factors and the environment, are likely to contribute to the development of GDM. Genetic factors are particularly important, with 30% of women with GDM having at least one parent with T2D. Fetal epigenetic modifications occur in response to maternal GDM, and may mediate both multi- and transgenerational risk. Changes to the maternal metabolome in GDM are primarily related to fatty acid oxidation, inflammation and insulin resistance. These might be effective early biomarkers allowing the identification of women at risk of GDM prior to the development of hyperglycaemia. The impact of the intra-uterine environment on the developing fetus, "developmental programming", has a multisystem effect, but its influence on adipogenesis is particularly important as it will determine baseline insulin sensitivity, and the response to future metabolic challenges. Identifying the critical window of metabolic development and developing effective interventions are key to our ability to improve population metabolic health.
Collapse
Affiliation(s)
- Jennifer M. Thornton
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Nishel M. Shah
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Karen A. Lillycrop
- Institute of Developmental Sciences, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Wei Cui
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Mark R. Johnson
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Natasha Singh
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| |
Collapse
|
|
19
|
Yang MM, Wei J, Xu LL, Yan YS, Chen Y, Lv M, Jiang Y, Luo Q. Altered expression of long noncoding RNA MEG3 in the offspring of gestational diabetes mellitus induces impaired glucose tolerance in adulthood. Acta Diabetol 2024; 61:79-90. [PMID: 37688646 DOI: 10.1007/s00592-023-02169-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 08/02/2023] [Indexed: 09/11/2023]
Abstract
AIM Gestational diabetes mellitus (GDM) affects a significant number of women worldwide and has been associated with lifelong health consequences for their offspring, including increased susceptibility to obesity, insulin resistance, and type II diabetes. Recent studies have suggested that aberrant expression of the long non-coding RNA Meg3 in the liver may contribute to impaired glucose metabolism in individuals. In this study, we aimed to investigate whether intrauterine exposure to hyperglycemia affects glucose intolerance in puberty by mediating the overexpression of LncMeg3 in the liver. METHODS To test our hypothesis, we established an animal model of intrauterine hyperglycemia to mimic GDM. The progeny was observed for phenotypic changes, and intraperitoneal glucose tolerance tests, insulin tolerance tests, and pyruvate tolerance tests were conducted to assess glucose and insulin tolerance. We also measured LncMeg3 expression in the liver using real-time quantitative PCR and examined differential methylation areas (DMRs) in the Meg3 gene using pyrophosphoric sequencing. To investigate the role of LncMeg3 in glucose tolerance, we conducted Meg3 intervention by vein tail and analyzed the changes in the phenotype and transcriptome of the progeny using bioinformatics analysis. RESULTS We found that intrauterine exposure to hyperglycemia led to impaired glucose and insulin tolerance in the progeny, with a tendency toward increased fasting blood glucose in fat offspring at 16 weeks (P = 0.0004). LncMeg3 expression was significantly upregulated (P = 0.0061), DNMT3B expression downregulated (P = 0.0226), and DNMT3A (P = 0.0026), TET2 (P = 0.0180) expression upregulated in the liver. Pyrophosphoric sequencing showed hypomethylation in Meg3-DMRs (P = 0.0005). Meg3 intervention by vein tail led to a decrease in the percentage of obese and emaciated offspring (emaciation: 44% vs. 23%; obesity: 25% vs. 15%) and attenuated glucose intolerance. Bioinformatics analysis revealed significant differences in the transcriptome of the progeny, particularly in circadian rhythm and PPAR signaling pathways. CONCLUSION In conclusion, our study suggests that hypomethylation of Meg3-DMRs increases the expression of the imprinted gene Meg3 in the liver of males, which is associated with impaired glucose tolerance in GDM-F1. MEG3 interference may attenuate glucose intolerance, which may be related to transcriptional changes. Our findings provide new insights into the mechanisms underlying the long-term effects of intrauterine hyperglycemia on progeny health and highlight the potential of Meg3 as an intervention target for glucose intolerance.
Collapse
Affiliation(s)
- Meng Meng Yang
- Department of Obstetrics, Women's Hospital, of Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Wei
- Department of Obstetrics, Women's Hospital, of Zhejiang University School of Medicine, Hangzhou, China
| | - Li Li Xu
- Department of Obstetrics, Women's Hospital, of Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Shang Yan
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yuan Chen
- Department of Obstetrics, Women's Hospital, of Zhejiang University School of Medicine, Hangzhou, China
| | - Min Lv
- Department of Obstetrics, Women's Hospital, of Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Jiang
- Department of Obstetrics, Women's Hospital, of Zhejiang University School of Medicine, Hangzhou, China.
| | - Qiong Luo
- Department of Obstetrics, Women's Hospital, of Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
|
20
|
Wang GL, Yuan HJ, Kong QQ, Zhang J, Han X, Gong S, Xu MT, He N, Luo MJ, Tan JH. High glucose exposure of preimplantation embryos causes glucose intolerance and insulin resistance in F1 and F2 male offspring. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166921. [PMID: 37879502 DOI: 10.1016/j.bbadis.2023.166921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/10/2023] [Accepted: 10/18/2023] [Indexed: 10/27/2023]
Abstract
BACKGROUND Although studies suggest that maternal high glucose (HG) increases offspring susceptibility to type 2 diabetes mellitus (T2DM), the underlying mechanisms are largely unclear. We studied whether glucose levels in oviducts are elevated when pregestational diabetic females get pregnant and whether the oviductal HG (OVHG) would act directly on embryos to increase offspring's T2DM susceptibility. METHODS We established an in vivo model of OVHG by injecting female mice with streptozotocin (STZ) during the preimplantation period and an in vitro model of embryo culture with HG (ECHG) by culturing preimplantation embryos with HG, before examining glucose tolerance and insulin resistance (IR) in F1 and F2 offspring. FINDINGS Injection of female mice with STZ induced a lasting significant glucose elevation in blood and oviduct fluid during the preimplantation period. The glucose tolerance test showed that both the STZ-induced OVHG and the ECHG caused glucose intolerance in F1 male and F1-sired F2 male offspring but had no effect on female offspring. Insulin tolerance test and the analysis for IR-related gene expression and glycogen contents in liver and muscle revealed significant IR in these male offspring. INTERPRETATION This study provided evidence that HG can act directly on preimplantation embryos to increase offspring's T2DM susceptibility suggesting that the preimplantation period is a critical stage for transmission of mother's diabetes to offspring. FUND: This study was supported by grants from the China National Natural Science Foundation (Nos. 31772599, 32072738, 31702114, and 31902160), and the Natural Science Foundation of Shandong Province (Nos. ZR2022MC036, ZR2017BC025 and ZR2020QC102).
Collapse
Affiliation(s)
- Guo-Liang Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Hong-Jie Yuan
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Qiao-Qiao Kong
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Jie Zhang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Xiao Han
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Shuai Gong
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Ming-Tao Xu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Nan He
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Ming-Jiu Luo
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China
| | - Jing-He Tan
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, PR China.
| |
Collapse
|
|
21
|
Dávila-Santacruz S, Corona-Quintanilla DL, Velázquez-Orozco V, Martínez-Gómez M, Castelán F, Cuevas-Romero E, Barrales-Fuentes B, Nicolás-Toledo L, Rodríguez-Antolín J. Sucrose consumption modifies the urethrogenital reflex and histological organization of the bulbospongiosus muscle in the male rat. Physiol Behav 2024; 273:114391. [PMID: 37907190 DOI: 10.1016/j.physbeh.2023.114391] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 10/06/2023] [Accepted: 10/28/2023] [Indexed: 11/02/2023]
Abstract
Disorders of the bulbospongiosus muscle (Bsm) are associated with male sexual dysfunction, such as premature ejaculation. We determined the effect of sucrose-water consumption during pregnancy-lactation and postnatal on reflex responses and morphology of Bsm fibers in adult male Wistar rat offspring. Female rats were mated and grouped into consumed tap water mothers and sucrose-water (5 %) mothers during pregnancy-lactation to obtain experimental groups. Male pups were weaned and assigned into four groups (n = 12; each group). Those from control mothers who continued drinking tap water (CM-CO group) or sucrose water (CM-SO group), and those from sucrose mothers who drank tap water (SM-CO group) or continued drinking sucrose water (SM-SO group) until adult life. In male rat offspring (n = 6 per group) was recorded the electrical activity of Bsm was recorded during penile stimulation and urethrogenital reflex (UGR). Other male rat offspring were designated for histological analysis (n = 6 per group). Sucrose consumption during prenatal stages increased the frequency of the Bsm during UGR, while pre and postnatal consumption modified muscle fiber cross-sectional area and increased the collagen content, suggesting that a combination of a diet with pre- and postnatal sucrose changes the Bsm morphophysiology possibly causing male sexual dysfunctions.
Collapse
Affiliation(s)
| | | | - Verónica Velázquez-Orozco
- Doctorado en Ciencias Biológicas, Universidad Autónoma de Tlaxcala, Mexico; Licenciatura en Química Clínica, Facultad de Ciencias de la Salud, Universidad Autónoma de Tlaxcala
| | - Margarita Martínez-Gómez
- Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, 90070 Mexico; Instituto de Investigaciones Biomédicas, Departamento de Biología Celular y Fisiología, Universidad Nacional Autónoma de México, Tlaxcala, Mexico
| | - Francisco Castelán
- Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, 90070 Mexico; Instituto de Investigaciones Biomédicas, Departamento de Biología Celular y Fisiología, Universidad Nacional Autónoma de México, Tlaxcala, Mexico
| | - Estela Cuevas-Romero
- Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, 90070 Mexico
| | | | - Leticia Nicolás-Toledo
- Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, 90070 Mexico
| | - Jorge Rodríguez-Antolín
- Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, 90070 Mexico.
| |
Collapse
|
|
22
|
Chang W, Li W, Li P. The anti-diabetic effects of metformin are mediated by regulating long non-coding RNA. Front Pharmacol 2023; 14:1256705. [PMID: 38053839 PMCID: PMC10694297 DOI: 10.3389/fphar.2023.1256705] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/02/2023] [Indexed: 12/07/2023] Open
Abstract
Type 2 diabetes (T2D) is a metabolic disease with complex etiology and mechanisms. Long non-coding ribonucleic acid (LncRNA) is a novel class of functional long RNA molecules that regulate multiple biological functions through various mechanisms. Studies in the past decade have shown that lncRNAs may play an important role in regulating insulin resistance and the progression of T2D. As a widely used biguanide drug, metformin has been used for glucose lowering effects in clinical practice for more than 60 years. For diabetic therapy, metformin reduces glucose absorption from the intestines, lowers hepatic gluconeogenesis, reduces inflammation, and improves insulin sensitivity. However, despite being widely used as the first-line oral antidiabetic drug, its mechanism of action remains largely elusive. Currently, an increasing number of studies have demonstrated that the anti-diabetic effects of metformin were mediated by the regulation of lncRNAs. Metformin-regulated lncRNAs have been shown to participate in the inhibition of gluconeogenesis, regulation of lipid metabolism, and be anti-inflammatory. Thus, this review focuses on the mechanisms of action of metformin in regulating lncRNAs in diabetes, including pathways altered by metformin via targeting lncRNAs, and the potential targets of metformin through modulation of lncRNAs. Knowledge of the mechanisms of lncRNA modulation by metformin in diabetes will aid the development of new therapeutic drugs for T2D in the future.
Collapse
Affiliation(s)
- Wenguang Chang
- Institute for Translational Medicine, The Affiliated Hospital, College of Medicine, Qingdao University, Qingdao, China
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital, College of Medicine, Qingdao University, Qingdao, China
| |
Collapse
|
|
23
|
Watanabe M, Eguchi A, Sakurai K, Yamamoto M, Mori C. Prediction of gestational diabetes mellitus using machine learning from birth cohort data of the Japan Environment and Children's Study. Sci Rep 2023; 13:17419. [PMID: 37833313 PMCID: PMC10575866 DOI: 10.1038/s41598-023-44313-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 10/06/2023] [Indexed: 10/15/2023] Open
Abstract
Recently, prediction of gestational diabetes mellitus (GDM) using artificial intelligence (AI) from medical records has been reported. We aimed to evaluate GDM-predictive AI-based models using birth cohort data with a wide range of information and to explore factors contributing to GDM development. This investigation was conducted as a part of the Japan Environment and Children's Study. In total, 82,698 pregnant mothers who provided data on lifestyle, anthropometry, and socioeconomic status before pregnancy and the first trimester were included in the study. We employed machine learning methods as AI algorithms, such as random forest (RF), gradient boosting decision tree (GBDT), and support vector machine (SVM), along with logistic regression (LR) as a reference. GBDT displayed the highest accuracy, followed by LR, RF, and SVM. Exploratory analysis of the JECS data revealed that health-related quality of life in early pregnancy and maternal birthweight, which were rarely reported to be associated with GDM, were found along with variables that were reported to be associated with GDM. The results of decision tree-based algorithms, such as GBDT, have shown high accuracy, interpretability, and superiority for predicting GDM using birth cohort data.
Collapse
Affiliation(s)
- Masahiro Watanabe
- Department of Sustainable Health Science, Center for Preventive Medical Sciences, Chiba University, 1-33, Yayoicho, Inage-ku, Chiba, 263-8522, Japan.
| | - Akifumi Eguchi
- Department of Sustainable Health Science, Center for Preventive Medical Sciences, Chiba University, 1-33, Yayoicho, Inage-ku, Chiba, 263-8522, Japan
| | - Kenichi Sakurai
- Department of Nutrition and Metabolic Medicine, Center for Preventive Medical Sciences, Chiba University, Chiba, Japan
| | - Midori Yamamoto
- Department of Sustainable Health Science, Center for Preventive Medical Sciences, Chiba University, 1-33, Yayoicho, Inage-ku, Chiba, 263-8522, Japan
| | - Chisato Mori
- Department of Sustainable Health Science, Center for Preventive Medical Sciences, Chiba University, 1-33, Yayoicho, Inage-ku, Chiba, 263-8522, Japan
- Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| |
Collapse
|
|
24
|
Liang X, Fu Y, Lu S, Shuai M, Miao Z, Gou W, Shen L, Liang Y, Xu F, Tian Y, Wang J, Zhang K, Xiao C, Jiang Z, Shi MQ, Wu YY, Wang XH, Hu WS, Zheng JS. Continuous glucose monitoring-derived glycemic metrics and adverse pregnancy outcomes among women with gestational diabetes: a prospective cohort study. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2023; 39:100823. [PMID: 37927990 PMCID: PMC10625020 DOI: 10.1016/j.lanwpc.2023.100823] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/11/2023] [Accepted: 05/30/2023] [Indexed: 11/07/2023]
Abstract
Background Continuous glucose monitoring (CGM) has shown potential in improving maternal and neonatal outcomes in individuals with type 1/2 diabetes, but data in gestational diabetes mellitus (GDM) is limited. We aimed to explore the relationship between CGM-derived metrics during pregnancy and pregnancy outcomes among women with GDM. Methods We recruited 1302 pregnant women with GDM at a mean gestational age of 26.0 weeks and followed them until delivery. Participants underwent a 14-day CGM measurement upon recruitment. The primary outcome was any adverse pregnancy outcome, defined as having at least one of the outcomes: preterm birth, large-for-gestational-age (LGA) birth, fetal distress, premature rupture of membranes, and neonatal intensive care unit (NICU) admission. The individual outcomes included in the primary outcome were considered as secondary outcomes. We conducted multivariable logistic regression to evaluate the association of CGM-derived metrics with these outcomes. Findings Per 1-SD difference in time above range (TAR), glucose area under the curve (AUC), nighttime mean blood glucose (MBG), daytime MBG, and daily MBG was associated with higher risk of any adverse pregnancy outcome, with odds ratio: 1.22 (95% CI 1.08-1.36), 1.22 (95% CI 1.09-1.37), 1.18 (95% CI 1.05-1.32), 1.21 (95% CI 1.07-1.35), and 1.22 (95% CI 1.09-1.37), respectively. Time in range, TAR, AUC, nighttime MBG, daytime MBG, daily MBG, and mean amplitude of glucose excursions were positively associated, while time blow range was inversely associated with the risk of LGA. Additionally, higher value for TAR was associated with higher risk of NICU admission. We further summarized the potential thresholds of TAR (2.5%) and daily MBG (4.8 mmol/L) to distinguish individuals with and without any adverse pregnancy outcome. Interpretation The CGM-derived metrics may help identify individuals at higher risk of adverse pregnancy outcomes. These CGM biomarkers could serve as potential new intervention targets to maintain a healthy pregnancy status among women with GDM. Funding National Key R&D Program of China, National Natural Science Foundation of China, and Westlake Laboratory of Life Sciences and Biomedicine.
Collapse
Affiliation(s)
- Xinxiu Liang
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Yuanqing Fu
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Sha Lu
- Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
- Department of Obstetrics and Gynecology, The Affiliated Hangzhou Women’s Hospital of Hangzhou Normal University, Hangzhou, China
| | - Menglei Shuai
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Zelei Miao
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Wanglong Gou
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Luqi Shen
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Yuhui Liang
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Fengzhe Xu
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Yunyi Tian
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Jiali Wang
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Ke Zhang
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Congmei Xiao
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Zengliang Jiang
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Mei-Qi Shi
- Department of Nutrition, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Ying-Ying Wu
- Department of Nursing, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Xu-Hong Wang
- Department of Nutrition, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Wen-Sheng Hu
- Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
- Department of Obstetrics and Gynecology, The Affiliated Hangzhou Women’s Hospital of Hangzhou Normal University, Hangzhou, China
| | - Ju-Sheng Zheng
- Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| |
Collapse
|
|
25
|
Elsayed AK, Alajez NM, Abdelalim EM. Genome-wide differential expression profiling of long non-coding RNAs in FOXA2 knockout iPSC-derived pancreatic cells. Cell Commun Signal 2023; 21:229. [PMID: 37670346 PMCID: PMC10478503 DOI: 10.1186/s12964-023-01212-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/01/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND Our recent studies have demonstrated the crucial involvement of FOXA2 in the development of human pancreas. Reduction of FOXA2 expression during the differentiation of induced pluripotent stem cells (iPSCs) into pancreatic islets has been found to reduce α-and β-cell masses. However, the extent to which such changes are linked to alterations in the expression profile of long non-coding RNAs (lncRNAs) remains unraveled. METHODS Here, we employed our recently established FOXA2-deficient iPSCs (FOXA2-/- iPSCs) to investigate changes in lncRNA profiles and their correlation with dysregulated mRNAs during the pancreatic progenitor (PP) and pancreatic islet stages. Furthermore, we constructed co-expression networks linking significantly downregulated lncRNAs with differentially expressed pancreatic mRNAs. RESULTS Our results showed that 442 lncRNAs were downregulated, and 114 lncRNAs were upregulated in PPs lacking FOXA2 compared to controls. Similarly, 177 lncRNAs were downregulated, and 59 lncRNAs were upregulated in islet cells lacking FOXA2 compared to controls. At both stages, we observed a strong correlation between lncRNAs and several crucial pancreatic genes and TFs during pancreatic differentiation. Correlation analysis revealed 12 DE-lncRNAs that strongly correlated with key downregulated pancreatic genes in both PPs and islet cell stages. Selected DE-lncRNAs were validated using RT-qPCR. CONCLUSIONS Our data indicate that the observed defects in pancreatic islet development due to the FOXA2 loss is associated with significant alterations in the expression profile of lncRNAs. Therefore, our findings provide novel insights into the role of lncRNA and mRNA networks in regulating pancreatic islet development, which warrants further investigations. Video Abstract.
Collapse
Affiliation(s)
- Ahmed K Elsayed
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
- Stem Cell Core, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Nehad M Alajez
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Essam M Abdelalim
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
| |
Collapse
|
|
26
|
Bartel I, Koszarska M, Strzałkowska N, Tzvetkov NT, Wang D, Horbańczuk JO, Wierzbicka A, Atanasov AG, Jóźwik A. Cyanidin-3-O-glucoside as a Nutrigenomic Factor in Type 2 Diabetes and Its Prominent Impact on Health. Int J Mol Sci 2023; 24:ijms24119765. [PMID: 37298715 DOI: 10.3390/ijms24119765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/29/2023] [Accepted: 06/03/2023] [Indexed: 06/12/2023] Open
Abstract
Type 2 diabetes (T2D) accounts for a global health problem. It is a complex disease as a result of the combination of environmental as well as genetic factors. Morbidity is still increasing across the world. One of the possibilities for the prevention and mitigation of the negative consequences of type 2 diabetes is a nutritional diet rich in bioactive compounds such as polyphenols. This review is focused on cyanidin-3-O-glucosidase (C3G), which belongs to the anthocyanins subclass, and its anti-diabetic properties. There are numerous pieces of evidence that C3G exerts positive effects on diabetic parameters, including in vitro and in vivo studies. It is involved in alleviating inflammation, reducing blood glucose, controlling postprandial hyperglycemia, and gene expression related to the development of T2D. C3G is one of the beneficial polyphenolic compounds that may help to overcome the public health problems associated with T2D.
Collapse
Affiliation(s)
- Iga Bartel
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Magdalena Koszarska
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Nina Strzałkowska
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Nikolay T Tzvetkov
- Department of Biochemical Pharmacology and Drug Design, Institute of Molecular Biology "Roumen Tsanev", Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria
| | - Dongdong Wang
- Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Jarosław O Horbańczuk
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Agnieszka Wierzbicka
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Atanas G Atanasov
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
- Ludwig Boltzmann Institute Digital Health and Patient Safety, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria
| | - Artur Jóźwik
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| |
Collapse
|
|
27
|
Yan YS, Feng C, Yu DQ, Tian S, Zhou Y, Huang YT, Cai YT, Chen J, Zhu MM, Jin M. Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia. Front Nutr 2023; 10:1067282. [PMID: 37255932 PMCID: PMC10226394 DOI: 10.3389/fnut.2023.1067282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 04/06/2023] [Indexed: 06/01/2023] Open
Abstract
Diabetes mellitus during pregnancy, which can be classified into pregestational diabetes and gestational diabetes, has become much more prevalent worldwide. Maternal diabetes fosters an intrauterine abnormal environment for fetus, which not only influences pregnancy outcomes, but also leads to fetal anomaly and development of diseases in later life, such as metabolic and cardiovascular diseases, neuropsychiatric outcomes, reproduction malformation, and immune dysfunction. The underlying mechanisms are comprehensive and ambiguous, which mainly focus on microbiota, inflammation, reactive oxygen species, cell viability, and epigenetics. This review concluded with the influence of intrauterine hyperglycemia on fetal structure development and organ function on later life and outlined potential mechanisms that underpin the development of diseases in adulthood. Maternal diabetes leaves an effect that continues generations after generations through gametes, thus more attention should be paid to the prevention and treatment of diabetes to rescue the pathological attacks of maternal diabetes from the offspring.
Collapse
Affiliation(s)
- Yi-Shang Yan
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chun Feng
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dan-Qing Yu
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shen Tian
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yin Zhou
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi-Ting Huang
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi-Ting Cai
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Chen
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| | - Miao-Miao Zhu
- Department of Operating Theatre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Min Jin
- Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
28
|
Guo H, Wu H, Li Z. The Pathogenesis of Diabetes. Int J Mol Sci 2023; 24:ijms24086978. [PMID: 37108143 PMCID: PMC10139109 DOI: 10.3390/ijms24086978] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/30/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Diabetes is the most common metabolic disorder, with an extremely serious effect on health systems worldwide. It has become a severe, chronic, non-communicable disease after cardio-cerebrovascular diseases. Currently, 90% of diabetic patients suffer from type 2 diabetes. Hyperglycemia is the main hallmark of diabetes. The function of pancreatic cells gradually declines before the onset of clinical hyperglycemia. Understanding the molecular processes involved in the development of diabetes can provide clinical care with much-needed updates. This review provides the current global state of diabetes, the mechanisms involved in glucose homeostasis and diabetic insulin resistance, and the long-chain non-coding RNA (lncRNA) associated with diabetes.
Collapse
Affiliation(s)
- Huiqin Guo
- Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China
| | - Haili Wu
- College of Life Science, Shanxi University, Taiyuan 030006, China
| | - Zhuoyu Li
- Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China
| |
Collapse
|
|
29
|
Luo SS, Zhu H, Huang HF, Ding GL. Sex differences in glycolipidic disorders after exposure to maternal hyperglycemia during early development. J Endocrinol Invest 2023:10.1007/s40618-023-02069-5. [PMID: 36976483 DOI: 10.1007/s40618-023-02069-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 03/10/2023] [Indexed: 03/29/2023]
Abstract
PURPOSE The aim of this review was to summarize sex differences in glycolipid metabolic phenotypes of human and animal models after exposure to maternal hyperglycemia and overview the underlying mechanisms, providing a new perspective on the maternal hyperglycemia-triggered risk of glycolipidic disorders in offspring. METHODS A comprehensive literature search within PubMed was performed. Selected publications related to studies on offspring exposed to maternal hyperglycemia investigating the sex differences of glycolipid metabolism were reviewed. RESULTS Maternal hyperglycemia increases the risk of glycolipid metabolic disorders in offspring, such as obesity, glucose intolerance and diabetes. Whether with or without intervention, metabolic phenotypes have been shown to exhibit sex differences between male and female offspring in response to maternal hyperglycemia, which may be related to gonadal hormones, organic intrinsic differences, placenta, and epigenetic modifications. CONCLUSION Sex may play a role in the different incidences and pathogenesis of abnormal glycolipid metabolism. More studies investigating both sexes are needed to understand how and why environmental conditions in early life affect long-term health between male and female individuals.
Collapse
Affiliation(s)
- S-S Luo
- School of Medicine, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - H Zhu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - H-F Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - G-L Ding
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
| |
Collapse
|
|
30
|
Yao X, Huang S, Li Y, Ge Y, Zhang Z, Ning J, Yang X. Transgenerational effects of zinc, selenium and chromium supplementation on glucose homeostasis in female offspring of gestational diabetes rats. J Nutr Biochem 2022; 110:109131. [PMID: 36028097 DOI: 10.1016/j.jnutbio.2022.109131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 07/26/2022] [Accepted: 08/01/2022] [Indexed: 01/13/2023]
Abstract
Clinical studies have demonstrated that maternal gestational diabetes mellitus (GDM) increases the offspring's risk of developing glucose intolerance. Our previous study reported that co-supplementation with zinc, selenium, and chromium improved insulin resistance in diet-induced GDM rats. Here, Transgenerational effects of supplementation with zinc (10 mg/kg.bw), selenium (20 μg/kg.bw), and chromium (20 μg/kg.bw) in F1 female offspring of both zinc, selenium and chromium (ZnSeCr)-treated, and untreated GDM rats daily by gavage from weaning to the postpartum were investigated in the present study. Glucose homeostasis in the F1 female offspring of GDM at different stages were evaluated. Maternal GDM did increase the birth mass of newborn F1 female offspring, as well as the serum glucose and insulin levels. Zinc, selenium and chromium supplementation attenuated the GDM-induced mass gain, increased serum glucose and insulin levels in the female neonates. The high fat and sucrose (HFS) diet-fed GDM-F1 offspring developed GDM, with glucose intolerance, hyperglycemia and insulin resistance during pregnancy. Moreover, endoplasmic reticulum (ER) stress-related protein levels were increased and the activation of insulin signaling pathways were reduced in the liver of HFS-fed GDM-F1 offspring. Whereas glucose homeostasis in parallel with insulin sensitivity was normalized in the female offspring of GDM by supplementation both F0 dams and F1 offspring with zinc, selenium and chromium, not in those either F0 or F1 elements supplemented offspring. Therefore, we speculate that zinc, selenium and chromium supplementation may have a potential beneficial transgenerational effect on the glucose homeostasis in the female offspring of GDM.
Collapse
Affiliation(s)
- Xueqiong Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shanshan Huang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yan Li
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanyan Ge
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhen Zhang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jie Ning
- Department of Endocrinology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua Central Hospital, Shenzhen, Guangdong, China.
| | - Xuefeng Yang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| |
Collapse
|
|
31
|
Cechinel LR, Batabyal RA, Freishtat RJ, Zohn IE. Parental obesity-induced changes in developmental programming. Front Cell Dev Biol 2022; 10:918080. [PMID: 36274855 PMCID: PMC9585252 DOI: 10.3389/fcell.2022.918080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 09/06/2022] [Indexed: 11/13/2022] Open
Abstract
Many studies support the link between parental obesity and the predisposition to develop adult-onset metabolic syndromes that include obesity, high blood pressure, dyslipidemia, insulin resistance, and diabetes in the offspring. As the prevalence of obesity increases in persons of childbearing age, so does metabolic syndrome in their descendants. Understanding how parental obesity alters metabolic programs in the progeny, predisposing them to adult-onset metabolic syndrome, is key to breaking this cycle. This review explores the basis for altered metabolism of offspring exposed to overnutrition by focusing on critical developmental processes influenced by parental obesity. We draw from human and animal model studies, highlighting the adaptations in metabolism that occur during normal pregnancy that become maladaptive with obesity. We describe essential phases of development impacted by parental obesity that contribute to long-term alterations in metabolism in the offspring. These encompass gamete formation, placentation, adipogenesis, pancreas development, and development of brain appetite control circuits. Parental obesity alters the developmental programming of these organs in part by inducing epigenetic changes with long-term consequences on metabolism. While exposure to parental obesity during any of these phases is sufficient to alter long-term metabolism, offspring often experience multiple exposures throughout their development. These insults accumulate to increase further the susceptibility of the offspring to the obesogenic environments of modern society.
Collapse
|
|
32
|
Pan HT, Xiong YM, Zhu HD, Shi XL, Yu B, Ding HG, Xu RJ, Ding JL, Zhang T, Zhang J. Proteomics and bioinformatics analysis of cardiovascular related proteins in offspring exposed to gestational diabetes mellitus. Front Cardiovasc Med 2022; 9:1021112. [PMID: 36277748 PMCID: PMC9582427 DOI: 10.3389/fcvm.2022.1021112] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction Previous studies have demonstrated that exposed to the initial suboptimal intrauterine environment of gestational diabetes mellitus (GDM) may increase risk of cardiovascular disease in adulthood. Methods In order to investigate the underlying mechanisms involved in the increased risk of cardiovascular diseases (CVDs) in the offspring of GDM, we applied a high-throughput proteomics approach to compare the proteomic expression profile of human umbilical vessels of normal and GDM offspring. Results A total of significantly different 100 proteins were identified in umbilical vessels from GDM group compared with normal controls, among which 31 proteins were up-regulated, while 69 proteins were down-regulated. Differentially expressed proteins (DEPs) are validated using Western blotting analysis. The analysis of these differently expressed proteins (DEPs) related diseases and functions results, performed by Ingenuity Pathway Analysis (IPA) software. Based on "Diseases and Disorders" analysis, 17 proteins (ACTA2, ADAR, CBFB, DDAH1, FBN1, FGA, FGB, FGG, GLS, GSTM1, HBB, PGM3, PPP1R13L, S100A8, SLC12A4, TPP2, VCAN) were described to be associated with CVD, especially in Anemia, Thrombus and Myocardial infarction. Functional analysis indicated that DEPs involved in many cardiovascular functions, especially in "vasoconstriction of blood vessel" (related DEPs: ACTA2, DDAH1, FBN1, FGA, FGB, and FGG). Upstream regulator analyses of DEPs identifies STAT3 as inhibitor of ACTA2, FGA, FGB, and FGG. Conclusion The results of this study indicate that intrauterine hyperglycemia is associated with an elevated risk of cardiovascular risk in the offspring.
Collapse
Affiliation(s)
- Hai-Tao Pan
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Yi-Meng Xiong
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hong-Dan Zhu
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Xiao-Liang Shi
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Bin Yu
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Hai-Gang Ding
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Ren-Jie Xu
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Jin-Long Ding
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Tao Zhang
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China,*Correspondence: Tao Zhang,
| | - Juan Zhang
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China,Juan Zhang,
| |
Collapse
|
|
33
|
Mo J, Liu X, Huang Y, He R, Zhang Y, Huang H. Developmental origins of adult diseases. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:450-470. [PMID: 37724166 PMCID: PMC10388800 DOI: 10.1515/mr-2022-0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 10/11/2022] [Indexed: 09/20/2023]
Abstract
The occurrence and mechanisms of developmental adult diseases have gradually attracted attention in recent years. Exposure of gametes and embryos to adverse environments, especially during plastic development, can alter the expression of certain tissue-specific genes, leading to increased susceptibility to certain diseases in adulthood, such as diabetes, cardiovascular disease, neuropsychiatric, and reproductive system diseases, etc. The occurrence of chronic disease in adulthood is partly due to genetic factors, and the remaining risk is partly due to environmental-dependent epigenetic information alteration, including DNA methylation, histone modifications, and noncoding RNAs. Changes in this epigenetic information potentially damage our health, which has also been supported by numerous epidemiological and animal studies in recent years. Environmental factors functionally affect embryo development through epimutation, transmitting diseases to offspring and even later generations. This review mainly elaborated on the concept of developmental origins of adult diseases, and revealed the epigenetic mechanisms underlying these events, discussed the theoretical basis for the prevention and treatment of related diseases.
Collapse
Affiliation(s)
- Jiaying Mo
- Department of Obstetrics and Gynecology, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Xuanqi Liu
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yutong Huang
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Renke He
- Department of Obstetrics and Gynecology, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yu Zhang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Hefeng Huang
- Department of Obstetrics and Gynecology, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China
| |
Collapse
|
|
34
|
The epigenetic mechanisms underlying gamete origin of adult-onset diseases. Sci Bull (Beijing) 2022; 67:1724-1727. [PMID: 36546054 DOI: 10.1016/j.scib.2022.07.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
|
|
35
|
Xu H, Li J, Jin L, Zhang D, Chen B, Liu X, Lin X, Huang Y, Ke Z, Liu J, Gao L, Sheng J, Huang H. Intrauterine hyperglycemia impairs endometrial receptivity via up-regulating SGK1 in diabetes. SCIENCE CHINA. LIFE SCIENCES 2022; 65:1578-1589. [PMID: 35287185 DOI: 10.1007/s11427-021-2035-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 12/22/2021] [Indexed: 06/14/2023]
Abstract
Diabetes is a complex metabolic disorder which can adversely affect reproductive function. SGK1 is found to be up-regulated in multiple tissues of diabetic patients. However, the effects of diabetes on endometrial SGK1 expression and endometrial receptivity remain unknown. In this study, we established a streptozotocin-induced diabetic mouse model and observed reduced implantation sites, retarded development of pinopodes, increased SGK1, and aberrant expression of LIF and MUC1 in the endometrial epithelium. We injected the uterine lumen of normal mice with high-glucose solution and cultured endometrial cells in high-glucose medium to mimic intrauterine hyperglycemia. Both studies provided compelling evidence that hyperglycemia could lead to diminished embryo implantation and dysregulated SGK1, LIF and MUC1. Additionally, through over-expression of SGK1 in vivo and in vitro, we found that enhanced SGK1 also decreased LIF expression, increased MUC1 expression, and attenuated embryo implantation rate. We further identified that hyperglycemia-activated SMAD2/3 might be responsible for the enhancement of SGK1 and verified directly the interaction between SMAD3 and corresponding SMAD binding elements within SGK1 promoter. Taken together, our study confirmed the association between diabetes-related hyperglycemia and endometrial receptivity defects. Hyperglycemia-induced SGK1 has a tremendous role in this pathological process, rendering it as an attractive therapeutic target for diabetes-related reproductive disorders.
Collapse
Affiliation(s)
- Haiyan Xu
- Reproductive Medicine Center, Ningbo First Hospital, Ningbo, 315100, China
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
| | - Jingyi Li
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Luyang Jin
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
| | - Dan Zhang
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Bin Chen
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
| | - Xinmei Liu
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Xianhua Lin
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Yiting Huang
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
| | - Zhanghong Ke
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
| | - Juan Liu
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Lin Gao
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Jianzhong Sheng
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China.
- Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Hefeng Huang
- Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, 310058, China.
- Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
| |
Collapse
|
|
36
|
Kumar A, Datta M. H19 inhibition increases HDAC6 and regulates IRS1 levels and insulin signaling in the skeletal muscle during diabetes. Mol Med 2022; 28:81. [PMID: 35842608 PMCID: PMC9287888 DOI: 10.1186/s10020-022-00507-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 07/07/2022] [Indexed: 12/03/2022] Open
Abstract
Background Histone deacetylases (HDACs) that catalyze removal of acetyl groups from histone proteins, are strongly associated with several diseases including diabetes, yet the precise regulatory events that control the levels and activity of the HDACs are not yet well elucidated. Methods Levels of H19 and HDACs were evaluated in skeletal muscles of normal and diabetic db/db mice by Western Blot analysis. C2C12 cells were differentiated and transfected with either the scramble or H19 siRNA and the levels of HDACs and Prkab2, Pfkfb3, Srebf1, Socs2, Irs1 and Ppp2r5b were assessed by Western Blot analysis and qRT-PCR, respectively. Levels of H9, HDAC6 and IRS1 were evaluated in skeletal muscles of scramble/ H19 siRNA injected mice and chow/HFD-fed mice. Results Our data show that the lncRNA H19 and HDAC6 exhibit inverse patterns of expression in the skeletal muscle of diabetic db/db mice and in C2C12 cells, H19 inhibition led to significant increase in HDAC activity and in the levels of HDAC6, both at the transcript and protein levels. This was associated with downregulation of IRS1 levels that were prevented in the presence of the HDAC inhibitor, SAHA, and HDAC6 siRNA suggesting the lncRNA H19-HDAC6 axis possibly regulates cellular IRS1 levels. Such patterns of H19, HDAC6 and IRS1 expression were also validated and confirmed in high fat diet-fed mice where as compared to normal chow-fed mice, H19 levels were significantly inhibited in the skeletal muscle of these mice and this was accompanied with elevated HDAC6 levels and decreased IRS1 levels. In-vivo inhibition of H19 led to significant increase in HDAC6 levels and this was associated with a decrease in IRS1 levels in the skeletal muscle. Conclusions Our results suggest a critical role for the lncRNA H19-HDAC6 axis in regulating IRS1 levels in the skeletal muscle during diabetes and therefore restoring normal H19 levels might hold a therapeutic potential for the management of aberrant skeletal muscle physiology during insulin resistance and type 2 diabetes.
Collapse
Affiliation(s)
- Amit Kumar
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India.,Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad, 201002, Uttar Pradesh, India
| | - Malabika Datta
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India. .,Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad, 201002, Uttar Pradesh, India.
| |
Collapse
|
|
37
|
Li W, Feng Q, Wang C, Yin Z, Li X, Li L. LncXIST Facilitates Iron Overload and Iron Overload-Induced Islet Beta Cell Injury in Type 2 Diabetes through miR-130a-3p/ALK2 Axis. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:6390812. [PMID: 35720932 PMCID: PMC9203195 DOI: 10.1155/2022/6390812] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/14/2022] [Accepted: 04/26/2022] [Indexed: 11/17/2022]
Abstract
Iron overload is directly associated with diabetes mellitus, loss of islet beta cell, and insulin resistance. Likewise, long noncoding RNA (lncRNA) is associated with type 2 diabetes (T2D). Moreover, lncRNAs could be induced by iron overload. Therefore, we are going to explore the molecular mechanism of lncRNA XIST in iron overload-related T2D. Real-time quantitative PCR and Western blot were used to detect gene and protein levels, respectively. TUNEL and MTT assay were performed to examine cell survival. The glucose test strip, colorimetric analysis kit, ferritin ELISA kit, and insulin ELISA kit were performed to examine the levels of glycolic, iron, and total iron-binding capacity, ferritin, and insulin in serum. Fluorospectrophotometry assay was used to examine labile iron pool level. XIST was higher expressed in T2D and iron overload-related T2D rat tissues and cells, and iron overload-induced promoted XIST expression in T2D. Higher XIST expression was associated with iron overload in patients with T2D. Knockdown of XIST alleviated iron overload and iron overload-induced INS-1 cells injury. Further, we found that XIST can sponge miR-130a-3p to trigger receptor-like kinase 2 (ALK2) expression. Moreover, knockdown of ALK2 alleviated iron overload and iron overload-induced INS-1 cells injury by inhibiting bone morphogenetic protein 6 (BMP6)/ALK2/SMAD1/5/8 axis but reversed with XIST upregulation, which was terminally boosted by overexpression of miR-130a-3p. XIST has the capacity to promote iron overload and iron overload-related T2D initiation and development through inhibition of ALK2 expression by sponging miR-130a-3p, and that targeting this axis may be an effective strategy for treating patients with T2D.
Collapse
Affiliation(s)
- Weiyuan Li
- Department of Geriatrics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Qiu Feng
- Department of Geriatrics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Chenrong Wang
- Medical Laboratory, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Zhao Yin
- Department of Geriatrics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Xiaolu Li
- Department of Geriatrics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Lei Li
- Department of Endocrine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| |
Collapse
|
|
38
|
Akhlaghipour I, Bina AR, Mogharrabi MR, Fanoodi A, Ebrahimian AR, Khojasteh Kaffash S, Babazadeh Baghan A, Khorashadizadeh ME, Taghehchian N, Moghbeli M. Single-nucleotide polymorphisms as important risk factors of diabetes among Middle East population. Hum Genomics 2022; 16:11. [PMID: 35366956 PMCID: PMC8976361 DOI: 10.1186/s40246-022-00383-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/23/2022] [Indexed: 12/16/2022] Open
Abstract
Diabetes is a chronic metabolic disorder that leads to the dysfunction of various tissues and organs, including eyes, kidneys, and cardiovascular system. According to the World Health Organization, diabetes prevalence is 8.8% globally among whom about 90% of cases are type 2 diabetes. There are not any significant clinical manifestations in the primary stages of diabetes. Therefore, screening can be an efficient way to reduce the diabetic complications. Over the recent decades, the prevalence of diabetes has increased alarmingly among the Middle East population, which has imposed exorbitant costs on the health care system in this region. Given that the genetic changes are among the important risk factors associated with predisposing people to diabetes, we examined the role of single-nucleotide polymorphisms (SNPs) in the pathogenesis of diabetes among Middle East population. In the present review, we assessed the molecular pathology of diabetes in the Middle East population that paves the way for introducing an efficient SNP-based diagnostic panel for diabetes screening among the Middle East population. Since, the Middle East has a population of 370 million people; the current review can be a reliable model for the introduction of SNP-based diagnostic panels in other populations and countries around the world.
Collapse
|
|
39
|
Abstract
Diabetes mellitus (DM) causes damage to major organs, including the heart, liver, brain, kidneys, eyes, and blood vessels, threatening the health of the individuals. Emerging evidence has demonstrated that lncRNAs has important functions in the pathogenesis of human diseases, such as cancers, neurodegenerative diseases, cardiac fibroblast phenotypes, hypertension, heart failure, atherosclerosis and diabetes. Recently, H19, a lncRNA, has been reported to shown to participate in the regulatory process of muscle differentiation, glucose metabolism, and tumor metastasis, as well as endometrial development. However, the roles of H19 in DM were still not completely understood. This review was conducted to summarize the functions of H19 in diabetes and discuss the challenges and possible strategies of H19 in DM.
Collapse
Affiliation(s)
- Ye Bi
- Department of Geriatrics, Shandong First Medical University, Jinan, China
| | - Yao Wang
- Shandong Institute of Endocrine and Metabolic Diseases, Medical University, Jinan, China
| | - Xianglan Sun
- Department of Geriatrics, Shandong First Medical University, Jinan, China
| |
Collapse
|
|
40
|
Li XY, Pan JX, Zhu H, Ding GL, Huang HF. Environmental epigenetic interaction of gametes and early embryos. Biol Reprod 2022; 107:196-204. [PMID: 35323884 DOI: 10.1093/biolre/ioac051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 11/14/2022] Open
Abstract
In recent years, the developmental origins of diseases have been increasingly recognized and accepted. As such, it has been suggested that most adulthood chronic diseases such as diabetes, obesity, cardiovascular disease, and even tumors may develop at a very early stage. In addition to intrauterine environmental exposure, germ cells carry an important inheritance role as the primary link between the two generations. Adverse external influences during differentiation and development can cause damage to germ cells, which may then increase the risk of chronic disease development later in life. Here, we further elucidate and clarify the concept of gamete and embryo origins of adult diseases by focusing on the environmental insults on germ cells, from differentiation to maturation and fertilization.
Collapse
Affiliation(s)
- Xin-Yuan Li
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences
| | - Jie-Xue Pan
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences
| | - Hong Zhu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences
| | - Guo-Lian Ding
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - He-Feng Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| |
Collapse
|
|
41
|
Akhabir L, Stringer R, Desai D, Mandhane PJ, Azad MB, Moraes TJ, Subbarao P, Turvey SE, Paré G, Anand SS, Anand SS, Atkinson SA, Azad MB, Becker AB, Brook J, Denburg JA, Desai D, de Souza RJ, Gupta M, Kobor M, Lefebvre DL, Lou W, Mandhane PJ, McDonald S, Mente A, Meyre D, Moraes TJ, Morrison K, Paré G, Sears MR, Subbarao P, Teo KK, Turvey SE, Wilson J, Yusuf S, Atkinson S, Wahi G, Zulyniak MA. DNA methylation changes in cord blood and the developmental origins of health and disease – a systematic review and replication study. BMC Genomics 2022; 23:221. [PMID: 35305575 PMCID: PMC8933946 DOI: 10.1186/s12864-022-08451-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 03/07/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance.
Methods
We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data.
Results
We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts.
Conclusions
Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants’ methylome.
Collapse
|
|
42
|
Luo SS, Zou KX, Zhu H, Cheng Y, Yan YS, Sheng JZ, Huang HF, Ding GL. Integrated Multi-Omics Analysis Reveals the Effect of Maternal Gestational Diabetes on Fetal Mouse Hippocampi. Front Cell Dev Biol 2022; 10:748862. [PMID: 35237591 PMCID: PMC8883435 DOI: 10.3389/fcell.2022.748862] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 01/19/2022] [Indexed: 11/25/2022] Open
Abstract
Growing evidence suggests that adverse intrauterine environments could affect the long-term health of offspring. Recent evidence indicates that gestational diabetes mellitus (GDM) is associated with neurocognitive changes in offspring. However, the mechanism remains unclear. Using a GDM mouse model, we collected hippocampi, the structure critical to cognitive processes, for electron microscopy, methylome and transcriptome analyses. Reduced representation bisulfite sequencing (RRBS) and RNA-seq in the GDM fetal hippocampi showed altered methylated modification and differentially expressed genes enriched in common pathways involved in neural synapse organization and signal transmission. We further collected fetal mice brains for metabolome analysis and found that in GDM fetal brains, the metabolites displayed significant changes, in addition to directly inducing cognitive dysfunction, some of which are important to methylation status such as betaine, fumaric acid, L-methionine, succinic acid, 5-methyltetrahydrofolic acid, and S-adenosylmethionine (SAM). These results suggest that GDM affects metabolites in fetal mice brains and further affects hippocampal DNA methylation and gene regulation involved in cognition, which is a potential mechanism for the adverse neurocognitive effects of GDM in offspring.
Collapse
Affiliation(s)
- Si-Si Luo
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Ke-Xin Zou
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Hong Zhu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Yi Cheng
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Yi-Shang Yan
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Jian-Zhong Sheng
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - He-Feng Huang
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China.,The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Guo-Lian Ding
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| |
Collapse
|
|
43
|
Mao Y, Yiran Z, Sisi L, Huixi C, Xia L, Ting W, Guolian D, Xinmei L, Sheng J, Meng Y, Huang H. Advanced paternal age increased metabolic risks in mice offspring. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166355. [DOI: 10.1016/j.bbadis.2022.166355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/07/2022] [Accepted: 01/25/2022] [Indexed: 10/19/2022]
|
|
44
|
Liao W, Xu N, Zhang H, Liao W, Wang Y, Wang S, Zhang S, Jiang Y, Xie W, Zhang Y. Persistent high glucose induced EPB41L4A-AS1 inhibits glucose uptake via GCN5 mediating crotonylation and acetylation of histones and non-histones. Clin Transl Med 2022; 12:e699. [PMID: 35184403 PMCID: PMC8858623 DOI: 10.1002/ctm2.699] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 12/12/2021] [Accepted: 12/20/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Persistent hyperglycemia decreases the sensitivity of insulin-sensitive organs to insulin, owing to which cells fail to take up and utilize glucose, which exacerbates the progression of type 2 diabetes mellitus (T2DM). lncRNAs' abnormal expression is reported to be associated with the progression of diabetes and plays a significant role in glucose metabolism. Herein, we study the detailed mechanism underlying the functions of lncRNA EPB41L4A-AS1in T2DM. METHODS Data from GEO datasets were used to analyze the expression of EPB41L4A-AS1 between insulin resistance or type 2 diabetes patients and the healthy people. Gene expression was evaluated by qRT-PCR and western blotting. Glucose uptake was measured by Glucose Uptake Fluorometric Assay Kit. Glucose tolerance of mice was detected by Intraperitoneal glucose tolerance tests. Cell viability was assessed by CCK-8 assay. The interaction between EPB41L4A-AS1 and GCN5 was explored by RNA immunoprecipitation, RNA pull-down and RNA-FISH combined immunofluorescence. Oxygen consumption rate was tested by Seahorse XF Mito Stress Test. RESULTS EPB41L4A-AS1 was abnormally increased in the liver of patients with T2DM and upregulated in the muscle cells of patients with insulin resistance and in T2DM cell models. The upregulation was associated with increased TP53 expression and reduced glucose uptake. Mechanistically, through interaction with GCN5, EPB41L4A-AS1 regulated histone H3K27 crotonylation in the GLUT4 promoter region and nonhistone PGC1β acetylation, which inhibited GLUT4 transcription and suppressed glucose uptake by muscle cells. In contrast, EPB41L4A-AS1 binding to GCN5 enhanced H3K27 and H3K14 acetylation in the TXNIP promoter region, which activated transcription by promoting the recruitment of the transcriptional activator MLXIP. This enhanced GLUT4/2 endocytosis and further suppressed glucose uptake. CONCLUSION Our study first showed that the EPB41L4A-AS1/GCN5 complex repressed glucose uptake via targeting GLUT4/2 and TXNIP by regulating histone and nonhistone acetylation or crotonylation. Since a weaker glucose uptake ability is one of the major clinical features of T2DM, the inhibition of EPB41L4A-AS1 expression seems to be a potentially effective strategy for drug development in T2DM treatment.
Collapse
Affiliation(s)
- Weijie Liao
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- School of Life SciencesTsinghua UniversityBeijingP. R. China
| | - Naihan Xu
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Open FIESTA CenterTsinghua UniversityShenzhenP. R. China
| | - Haowei Zhang
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- School of Life SciencesTsinghua UniversityBeijingP. R. China
| | - Weifang Liao
- College of life science and technologyWuhan Polytechnic UniversityWuhanP. R. China
| | - Yanzhi Wang
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- School of Life SciencesTsinghua UniversityBeijingP. R. China
| | - Songmao Wang
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- School of Life SciencesTsinghua UniversityBeijingP. R. China
| | - Shikuan Zhang
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- School of Life SciencesTsinghua UniversityBeijingP. R. China
| | - Yuyang Jiang
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
| | - Weidong Xie
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Open FIESTA CenterTsinghua UniversityShenzhenP. R. China
| | - Yaou Zhang
- State Key Laboratory of Chemical OncogenomicsTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Key Lab in Healthy Science and TechnologyDivision of Life ScienceTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhenP. R. China
- Open FIESTA CenterTsinghua UniversityShenzhenP. R. China
| |
Collapse
|
|
45
|
Harville EW, Wallace ME, He H, Bazzano LA. Lifetime cardiovascular risk factors and maternal and offspring birth outcomes: Bogalusa Babies. PLoS One 2022; 17:e0260703. [PMID: 35081112 PMCID: PMC8791492 DOI: 10.1371/journal.pone.0260703] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/15/2021] [Indexed: 11/24/2022] Open
Abstract
Both cardiovascular and reproductive complications may have origins in utero or in early life. Women in the Bogalusa Heart Study (n = 1401) had been linked to birth certificates for birthweight and gestational data, which were examined relative to childhood (ages 4–16) cardiometabolic indicators, indicated by mean levels overall and total risk factor burden as estimated by area under the curve (AUC) computed from longitudinal quadratic random-effects growth models. Women reported the birthweight and gestational age of each of their own pregnancies, and delivery medical records were linked to interview data where possible. Path analyses were conducted to examine the relationships among a woman’s own birth outcomes, childhood and preconception adult cardiovascular health, and birth outcomes. Mean blood pressure (systolic blood pressure (SBP) adjusted relative risk (aRR) per 1-SD increase, 1.27, 95% CI 1.04–1.57) and low-density lipoprotein (aRR 1.21, 95% CI 1.02–1.44) in childhood predicted preterm birth (PTB), while mean SBP (aRR 1.33, 95% CI 1.02–1.74) predicted term low birthweight. The AUC data suggested an association between blood pressure and PTB (aRR for SBP top 10%, 1.86, 95% CI 1.08–3.21). Pre-pregnancy total cholesterol was negatively associated with gestational age. In path analyses, positive associations were found for each step between own birthweight, childhood BMI, pre-pregnancy BMI, and child’s birthweight. Childhood levels of some, though not all, cardiovascular risk factors may predict adverse birth outcomes (preterm birth and reduced fetal growth).
Collapse
Affiliation(s)
- Emily W. Harville
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America
- * E-mail:
| | - Maeve E. Wallace
- Department of Global Community Health and Behavior, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America
| | - Hua He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America
| | - Lydia A. Bazzano
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America
| |
Collapse
|
|
46
|
Jiang Y, Zhu H, Chen Z, Yu YC, Guo XH, Chen Y, Yang MM, Chen BW, Sagnelli M, Xu D, Zhao BH, Luo Q. Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation. Front Endocrinol (Lausanne) 2022; 13:844707. [PMID: 35432202 PMCID: PMC9011096 DOI: 10.3389/fendo.2022.844707] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/24/2022] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE The offspring of women with gestational diabetes mellitus (GDM) have a high predisposition to developing type 2 diabetes during childhood and adulthood. The aim of the study was to evaluate how GDM exposure in the second half of pregnancy contributes to hepatic glucose intolerance through a mouse model. METHODS By creating a GDM mouse model, we tested glucose and insulin tolerance of offspring by intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). In addition, we checked the expression of genes IGF2/H19, FoxO1, and DNMTs in the mouse liver by RT-qPCR. Pyrosequencing was used to detect the methylation status on IGF2/H19 differentially methylated regions (DMRs). In vitro insulin stimulation experiments were performed to evaluate the effect of different insulin concentrations on HepG2 cells. Moreover, we detect the interaction between FoxO1 and DNMT3A by chromatin immunoprecipitation-quantitative PCR (Chip-qPCR) and knock-down experiments on HepG2 cells. RESULTS We found that the first generation of GDM offspring (GDM-F1) exhibited impaired glucose tolerance (IGT) and insulin resistance, with males being disproportionately affected. In addition, the expression of imprinted genes IGF2 and H19 was downregulated in the livers of male mice via hypermethylation of IGF2-DMR0 and IGF2-DMR1. Furthermore, increased expression of transcriptional factor FoxO1 was confirmed to regulate DNMT3A expression, which contributed to abnormal methylation of IGF2/H19 DMRs. Notably, different insulin treatments on HepG2 demonstrated those genetic alterations, suggesting that they might be induced by intrauterine hyperinsulinemia. CONCLUSION Our results demonstrated that the intrauterine hyperinsulinemia environment has increased hepatic FoxO1 levels and subsequently increased expression of DNMT3A and epigenetic alterations on IGF2/H19 DMRs. These findings provide potential molecular mechanisms responsible for glucose intolerance and insulin resistance in the first male generation of GDM mice.
Collapse
Affiliation(s)
- Ying Jiang
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Hong Zhu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Zi Chen
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Yi-Chen Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Xiao-Han Guo
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Yuan Chen
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Meng-Meng Yang
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Bang-Wu Chen
- Department of Obstetrics, Ninghai Maternal and Child Health Hospital, Ningbo, China
| | - Matthew Sagnelli
- University of Connecticut School of Medicine, Farmington, CT, United States
| | - Dong Xu
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Bai-Hui Zhao
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Qiong Luo
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- *Correspondence: Qiong Luo,
| |
Collapse
|
|
47
|
Zhang Q, Su R, Qin S, Wei Y. High glucose increases IGF-2/H19 expression by changing DNA methylation in HTR8/SVneo trophoblast cells. Placenta 2021; 118:32-37. [PMID: 35007927 DOI: 10.1016/j.placenta.2021.12.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Gestational diabetes mellitus (GDM) is associated with many adverse outcomes of pregnancy, especially macrosomia. The aim of our study was to verify whether high glucose concentrations change the methylation levels of the insulin-like growth factor-2 (IGF-2)/H19 gene promoters to increase the expression of IGF-2, a key gene in fetal growth regulation. METHODS HTR8/SVneo cells were used to establish a cell model of intrauterine hyperglycemia in pregnant women with GDM. The RNA expression levels of the IGF-2/H19 genes and the methylation levels of the IGF-2/H19 gene promoter regions were measured. Methylated and unmethylated IGF-2/H19 gene promoter plasmids were transfected into HTR8/SVneo cells. RESULTS Among the five groups of cells, the RNA levels of IGF-2 and H19 were lowest in the 5-mM (physiological blood glucose level) group, which was statistically significant (all P < 0.05). Compared with those in the 5-mM group, two cytosine-phosphate-guanine (CpG) sites in the promoter region of the IGF-2 gene and twelve CpG sites in the promoter region of the H19 gene had statistically significant changes in methylation levels (all P < 0.05). Additionally, luciferase activity was significantly higher in cells transfected with the methylated H19 gene promoter plasmid than in control cells transfected with the unmethylated plasmid (P < 0.01), while the methylated IGF-2 gene promoter plasmid produced lower luciferase activity than the unmethylated plasmid (P < 0.01). DISCUSSION High glucose concentrations may increase IGF-2/H19 expression by changing the methylation levels of the IGF-2 and H19 gene promoters.
Collapse
Affiliation(s)
- Qidi Zhang
- Peking University First Hospital Obstetrics and Gynecology, Beijing Key Laboratory of Maternal-Fetal Medicine of Gestational Diabetes Mellitus, China
| | - Rina Su
- Peking University First Hospital Obstetrics and Gynecology, Beijing Key Laboratory of Maternal-Fetal Medicine of Gestational Diabetes Mellitus, China
| | - Shengtang Qin
- Peking University First Hospital Obstetrics and Gynecology, Beijing Key Laboratory of Maternal-Fetal Medicine of Gestational Diabetes Mellitus, China
| | - Yumei Wei
- Peking University First Hospital Obstetrics and Gynecology, Beijing Key Laboratory of Maternal-Fetal Medicine of Gestational Diabetes Mellitus, China.
| |
Collapse
|
|
48
|
Paternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germline. Int J Mol Sci 2021; 23:ijms23010001. [PMID: 35008427 PMCID: PMC8744992 DOI: 10.3390/ijms23010001] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/02/2021] [Accepted: 12/05/2021] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND/AIMS Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease's (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. METHODS We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. RESULTS Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. CONCLUSION Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.
Collapse
|
|
49
|
Shu L, Hou X, Song G, Wang C, Ma H. Comparative analysis of long non‑coding RNA expression profiles induced by resveratrol and metformin treatment for hepatic insulin resistance. Int J Mol Med 2021; 48:206. [PMID: 34581420 PMCID: PMC8480386 DOI: 10.3892/ijmm.2021.5039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
Resveratrol (RSV) and metformin (MET) play a role in the treatment of diabetes; however, the mechanisms through which they mediate insulin resistance by regulating long non‑coding RNAs (lncRNAs) remain unknown. The present study was conducted to determine whether RSV and MET can improve insulin resistance in the livers of high‑fat diet (HFD)‑fed mice by regulating lncRNAs. C57BL/6J mice were fed a HFD for 8 weeks to establish a model of insulin resistance. The mice were subsequently treated with RSV or MET for 8 weeks and liver tissue samples were then collected. High‑throughput sequencing was utilized to analyze mouse liver tissue samples to obtain differential lncRNA expression profiles. RSV or MET both reduced the blood glucose levels, the insulin index and the area under the curve in HFD‑fed mice. Treatment also improved liver structure and decreased lipid deposition in liver tissues, as shown by H&E and Oil Red O staining. Compared with the MET group, there were 55 lncRNAs and 19 mRNAs with a differential expression. In total, eight lncRNAs were randomly selected and evaluated by reverse transcription‑quantitative PCR (RT‑qPCR). The results of seven lncRNAs corresponded to those of the sequencing analysis. Pathway analysis revealed that the PI3K/Akt signaling pathway had the highest enrichment score. In addition, the results of western blot analysis and RT‑qPCR revealed that the expression levels of forkhead box O1, glucose‑6‑phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 1 in the RSV and MET groups were significantly decreased compared with those in the HFD group. NONMMUT034936.2 and G6PC target genes exhibited similar expression patterns, indicating that RSV and MET may affect the PI3K/Akt signaling pathway through NONMMUT034936.2 to attenuate insulin resistance. On the whole, the present study provides novel biomarkers or contemporary perspectives for the use of RSV and MET in the treatment of insulin resistance and diabetes.
Collapse
Affiliation(s)
- Linyi Shu
- Research Center for Clinical Medical Sciences, Shijiazhuang Obstetrics and Gynecology Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xiaoyu Hou
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Guangyao Song
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Chao Wang
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Huijuan Ma
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| |
Collapse
|
|
50
|
He Z, Zhang J, Chen G, Cao J, Chen Y, Ai C, Wang H. H19/let-7 axis mediates caffeine exposure during pregnancy induced adrenal dysfunction and its multi-generation inheritance. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 792:148440. [PMID: 34465058 DOI: 10.1016/j.scitotenv.2021.148440] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/01/2021] [Accepted: 06/09/2021] [Indexed: 06/13/2023]
Abstract
Previously, we systemically confirmed that prenatal caffeine exposure (PCE) could cause intrauterine growth retardation (IUGR) and adrenal steroid synthesis dysfunction in offspring rats. However, the multi-generation inheritance of adrenal dysfunction and its epigenetic mechanism has not been reported. In this study, the PCE rat model was established, part of the pregnant rats were executed on gestational day 20, while the others were delivered normally and the fetal rats were reared into adulthood. The PCE female rats of filial generation 1 (F1) were mated with wild males to produce F2 offspring, and the same way to produce F3 offspring. All the adult female rats of three generations were sacrificed for the related detection. Results showed that PCE could decrease fetal weight, increase IUGR rate, and elevate serum corticosterone level. Meanwhile, the expression of fetal adrenal GR, DNMT3a/3b, miRNA let-7c increased while those of CTCF, H19, and StAR decreased, and the total methylation rate of the H19 promoter region was enhanced. We used SW-13 cells to clarify the molecular mechanism and found that cortisol-induced in vitro changes of these indexes were consistent with those in vivo. We confirmed that high level of cortisol through activating GR, on the one hand, promoted let-7 expression and inhibited StAR expression; on the other hand, caused high methylation and low expression of H19 by down-regulating CTCF and up-regulating DNMT3a/3b, then enhanced let-7 inhibitory effect on StAR by "molecular sponge" effect. Finally, in vivo experiments showed that the adrenal steroid synthesis function and H19/let-7 axis presented the glucocorticoid-dependent changes in the adult female F1, F2, and F3. In conclusion, PCE can cause female adrenal dysfunction with matrilineal multi-generation inheritance, which is related to the programming alteration of the H19/let-7 axis. This study provides a novel perspective to explain the multi-generation inheritance of fetal-originated disease in IUGR offspring.
Collapse
Affiliation(s)
- Zheng He
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jinzhi Zhang
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China
| | - Guanghui Chen
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China
| | - Jiangang Cao
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China
| | - Yawen Chen
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China
| | - Can Ai
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China
| | - Hui Wang
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071, China.
| |
Collapse
|