|
1
|
Geng C, Li X, Dan L, Xie L, Zhou M, Guan K, Chen Q, Xu Y, Ding R, Li J, Zhang Y, Sharifzadeh M, Liu R, Li W, Lu H. Female mice exposed to varying ratios of stearic to palmitic acid in a high-fat diet during gestation and lactation shows differential impairments of beta-cell function. Life Sci 2025; 369:123532. [PMID: 40057226 DOI: 10.1016/j.lfs.2025.123532] [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: 01/03/2025] [Revised: 02/19/2025] [Accepted: 03/03/2025] [Indexed: 03/30/2025]
Abstract
AIMS While emerging evidence implicates an abnormal stearic-to-palmitic acid ratio in saturated fats in beta-cell dysfunction, their gestational/lactational impacts remain underexplored. This study evaluates the differential transient and long-lasting effects of high-fat diets with contrasting stearic-to-palmitic acid ratios on maternal beta-cell function. MATERIALS AND METHODS Female mice were fed high-fat diets with high/low stearic-to-palmitic acid ratios during gestation/lactation, followed by a recovery period and subsequent exposure to an obesogenic diet. Beta-cell function was assessed using ex-vivo glucose-stimulated insulin secretion (GSIS) and immunohistochemistry. Islets mRNA profiling was performed using RNA-sequencing. KEY FINDINGS Both high- and low-ratio groups showed impaired GSIS post-lactation. High-ratio-fed dams exhibited pronounced compensatory responses, including increased islet size, number, and elevated Stx1a, Stx4, Pdx1, Mafa expression. Following metabolic re-challenge, high-ratio group demonstrated more severely impaired ex vivo insulin release. No significant differences in islet apoptosis and senescence were observed between the two groups. Transcriptomic profiling, however, revealed distinct mechanistic pathways: the high-ratio diet was likely to disrupt beta-cell organelles ultrastructure, while the low-ratio diet predominantly dysregulated chemokine-mediated immune signaling networks. SIGNIFICANCE Gestational/lactational exposure to high-fat diets with both high and low ratios of stearic-to-palmitic acid exerts pronounced transient impacts on beta-cell function, with the high-ratio diet inducing more severe and persistent detrimental effects. These findings highlight the critical influence and importance of dietary saturated fatty acid composition in maternal metabolic programming and beta-cell vulnerability.
Collapse
Affiliation(s)
- Chenchen Geng
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Xiaohan Li
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Lingfeng Dan
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Liyan Xie
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Min Zhou
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Kaile Guan
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Qi Chen
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Yan Xu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Rong Ding
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Jiaqi Li
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Yue Zhang
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Mohammad Sharifzadeh
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Rui Liu
- Department of Tropical and Liver Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570100, China.
| | - Wenting Li
- Department of Tropical and Liver Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570100, China; Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Huimin Lu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| |
Collapse
|
|
2
|
Haidery F, Lambertini L, Tse I, Dodda S, Garcia-Ocaña A, Scott DK, Baumel-Alterzon S. NRF2 deficiency leads to inadequate beta cell adaptation during pregnancy and gestational diabetes. Redox Biol 2025; 81:103566. [PMID: 40054060 PMCID: PMC11930207 DOI: 10.1016/j.redox.2025.103566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/12/2025] Open
Abstract
The late stages of mammalian pregnancy are accompanied by a mild increase in insulin resistance likely due to enhanced glucose demand of the growing fetus. Therefore, as an adaptive process to maintain euglycemia during pregnancy, maternal β-cell mass expands leading to increased insulin release. Defects in functional β-cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). While the exact mechanisms that promote GDM are poorly understood, GDM is associated with inadequate functional β-cell mass expansion and with a systematic increase of oxidative stress. Here, we show that NRF2 levels are upregulated in mouse β-cells at gestational day 15 (GD15). Inducible β-cell-specific Nrf2 deleted (βNrf2KO) mice display reduced β-cell proliferation, increased β-cell oxidative stress and lipid peroxidation, compromised β-cell function, and elevated β-cell death, leading to impaired β-cell mass expansion and dysregulated glucose homeostasis towards the end of pregnancy. Importantly, the gestational hormone 17-β-estradiol (E2) increases NRF2 levels, and downregulation of NRF2 suppresses E2-induced protection of β-cells against oxidative stress, suggesting that E2 exerts its antioxidant effects through activation of NRF2 signaling in β-cells. Collectively, these data highlight the critical role of NRF2 in regulating oxidative stress during the adaptive response of β-cells in pregnancy and identify NRF2 as a potential therapeutic target for GDM treatment.
Collapse
Affiliation(s)
- Fatema Haidery
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Luca Lambertini
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Isabelle Tse
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sriya Dodda
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adolfo Garcia-Ocaña
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA, USA.
| |
Collapse
|
|
3
|
Mittal R, Prasad K, Lemos JRN, Arevalo G, Hirani K. Unveiling Gestational Diabetes: An Overview of Pathophysiology and Management. Int J Mol Sci 2025; 26:2320. [PMID: 40076938 PMCID: PMC11900321 DOI: 10.3390/ijms26052320] [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: 12/06/2024] [Revised: 02/14/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Gestational diabetes mellitus (GDM) is characterized by an inadequate pancreatic β-cell response to pregnancy-induced insulin resistance, resulting in hyperglycemia. The pathophysiology involves reduced incretin hormone secretion and signaling, specifically decreased glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), impairing insulinotropic effects. Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), impair insulin receptor substrate-1 (IRS-1) phosphorylation, disrupting insulin-mediated glucose uptake. β-cell dysfunction in GDM is associated with decreased pancreatic duodenal homeobox 1 (PDX1) expression, increased endoplasmic reticulum stress markers (CHOP, GRP78), and mitochondrial dysfunction leading to impaired ATP production and reduced glucose-stimulated insulin secretion. Excessive gestational weight gain exacerbates insulin resistance through hyperleptinemia, which downregulates insulin receptor expression via JAK/STAT signaling. Additionally, hypoadiponectinemia decreases AMP-activated protein kinase (AMPK) activation in skeletal muscle, impairing GLUT4 translocation. Placental hormones such as human placental lactogen (hPL) induce lipolysis, increasing circulating free fatty acids which activate protein kinase C, inhibiting insulin signaling. Placental 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overactivity elevates cortisol levels, which activate glucocorticoid receptors to further reduce insulin sensitivity. GDM diagnostic thresholds (≥92 mg/dL fasting, ≥153 mg/dL post-load) are lower than type 2 diabetes to prevent fetal hyperinsulinemia and macrosomia. Management strategies focus on lifestyle modifications, including dietary carbohydrate restriction and exercise. Pharmacological interventions, such as insulin or metformin, aim to restore AMPK signaling and reduce hepatic glucose output. Emerging therapies, such as glucagon-like peptide-1 receptor (GLP-1R) agonists, show potential in improving glycemic control and reducing inflammation. A mechanistic understanding of GDM pathophysiology is essential for developing targeted therapeutic strategies to prevent both adverse pregnancy outcomes and the progression to overt diabetes in affected women.
Collapse
Affiliation(s)
| | | | | | | | - Khemraj Hirani
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (K.P.); (J.R.N.L.); (G.A.)
| |
Collapse
|
|
4
|
Dubey V, Tanday N, Irwin N, Tarasov AI, Flatt PR, Moffett RC. Cafeteria diet compromises natural adaptations of islet cell transdifferentiation and turnover in pregnancy. Diabet Med 2025; 42:e15434. [PMID: 39255356 PMCID: PMC11635593 DOI: 10.1111/dme.15434] [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: 06/20/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 09/12/2024]
Abstract
BACKGROUND Pancreatic islet β-cell mass expands during pregnancy, but underlying mechanisms are not fully understood. This study examines the impact of pregnancy and cafeteria diet on islet morphology, associated cellular proliferation/apoptosis rates as well as β-cell lineage. METHODS Non-pregnant and pregnant Ins1Cre/+;Rosa26-eYFP transgenic mice were maintained on either normal or high-fat cafeteria diet, with pancreatic tissue obtained at 18 days gestation. Immunohistochemical changes in islet morphology, β-/α-cell proliferation and apoptosis, as well as islet cell identity, neogenesis and ductal cell transdifferentiation were assessed. RESULTS Pregnant normal diet mice displayed an increase in body weight and glycaemia. Cafeteria feeding attenuated this weight gain while causing overt hyperglycaemia. Pregnant mice maintained on a normal diet exhibited typical expansion in islet and β-cell area, owing to increased β-cell proliferation and survival as well as ductal to β-cell transdifferentiation and β-cell neogenesis, alongside decreased β-cell dedifferentiation. Such pregnancy-induced islet adaptations were severely restricted by cafeteria diet. Accordingly, islets from these mice displayed high levels of β-cell apoptosis and dedifferentiation, together with diminished β-cell proliferation and lack of pregnancy-induced β-cell neogenesis and transdifferentiation, entirely opposing islet cell modifications observed in pregnant mice maintained on a normal diet. CONCLUSION Augmentation of β-cell mass during gestation arises through various mechanisms that include proliferation and survival of existing β-cells, transdifferentiation of ductal cells as well as β-cell neogenesis. Remarkably, cafeteria feeding almost entirely annuls pregnancy-induced islet adaptations, which may contribute to the development of gestational diabetes in the setting of dietary provoked metabolic stress.
Collapse
Affiliation(s)
- Vaibhav Dubey
- Centre for Diabetes, School of Biomedical SciencesUlster UniversityColeraineNorthern IrelandUK
| | - Neil Tanday
- Centre for Diabetes, School of Biomedical SciencesUlster UniversityColeraineNorthern IrelandUK
| | - Nigel Irwin
- Centre for Diabetes, School of Biomedical SciencesUlster UniversityColeraineNorthern IrelandUK
| | - Andrei I. Tarasov
- Centre for Diabetes, School of Biomedical SciencesUlster UniversityColeraineNorthern IrelandUK
| | - Peter R. Flatt
- Centre for Diabetes, School of Biomedical SciencesUlster UniversityColeraineNorthern IrelandUK
| | - R. Charlotte Moffett
- Centre for Diabetes, School of Biomedical SciencesUlster UniversityColeraineNorthern IrelandUK
| |
Collapse
|
|
5
|
Mullins TP, Gallo LA, McIntyre HD, Barrett HL. The influence of fetal sex on antenatal maternal glucose and insulin dynamics. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2024; 5:1351317. [PMID: 39742292 PMCID: PMC11685148 DOI: 10.3389/fcdhc.2024.1351317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 11/29/2024] [Indexed: 01/03/2025]
Abstract
The 'Developmental Origins of Health and Disease' (DOHaD) hypothesis postulates that exposures during critical periods of development and growth, including maternal hyperglycemia, can have significant consequences for short- and long-term health in offspring. The influence of fetal status on maternal (patho)physiology is less well understood but gaining attention. Fetal sex specifically may be an independent risk factor for a range of adverse pregnancy outcomes, including increased gestational diabetes mellitus (GDM) frequency with male fetuses in multi-ethnic populations. Fetal sex has been thought to modulate maternal glucose metabolism, including insulin dynamics, through complex genetic and hormonal interactions. Mechanisms have not been fully elucidated, however, but may relate to sexual dimorphism in maternal-fetal-placental interactions. We review current evidence on the potential influence of fetal sex on maternal glucose and insulin dynamics, and fetal outcomes.
Collapse
Affiliation(s)
- Thomas P. Mullins
- Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Linda A. Gallo
- School of Health, University of the Sunshine Coast, Petrie, QLD, Australia
| | - H. David McIntyre
- Mater Research Institute, The University of Queensland, and Mater Hospital Brisbane, Brisbane, QLD, Australia
| | - Helen L. Barrett
- Obstetric Medicine, Royal Hospital for Women, Randwick and Medicine at The University of New South Wales, Sydney, NSW, Australia
| |
Collapse
|
|
6
|
Brudner Y, Issa A, Sharabi H, Shafat L, Weisz B, Shrim A. The Role of Chorionicity in Placenta-Related Disorders. Fetal Diagn Ther 2024; 52:24-29. [PMID: 39312889 DOI: 10.1159/000541457] [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: 02/06/2024] [Accepted: 09/05/2024] [Indexed: 09/25/2024]
Abstract
INTRODUCTION Twin pregnancy is associated with higher rates of maternal morbidities including gestational diabetes and hypertension. Dichorionic twins are believed to have greater placental mass. Our objective was to study the incidence of two placenta-related disorders: gestational diabetes and hypertension, in dichorionic versus monochorionic twin pregnancies. METHODS Patients' data of all consecutive twin pregnancies over a period of 12 years were collected from medical records. Data on chorionicity were retrieved from 1st trimester ultrasound reports. Maternal complications including gestational hypertension and diabetes were collected, and incidence was compared between dichorionic and monochorionic twin pregnancies. Records lacking chorionicity data and cases with pregestational diabetes were excluded. RESULTS A total of 960 twin pregnancies, 121 monochorionic and 839 dichorionic, were included. Average maternal age did not differ significantly between the groups. The median gestational age at delivery was 36.0 weeks in monochorionic and 36.7 in dichorionic twins. Primiparity (40.4% vs. 23.1%, p < 0.001) and the rate of infertility treatments (51.5% vs. 7.4%, p < 0.001) were both more common in the dichorionic group. The incidence of gestational hypertension disorders was 14% in monochorionic versus 11% in dichorionic twins (p = 0.36). Gestational diabetes was more common in dichorionic compared to monochorionic twins (9.4% and 2.5%, respectively); however, logistic multivariate analysis showed that gestational diabetes was highly correlated with maternal age (p < 0.001) and infertility treatments (p < 0.001) but not with chorionicity (p = 0.136). CONCLUSION Our results may imply that greater placental mass does not increase the risk for gestational hypertension and diabetes. This might support the role of additional multiple maternal factors associated with these complications.
Collapse
Affiliation(s)
- Yana Brudner
- Department of Obstetrics and Gynecology Ultrasound, Hillel Yaffe Medical Center, Hadera, Israel
- Affiliated with the Technion, Israel Institute of Technology, Haifa, Israel
| | - Arwa Issa
- Technion, Israel Institute of Technology, Haifa, Israel
| | - Hila Sharabi
- Department of Obstetrics and Gynecology Ultrasound, Hillel Yaffe Medical Center, Hadera, Israel
- Affiliated with the Technion, Israel Institute of Technology, Haifa, Israel
| | - Livna Shafat
- Department of Obstetrics and Gynecology Ultrasound, Hillel Yaffe Medical Center, Hadera, Israel
- Affiliated with the Technion, Israel Institute of Technology, Haifa, Israel
| | - Boaz Weisz
- Department Obstetrics and Gynecology Ultrasound, Sheba Medical Center, Ramat Gan, Israel
- Affiliated with Tel Aviv University Sackler School of Medicine, Tel Aviv, Israel
| | - Alon Shrim
- Department of Obstetrics and Gynecology Ultrasound, Hillel Yaffe Medical Center, Hadera, Israel
- Affiliated with the Technion, Israel Institute of Technology, Haifa, Israel
| |
Collapse
|
|
7
|
Hatano R, Zhang X, Lee E, Kaneda A, Tanaka T, Miki T. Mosaic ablation of pancreatic β cells induces de-differentiation and repetitive proliferation of residual β cells in adult mice. iScience 2024; 27:110656. [PMID: 39310764 PMCID: PMC11416228 DOI: 10.1016/j.isci.2024.110656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/27/2024] [Accepted: 07/31/2024] [Indexed: 09/25/2024] Open
Abstract
Diabetes mellitus is induced by quantitative and qualitative decline in pancreatic β cells. Although its radical therapy has not yet been established, β cell regeneration is a promising option. We investigate here two mouse models of β cell regeneration induced after ∼80% reduction in β cell number: Cre/loxP-mediated β cell ablation and partial pancreatectomy. Cre/loxP-mediated, mosaic-pattern of β cell ablation by diphtheria toxin (DT) prompted rapid β cell replenishment through repeated proliferation of rare, highly proliferative DT receptor-negative β cells along with increase in Hes1, Neurog3, Ascl1, and Aldh1a3 (immature/dedifferentiated β cell markers) and decrease in Mafa (a mature β cell marker) in the islets. In contrast, pancreatectomy also prompted active proliferation, but with no change in these immature/dedifferentiated or mature β cell markers. Our findings demonstrate that the mode of β cell regeneration differs between Cre/loxP-mediated β cell ablation and surgical β cell reduction, and the former involves β cell dedifferentiation followed by active repetitive cell proliferation of a small population of β cells.
Collapse
Affiliation(s)
- Ryo Hatano
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Xilin Zhang
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Eunyoung Lee
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
- Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tomoaki Tanaka
- Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
- Department of Molecular Diagnosis, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Takashi Miki
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
- Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| |
Collapse
|
|
8
|
Brito Nunes C, Borges MC, Freathy RM, Lawlor DA, Qvigstad E, Evans DM, Moen GH. Understanding the Genetic Landscape of Gestational Diabetes: Insights into the Causes and Consequences of Elevated Glucose Levels in Pregnancy. Metabolites 2024; 14:508. [PMID: 39330515 PMCID: PMC11434570 DOI: 10.3390/metabo14090508] [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: 08/26/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024] Open
Abstract
Background/Objectives: During pregnancy, physiological changes in maternal circulating glucose levels and its metabolism are essential to meet maternal and fetal energy demands. Major changes in glucose metabolism occur throughout pregnancy and consist of higher insulin resistance and a compensatory increase in insulin secretion to maintain glucose homeostasis. For some women, this change is insufficient to maintain normoglycemia, leading to gestational diabetes mellitus (GDM), a condition characterized by maternal glucose intolerance and hyperglycaemia first diagnosed during the second or third trimester of pregnancy. GDM is diagnosed in approximately 14.0% of pregnancies globally, and it is often associated with short- and long-term adverse health outcomes in both mothers and offspring. Although recent studies have highlighted the role of genetic determinants in the development of GDM, research in this area is still lacking, hindering the development of prevention and treatment strategies. Methods: In this paper, we review recent advances in the understanding of genetic determinants of GDM and glycaemic traits during pregnancy. Results/Conclusions: Our review highlights the need for further collaborative efforts as well as larger and more diverse genotyped pregnancy cohorts to deepen our understanding of the genetic aetiology of GDM, address research gaps, and further improve diagnostic and treatment strategies.
Collapse
Affiliation(s)
- Caroline Brito Nunes
- Institute for Molecular Bioscience, The University of Queensland, Brisbane 4067, Australia
| | - Maria Carolina Borges
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK
| | - Rachel M. Freathy
- Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX4 4PY, UK;
| | - Deborah A. Lawlor
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK
| | - Elisabeth Qvigstad
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, 0424 Oslo, Norway
| | - David M. Evans
- Institute for Molecular Bioscience, The University of Queensland, Brisbane 4067, Australia
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK
- Frazer Institute, University of Queensland, Brisbane 4102, Australia
| | - Gunn-Helen Moen
- Institute for Molecular Bioscience, The University of Queensland, Brisbane 4067, Australia
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway
- Frazer Institute, University of Queensland, Brisbane 4102, Australia
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| |
Collapse
|
|
9
|
He L, Wang X, Chen X. Unveiling the role of microRNAs in metabolic dysregulation of Gestational Diabetes Mellitus. Reprod Biol 2024; 24:100924. [PMID: 39013209 DOI: 10.1016/j.repbio.2024.100924] [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: 05/01/2024] [Revised: 05/26/2024] [Accepted: 06/05/2024] [Indexed: 07/18/2024]
Abstract
Gestational Diabetes Mellitus (GDM) presents a significant health concern globally, necessitating a comprehensive understanding of its metabolic intricacies for effective management. MicroRNAs (miRNAs) have emerged as pivotal regulators in GDM pathogenesis, influencing glucose metabolism, insulin signaling, and lipid homeostasis during pregnancy. Dysregulated miRNA expression, both upregulated and downregulated, contributes to GDM-associated metabolic abnormalities. Ethnic and temporal variations in miRNA expression underscore the multifaceted nature of GDM susceptibility. This review examines the dysregulation of miRNAs in GDM and their regulatory functions in metabolic disorders. We discuss the involvement of specific miRNAs in modulating key pathways implicated in GDM pathogenesis, such as glucose metabolism, insulin signaling, and lipid homeostasis. Furthermore, we explore the potential diagnostic and therapeutic implications of miRNAs in GDM management, highlighting the promise of miRNA-based interventions for mitigating the adverse consequences of GDM on maternal and offspring health.
Collapse
Affiliation(s)
- Ling He
- Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Wang
- Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyi Chen
- Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
10
|
Khoshkerdar A, Eid N, Batra V, Baker N, Holmes N, Henson S, Sang F, Wright V, McLaren J, Shakesheff K, Woad KJ, Morgan HL, Watkins AJ. Sub-Optimal Paternal Diet at the Time of Mating Disrupts Maternal Adaptations to Pregnancy in the Late Gestation Mouse. Nutrients 2024; 16:1879. [PMID: 38931234 PMCID: PMC11206308 DOI: 10.3390/nu16121879] [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: 04/24/2024] [Revised: 06/05/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Pregnancy represents a stage during which maternal physiology and homeostatic regulation undergo dramatic change and adaptation. The fundamental purpose of these adaptations is to ensure the survival of her offspring through adequate nutrient provision and an environment that is tolerant to the semi-allogenic foetus. While poor maternal diet during pregnancy is associated with perturbed maternal adaptations during pregnancy, the influence of paternal diet on maternal well-being is less clearly defined. We fed C57BL/6 male mice either a control (CD), low protein diet (LPD), a high fat/sugar Western diet (WD) or the LPD or WD supplemented with methyl donors (MD-LPD and MD-WD, respectively) for a minimum of 8 weeks prior to mating with C57BL/6 females. Mated females were culled at day 17 of gestation for the analysis of maternal metabolic, gut, cardiac and bone health. Paternal diet had minimal influences on maternal serum and hepatic metabolite levels or gut microbiota diversity. However, analysis of the maternal hepatic transcriptome revealed distinct profiles of differential gene expression in response to the diet of the father. Paternal LPD and MD-LPD resulted in differential expression of genes associated with lipid metabolism, transcription, ubiquitin conjugation and immunity in dams, while paternal WD and MD-WD modified the expression of genes associated with ubiquitin conjugation and cardiac morphology. Finally, we observed changes in maternal femur length, volume of trabecular bone, trabecular connectivity, volume of the cortical medullar cavity and thickness of the cortical bone in response to the father's diets. Our current study demonstrates that poor paternal diet at the time of mating can influence the patterns of maternal metabolism and gestation-associated adaptations to her physiology.
Collapse
Affiliation(s)
- Afsaneh Khoshkerdar
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK; (A.K.); (N.E.); (V.B.); (N.B.); (H.L.M.)
| | - Nader Eid
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK; (A.K.); (N.E.); (V.B.); (N.B.); (H.L.M.)
| | - Vipul Batra
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK; (A.K.); (N.E.); (V.B.); (N.B.); (H.L.M.)
| | - Nichola Baker
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK; (A.K.); (N.E.); (V.B.); (N.B.); (H.L.M.)
| | - Nadine Holmes
- Deep Seq, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK; (N.H.); (S.H.); (F.S.); (V.W.)
| | - Sonal Henson
- Deep Seq, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK; (N.H.); (S.H.); (F.S.); (V.W.)
| | - Fei Sang
- Deep Seq, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK; (N.H.); (S.H.); (F.S.); (V.W.)
| | - Victoria Wright
- Deep Seq, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK; (N.H.); (S.H.); (F.S.); (V.W.)
| | - Jane McLaren
- Regenerative Medicine and Cellular Therapies, School of Pharmacy, University of Nottingham, Nottingham NG7 2UH, UK; (J.M.)
| | - Kevin Shakesheff
- Regenerative Medicine and Cellular Therapies, School of Pharmacy, University of Nottingham, Nottingham NG7 2UH, UK; (J.M.)
| | - Kathryn J. Woad
- School of Veterinary Medicine and Science, University of Nottingham, Loughborough LE12 5RD, UK;
| | - Hannah L. Morgan
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK; (A.K.); (N.E.); (V.B.); (N.B.); (H.L.M.)
| | - Adam J. Watkins
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK; (A.K.); (N.E.); (V.B.); (N.B.); (H.L.M.)
| |
Collapse
|
|
11
|
Milan KL, Jayasuriya R, Harithpriya K, Anuradha M, Ramkumar KM. MicroRNA-125b regulates vitamin D resistance by targeting CYP24A1 in the progression of gestational diabetes mellitus. J Steroid Biochem Mol Biol 2024; 239:106475. [PMID: 38350553 DOI: 10.1016/j.jsbmb.2024.106475] [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: 08/25/2023] [Revised: 01/25/2024] [Accepted: 01/30/2024] [Indexed: 02/15/2024]
Abstract
Vitamin D deficiency is prevalent in pregnancy and has been associated with increased occurrences of preeclampsia, cesarean delivery, neonatal bacterial vaginosis, and gestational diabetes. CYP24A1, recognized as a key factor in vitamin D metabolism homeostasis, encodes 24-hydroxylase responsible for converting 25(OH)D3 and 1,25(OH)2D3 into inactive metabolites. Recently, we have reported CYP24A1 overexpression in patients with gestational diabetes mellitus (GDM) and trophoblast cells exposed to hyperglycemia. In this study, we explored miRNA-mediated regulation of CYP24A1 in GDM progression, validating our findings through silencing experiments in a trophoblast cell line. In silico tools identified miR-125b-5p as a putative target of CYP24A1. Expression analysis revealed downregulation of miR-125b-5p in blood samples from early GDM and GDM compared to healthy pregnant women, positively correlating with vitamin D levels. Hyperglycemic exposure in human trophoblastic cell lines (BeWo) decreased miR-125b-5p expression, concomitant with an increase in CYP24A1. To confirm the regulatory role of miR-125b on CYP24A1, we transfected BeWo cells with antimiR-125b or miR-125b mimic. AntimiR-125b transfection heightened CYP24A1 levels, while miR-125b mimic overexpression resulted in decreased CYP24A1 expression. These findings establish miR-125b as a regulator of CYP24A1. To explore the influence of miR-125b on vitamin D metabolism, trophoblast cells overexpressing miR-125b were treated with 0.1 and 1 µM calcitriol. Hyperglycemic conditions exhibited a reduction in CYP24A1 levels. Collectively, our results indicate that miR-125b may regulate vitamin D metabolism by targeting CYP24A1, contributing to GDM progression. These findings may pave the way for understanding vitamin D resistance in concurrent GDM development and identifying novel miRNAs targeting CYP24A1.
Collapse
Affiliation(s)
- K L Milan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Ravichandran Jayasuriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Kannan Harithpriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - M Anuradha
- Department of Obstetrics & Gynaecology, SRM Medical College Hospital and Research Centre, Kattankulathur 603203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India.
| |
Collapse
|
|
12
|
Milionis C, Ilias I, Lekkou A, Venaki E, Koukkou E. Future clinical prospects of C-peptide testing in the early diagnosis of gestational diabetes. World J Exp Med 2024; 14:89320. [PMID: 38590302 PMCID: PMC10999065 DOI: 10.5493/wjem.v14.i1.89320] [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: 10/27/2023] [Revised: 12/11/2023] [Accepted: 12/28/2023] [Indexed: 03/19/2024] Open
Abstract
Gestational diabetes is typically diagnosed in the late second or third trimester of pregnancy. It is one of the most common metabolic disorders among expectant mothers, with potential serious short- and long-term complications for both maternal and offspring health. C-peptide is secreted from pancreatic beta-cells into circulation in equimolar amounts with insulin. It is a useful biomarker to estimate the beta-cell function because it undergoes negligible hepatic clearance and consequently it has a longer half-life compared to insulin. Pregnancy induces increased insulin resistance due to physiological changes in hormonal and metabolic homeostasis. Inadequate compensation by islet beta-cells results in hyperglycemia. The standard oral glucose tolerance test at 24-28 wk of gestation sets the diagnosis. Accumulated evidence from prospective studies indicates a link between early pregnancy C-peptide levels and the risk of subsequent gestational diabetes. Elevated C-peptide levels and surrogate glycemic indices at the beginning of pregnancy could prompt appropriate strategies for secondary prevention.
Collapse
Affiliation(s)
- Charalampos Milionis
- Department of Endocrinology, Diabetes, and Metabolism, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
| | - Ioannis Ilias
- Department of Endocrinology, Diabetes, and Metabolism, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
| | - Anastasia Lekkou
- Department of Endocrinology, Diabetes, and Metabolism, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
| | - Evangelia Venaki
- Department of Endocrinology, Diabetes, and Metabolism, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
| | - Eftychia Koukkou
- Department of Endocrinology, Diabetes, and Metabolism, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
| |
Collapse
|
|
13
|
Tanday N, Tarasov AI, Moffett RC, Flatt PR, Irwin N. Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable? Diabetes Obes Metab 2024; 26:16-31. [PMID: 37845573 DOI: 10.1111/dom.15300] [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: 07/31/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 10/18/2023]
Abstract
The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in response to small changes in environmental stimuli. Cell differentiation is driven by transcription factors that are also critical for the maintenance of the mature islet cell phenotype. Alteration of the insulin-secreting β-cell transcription factor set by prolonged metabolic stress, associated with the pathogenesis of diabetes, obesity or pregnancy, results in the loss of β-cell identity through de- or transdifferentiation. Importantly, the glucose-lowering effects of approved and experimental antidiabetic agents, including glucagon-like peptide-1 mimetics, novel peptides and small molecules, have been associated with preventing or reversing β-cell dedifferentiation or promoting the transdifferentiation of non-β-cells towards an insulin-positive β-cell-like phenotype. Therefore, we review the manifestations of islet cell plasticity in various experimental settings and discuss the physiological and therapeutic sides of this phenomenon, focusing on strategies for preventing β-cell loss or generating new β-cells in diabetes. A better understanding of the molecular mechanisms underpinning islet cell plasticity is a prerequisite for more targeted therapies to help prevent β-cell decline in diabetes.
Collapse
Affiliation(s)
- Neil Tanday
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
| | - Andrei I Tarasov
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - R Charlotte Moffett
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Nigel Irwin
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| |
Collapse
|
|
14
|
Usman TO, Chhetri G, Yeh H, Dong HH. Beta-cell compensation and gestational diabetes. J Biol Chem 2023; 299:105405. [PMID: 38229396 PMCID: PMC10694657 DOI: 10.1016/j.jbc.2023.105405] [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: 08/28/2023] [Revised: 10/16/2023] [Accepted: 10/18/2023] [Indexed: 01/18/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without a previous diagnosis of diabetes. While the etiology of GDM remains elusive, the close association of GDM with increased maternal adiposity and advanced gestational age implicates insulin resistance as a culpable factor for the pathogenesis of GDM. Pregnancy is accompanied by the physiological induction of insulin resistance in the mother secondary to maternal weight gain. This effect serves to spare blood glucose for the fetus. To overcome insulin resistance, maternal β-cells are conditioned to release more insulin into the blood. Such an adaptive response, termed β-cell compensation, is essential for maintaining normal maternal metabolism. β-cell compensation culminates in the expansion of β-cell mass and augmentation of β-cell function, accounting for increased insulin synthesis and secretion. As a result, a vast majority of mothers are protected from developing GDM during pregnancy. In at-risk pregnant women, β-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. However, gestational β-cell compensation ensues in early pregnancy, prior to the establishment of insulin resistance in late pregnancy. How β-cells compensate for pregnancy and what causes β-cell failure in GDM are subjects of investigation. In this mini-review, we will provide clinical and preclinical evidence that β-cell compensation is pivotal for overriding maternal insulin resistance to protect against GDM. We will highlight key molecules whose functions are critical for integrating gestational hormones to β-cell compensation for pregnancy. We will provide mechanistic insights into β-cell decompensation in the etiology of GDM.
Collapse
Affiliation(s)
- Taofeek O Usman
- Division of Endocrinology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Goma Chhetri
- Division of Endocrinology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Hsuan Yeh
- Division of Endocrinology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - H Henry Dong
- Division of Endocrinology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
| |
Collapse
|
|
15
|
de Oliveira JM, Dualib PM, Ferraro AA, Carvalho CRDS, Mattar R, Dib SA, de Almeida-Pititto B. Prolactin does not seem to mediate the improvement on insulin resistance markers and blood glucose levels related to breastfeeding. Front Endocrinol (Lausanne) 2023; 14:1219119. [PMID: 37711904 PMCID: PMC10499379 DOI: 10.3389/fendo.2023.1219119] [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: 05/08/2023] [Accepted: 07/25/2023] [Indexed: 09/16/2023] Open
Abstract
Introduction The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. Strategies to decrease this risk should be strongly encouraged. Lactation has been associated, for the mother, with reduction in future T2DM risk in several studies. The mechanisms behind this phenomenon, however, are poorly understood. The aims of this study were, first, to compare blood glucose levels and markers of insulin resistance (MIR) in early postpartum women with overweight/obesity according to their breastfeeding status and, second, to evaluate whether prolactin (PRL) levels could mediate improvements in these parameters. Methods The prospective study followed 95 women older than 18 years from early pregnancy for up to 60 to 180 days postpartum. All participants had a BMI > 25 kg/m2 and a singleton pregnancy. At each visit, questionnaires and clinical and biochemical evaluations were performed. Participants were divided into two groups according to the breastfeeding status as "yes" for exclusive or predominant breastfeeding, and "no" for not breastfeeding. Results Breastfeeding women (n = 44) had significantly higher PRL levels [47.8 (29.6-88.2) vs. 20.0 (12.0-33.8), p< 0.001]. They also had significantly lower fasting blood glucose levels [89.0 (8.0) vs. 93.9 (12.6) mg/dl, p = 0.04], triglycerides (TG) [92.2 (37.9) vs. 122.4 (64.4) mg/dl, p = 0.01], TG/HDL ratio [1.8 (0.8) vs. 2.4 (1.6) mg/dl, p = 0.02], TyG index [8.24 (0.4) vs. 8.52 (0.53), p = 0.005], fasting serum insulin [8.9 (6.3-11.6) vs. 11.4 (7.7-17.0), p = 0.048], and HOMA-IR [2.0 (1.3-2.7) vs. 2.6 (1.6-3.9), p = 0.025] in the postpartum period compared to the non-breastfeeding group. Groups were homogeneous in relation to prevalence of GDM, pre-gestational BMI, as well as daily caloric intake, physical activity, and weight loss at postpartum. Linear regression analysis with adjustments for confounders showed a statistically significant association of breastfeeding with fasting blood glucose [-6.37 (-10.91 to -1.83), p = 0.006], HOMA-IR [-0.27 (-0.51 to -0.04), p = 0.024], TyG index [-0.04 (-0.06 to -0.02), p = 0.001], and TG/HDL ratio [-0.25 (-0.48 to -0.01), p = 0.038]. Mediation analysis showed that PRL did not mediate these effects. Sensitivity analyses considering different cutoffs for PRL levels also did not show modification effect in the mediation analyses. Conclusion Breastfeeding was associated with improvement in glucose metabolism and MIR 60 to 180 days after birth in overweight and obese women, even when adjusted for confounders. PRL levels were not found to mediate the association between breastfeeding and improvement in MIR.
Collapse
Affiliation(s)
- Julia Martins de Oliveira
- Post-Graduation Program in Endocrinology and Metabology, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Patricia Medici Dualib
- Post-Graduation Program in Endocrinology and Metabology, Universidade Federal de Sao Paulo, São Paulo, Brazil
- Department of Medicine, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | | | | | - Rosiane Mattar
- Department of Obstetrics, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Sérgio Atala Dib
- Post-Graduation Program in Endocrinology and Metabology, Universidade Federal de Sao Paulo, São Paulo, Brazil
- Department of Medicine, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Bianca de Almeida-Pititto
- Post-Graduation Program in Endocrinology and Metabology, Universidade Federal de Sao Paulo, São Paulo, Brazil
- Department of Preventive Medicine, Universidade Federal de Sao Paulo, São Paulo, Brazil
| |
Collapse
|
|
16
|
Baumel-Alterzon S, Tse I, Heidery F, Garcia-Ocaña A, Scott DK. NRF2 Dysregulation in Mice Leads to Inadequate Beta-Cell Mass Expansion during Pregnancy and Gestational Diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.28.555207. [PMID: 37693560 PMCID: PMC10491153 DOI: 10.1101/2023.08.28.555207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
The late stages of the mammalian pregnancy are accompanied with increased insulin resistance due to the increased glucose demand of the growing fetus. Therefore, as a compensatory response to maintain the maternal normal blood glucose levels, maternal beta-cell mass expands leading to increased insulin release. Defects in beta-cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). Although the exact mechanisms that promote GDM are poorly understood, GDM strongly associates with impaired beta-cell proliferation and with increased levels of reactive oxygen species (ROS). Here, we show that NRF2 levels are upregulated in mouse beta-cells at gestation day 15 (GD15) concomitant with increased beta-cell proliferation. Importantly, mice with tamoxifen-induced beta-cell-specific NRF2 deletion display inhibition of beta-cell proliferation, increased beta-cell oxidative stress and elevated levels of beta-cell death at GD15. This results in attenuated beta-cell mass expansion and disturbed glucose homeostasis towards the end of pregnancy. Collectively, these results highlight the importance of NRF2-oxidative stress regulation in beta-cell mass adaptation to pregnancy and suggest NRF2 as a potential therapeutic target for treating GDM.
Collapse
Affiliation(s)
- Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Isabelle Tse
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Fatema Heidery
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Adolfo Garcia-Ocaña
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA
| | - Donald K. Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| |
Collapse
|
|
17
|
Lopez-Tello J, Yong HEJ, Sandovici I, Dowsett GKC, Christoforou ER, Salazar-Petres E, Boyland R, Napso T, Yeo GSH, Lam BYH, Constancia M, Sferruzzi-Perri AN. Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene. Cell Metab 2023; 35:1195-1208.e6. [PMID: 37437545 DOI: 10.1016/j.cmet.2023.06.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/12/2023] [Accepted: 06/09/2023] [Indexed: 07/14/2023]
Abstract
Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental nutrient transfer, but the mechanisms involved remain unclear. The imprinted Igf2 gene is highly expressed in murine placental endocrine cells. Here, we show that Igf2 deletion in these cells impairs placental endocrine signaling to the mother, without affecting placental morphology. Igf2 controls placental hormone production, including prolactins, and is crucial to establish pregnancy-related insulin resistance and to partition nutrients to the fetus. Consequently, fetuses lacking placental endocrine Igf2 are growth restricted and hypoglycemic. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis, actions dependent on the placental endocrine cell type. Igf2 loss also has additional long-lasting effects on offspring metabolism in adulthood. Our study provides compelling evidence for an intrinsic fetal manipulation system operating in placenta that modifies maternal metabolism and fetal resource allocation, with long-term consequences for offspring metabolic health.
Collapse
Affiliation(s)
- Jorge Lopez-Tello
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
| | - Hannah E J Yong
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A(∗)STAR), 30 Medical Drive, Singapore 117609, Singapore
| | - Ionel Sandovici
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK; Medical Research Council (MRC) Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Georgina K C Dowsett
- Medical Research Council (MRC) Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Efthimia R Christoforou
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Esteban Salazar-Petres
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Rebecca Boyland
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Royal Devon and Exeter Hospital NHS Trust, Barrack Rd, Exeter EX2 5DW, UK
| | - Tina Napso
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Giles S H Yeo
- Medical Research Council (MRC) Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Brian Y H Lam
- Medical Research Council (MRC) Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Miguel Constancia
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK; Medical Research Council (MRC) Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and, University of Cambridge, Cambridge CB2 0QQ, UK.
| | - Amanda N Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
| |
Collapse
|
|
18
|
Newman C, Rabbitt L, Ero A, Dunne FP. Focus on Metformin: Its Role and Safety in Pregnancy and Beyond. Drugs 2023:10.1007/s40265-023-01899-0. [PMID: 37354354 PMCID: PMC10322786 DOI: 10.1007/s40265-023-01899-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2023] [Indexed: 06/26/2023]
Abstract
Metformin is used worldwide in the treatment of type 2 diabetes and has been used in the treatment of diabetes in pregnancy since the 1970s. It is highly acceptable to patients due to its ease of administration, cost and adverse effect profile. It is effective in reducing macrosomia, large-for-gestational-age infants and reduces maternal weight gain. Despite its many advantages, metformin has been associated with reductions in foetal size and has been associated with an increase in infants born small-for-gestational-age in certain cohorts. In this article, we review its efficacy, adverse effects and long-term follow-up before, during and after pregnancy for both mother and infant. We also evaluate the other forms of treatment for gestational diabetes, including oral therapies, insulin therapy and emerging treatments.
Collapse
Affiliation(s)
- Christine Newman
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospital, Galway, Ireland.
- Diabetes Collaborative Clinical Trial Network, Clinical Research Facility, University of Galway, Galway, Ireland.
| | - Louise Rabbitt
- Department of Clinical Pharmacology and Therapeutics, Galway University Hospital, Galway, Ireland
- Discipline of Pharmacology and Therapeutics, School of Medicine, University of Galway, Galway, Ireland
| | - Adesuwa Ero
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospital, Galway, Ireland
| | - Fidelma P Dunne
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospital, Galway, Ireland
- Diabetes Collaborative Clinical Trial Network, Clinical Research Facility, University of Galway, Galway, Ireland
| |
Collapse
|
|
19
|
Zhu XZ, Deng ZM, Dai FF, Liu H, Cheng YX. The impact of early pregnancy metabolic disorders on pregnancy outcome and the specific mechanism. Eur J Med Res 2023; 28:197. [PMID: 37355665 DOI: 10.1186/s40001-023-01161-z] [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: 11/20/2022] [Accepted: 06/08/2023] [Indexed: 06/26/2023] Open
Abstract
Miscarriage is the most common complication of pregnancy. The most common causes of early miscarriage are chromosomal abnormalities of the embryo, maternal endocrine abnormalities, organ malformations, and abnormal immune factors. Late miscarriages are mostly caused by factors such as cervical insufficiency. However, the causes of 50% of miscarriages remain unknown. Recently, increasing attention has been given to the role of metabolic abnormalities in miscarriage. In this review, we mainly discuss the roles of four major metabolic pathways (glucose, lipid, and amino acid metabolism, and oxidation‒reduction balance) in miscarriage and the metabolism-related genes that lead to metabolic disorders in miscarriage. Depending on aetiology, the current treatments for miscarriage include hormonal and immunological drugs, as well as surgery, while there are few therapies for metabolism. Therefore, we also summarize the drugs for metabolism-related targets. The study of altered metabolism underlying miscarriage not only helps us to understand the mechanisms involved in miscarriage but also provides an important basis for clinical research on new therapies.
Collapse
Affiliation(s)
- Xi-Zi Zhu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, China
| | - Zhi-Min Deng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, China
| | - Fang-Fang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, China
| | - Hua Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, China.
| | - Yan-Xiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, China.
| |
Collapse
|
|
20
|
Lane A, Whitaker KM, Tahir M, Barone Gibbs B, Catov J, Carnethon M, Gunderson EP. Associations of Physical Activity and Lactation Duration With Cardiometabolic Risk Factors: The CARDIA Study. JACC. ADVANCES 2023; 2:100378. [PMID: 37584014 PMCID: PMC10426753 DOI: 10.1016/j.jacadv.2023.100378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 03/13/2023] [Accepted: 03/24/2023] [Indexed: 08/17/2023]
Abstract
BACKGROUND Physical activity (PA) and lactation benefit cardiometabolic health. OBJECTIVES The purpose of this study was to describe the joint associations of PA and lactation with cardiometabolic risk. METHODS We averaged PA across exams and summed lifetime lactation in Black and White parous women in the Coronary Artery Risk Development in Young Adults Study. Categories were created for PA (-PA: RESULTS The median PA was 256 exercise units and 54% reported lactation duration of ≥3 months. Of 1,068 participants, 303 were in the -PA/-L category, 231 in -PA/+L, 184 in +PA/-L, and 350 in +PA/+L. +PA/+L participants were older, had more years of education, lower body mass index, gained less weight, and less likely to be Black vs -PA/-L participants. Risk scores differed between categories except -PA/+L and +PA/-L (P = 0.08): -PA/-L: 0.23+/-0.04, -PA/+L: 0.08+/-0.04, +PA/-L: -0.02+/-0.05, and +PA/+L: -0.23+/-0.03. After adjustment, +PA/+L was associated with a lower/better risk score (β = -0.15, 95% CI: -0.25 to -0.04). CONCLUSIONS Above average PA throughout adulthood combined with ≥3 months of lactation was associated with lower risk scores. Participants with either behavior had lower risk vs those with neither behavior. Attaining these levels of behaviors may reduce cardiometabolic risk in parous women.
Collapse
Affiliation(s)
- Abbi Lane
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, USA
| | - Kara M. Whitaker
- Department of Health and Human Physiology, Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA
| | - Muna Tahir
- ICON plc, San Francisco, California, USA
| | - Bethany Barone Gibbs
- Department of Epidemiology and Biostatistics, School of Public Health, University of West Virginia, Morgantown, West Virginia, USA
| | - Janet Catov
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Obstetrics and Gynecology, Magee-Women’s Research Center, Pittsburgh, Pennsylvania, USA
| | - Mercedes Carnethon
- Department of Preventive Medicine, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Erica P. Gunderson
- Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA
| |
Collapse
|
|
21
|
Kahr MK, Antony KM, Galindo M, Whitham M, Hu M, Aagaard KM, Suter MA. SERUM GLP-2 is Increased in Association with Excess Gestational Weight Gain. Am J Perinatol 2023; 40:400-406. [PMID: 33940644 PMCID: PMC9970758 DOI: 10.1055/s-0041-1728828] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Obesity in pregnancy bears unique maternal and fetal risks. Obesity has also been associated with chronic inflammation, including elevated serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher serum lipopolysaccharide (LPS) levels have been implicated in driving this inflammation, a phenomenon called metabolic endotoxemia (ME). GLP-2, a proglucagon-derived peptide, is believed to be integral in maintaining the integrity of the intestine in the face of LPS-mediated endotoxemia. We hypothesized that obesity and/or excess weight gain in pregnancy would be associated with an increase in maternal and neonatal markers of ME, as well as GLP-2. STUDY DESIGN Paired maternal and neonatal (cord blood) serum samples (n = 159) were obtained from our pregnancy biobank repository. Serum levels of LPS, endotoxin core antibody-immunoglobulin M (EndoCAb-IgM), and GLP-2 were measured by ELISA. IL-6 and TNF-α were measured using a Milliplex assay. Results were stratified by maternal body mass index (BMI), maternal diabetes, and gestational weight gain (GWG). RESULTS Maternal IL-6 is significantly decreased in the obese, diabetic cohort compared with the nonobese, nondiabetic cohorts (95.28 vs. 99.48 pg/mL, p = 0.047), whereas GLP-2 is significantly increased (1.92 vs. 2.89 ng/mL, p = 0.026). Neonatal TNF-α is significantly decreased in the obese cohort compared with the nonobese cohort (12.43 vs. 13.93 pg/mL, p = 0.044). Maternal GLP-2 is significantly increased in women with excess GWG compared with those with normal GWG (2.27 vs. 1.48 ng/mL, p = 0.014). We further found that neonatal IL-6 and TNF-α are negatively correlated with maternal BMI (-0.186, p = 0.036 and -0.179, p = 0.044, respectively) and that maternal and neonatal IL-6 showed a positive correlation (0.348, p < 0.001). CONCLUSION Although we observed altered levels of markers of inflammation (IL-6 and TNF-α) with maternal obesity and diabetes, no changes in LPS or endoCAb-IgM were observed. We hypothesize that the increased GLP-2 levels in maternal serum in association with excess GWG may protect against ME in pregnancy. KEY POINTS · Maternal serum levels of GLP-2, a proglucagon-derived peptide, are increased in obese, diabetic gravidae.. · Maternal serum GLP-2 levels are also increased in association with excess gestational weight gain compared with normal gestational weight gain.. · GLP-2 may be increased in association with obesity and weight gain to protect against metabolic endotoxemia in pregnancy..
Collapse
Affiliation(s)
- Maike K. Kahr
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
- Department of Obstetrics and Gynecology, University Hospital Zurich, Zurich, Switzerland
| | - Kathleen M. Antony
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Megan Galindo
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Megan Whitham
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Min Hu
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Kjersti M. Aagaard
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Melissa A. Suter
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
- Address for correspondence Melissa Suter, PhD Department of Obstetrics and Gynecology, Baylor College of Medicine1 Baylor Plaza, Rm. 314C, Houston, TX 77030
| |
Collapse
|
|
22
|
Moyce Gruber BL, Dolinsky VW. The Role of Adiponectin during Pregnancy and Gestational Diabetes. Life (Basel) 2023; 13:301. [PMID: 36836658 PMCID: PMC9958871 DOI: 10.3390/life13020301] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Pregnancy involves a range of metabolic adaptations to supply adequate energy for fetal growth and development. Gestational diabetes (GDM) is defined as hyperglycemia with first onset during pregnancy. GDM is a recognized risk factor for both pregnancy complications and long-term maternal and offspring risk of cardiometabolic disease development. While pregnancy changes maternal metabolism, GDM can be viewed as a maladaptation by maternal systems to pregnancy, which may include mechanisms such as insufficient insulin secretion, dysregulated hepatic glucose output, mitochondrial dysfunction and lipotoxicity. Adiponectin is an adipose-tissue-derived adipokine that circulates in the body and regulates a diverse range of physiologic mechanisms including energy metabolism and insulin sensitivity. In pregnant women, circulating adiponectin levels decrease correspondingly with insulin sensitivity, and adiponectin levels are low in GDM. In this review, we summarize the current state of knowledge about metabolic adaptations to pregnancy and the role of adiponectin in these processes, with a focus on GDM. Recent studies from rodent model systems have clarified that adiponectin deficiency during pregnancy contributes to GDM development. The upregulation of adiponectin alleviates hyperglycemia in pregnant mice, although much remains to be understood for adiponectin to be utilized clinically for GDM.
Collapse
Affiliation(s)
- Brittany L. Moyce Gruber
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM), Research Theme of the Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada
| | - Vernon W. Dolinsky
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM), Research Theme of the Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada
| |
Collapse
|
|
23
|
Burgos-Gamez X, Morales-Castillo P, Fernandez-Mejia C. Maternal adaptations of the pancreas and glucose homeostasis in lactation and after lactation. Mol Cell Endocrinol 2023; 559:111778. [PMID: 36162635 DOI: 10.1016/j.mce.2022.111778] [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: 05/01/2022] [Revised: 09/04/2022] [Accepted: 09/13/2022] [Indexed: 02/03/2023]
Abstract
During lactation, the maternal physiology adapts to bear the nutritional requirements of the offspring. The exocrine and endocrine pancreas are central to nutrient handling, promoting digestion and metabolism. In concert with prolactin, insulin is a determinant factor for milk synthesis. The investigation of the pancreas during lactation has been scattered over several periods. The investigations that laid the foundation of lactating pancreatic physiology and glucose homeostasis were conducted in the decades of 1970-1980. With the development of molecular biology, newer studies have revealed the molecular mechanisms involved in the endocrine pancreas during breastfeeding. There has been a surge of information recently about unexpected changes in the pancreas at the end of the lactation period and after weaning. In this review, we aim to gather information on the changes in the pancreas and glucose homeostasis during and after lactation and discuss the outcomes derived from the current discoveries.
Collapse
Affiliation(s)
- Xadeni Burgos-Gamez
- Unidad de Genética de la Nutrición. Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México/ Instituto Nacional de Pediatría. Avenida del Iman#1, 4th floor, Mexico City, 04500, Mexico
| | - Paulina Morales-Castillo
- Unidad de Genética de la Nutrición. Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México/ Instituto Nacional de Pediatría. Avenida del Iman#1, 4th floor, Mexico City, 04500, Mexico
| | - Cristina Fernandez-Mejia
- Unidad de Genética de la Nutrición. Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México/ Instituto Nacional de Pediatría. Avenida del Iman#1, 4th floor, Mexico City, 04500, Mexico.
| |
Collapse
|
|
24
|
Nambiar SM, Lee J, Yanum JA, Garcia V, Jiang H, Dai G. Maternal hepatocytes heterogeneously and dynamically exhibit developmental phenotypes partially via yes-associated protein 1 during pregnancy. Am J Physiol Gastrointest Liver Physiol 2023; 324:G38-G50. [PMID: 36283963 PMCID: PMC9799147 DOI: 10.1152/ajpgi.00197.2022] [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: 08/08/2022] [Revised: 10/11/2022] [Accepted: 10/21/2022] [Indexed: 02/08/2023]
Abstract
Pregnancy induces reprogramming of maternal physiology to support fetal development and growth. Maternal hepatocytes undergo hypertrophy and hyperplasia to drive maternal liver growth and alter their gene expression profiles simultaneously. This study aimed to further understand maternal hepatocyte adaptation to pregnancy. Timed pregnancies were generated in mice. In a nonpregnant state, most hepatocytes expressed Cd133, α-fetal protein (Afp) and epithelial cell adhesion molecule (Epcam) mRNAs, whereas overall, at the protein level, they exhibited a CD133-/AFP- phenotype; however, pericentral hepatocytes were EpCAM+. As pregnancy advanced, although most maternal hepatocytes retained Cd133, Afp, and Epcam mRNA expression, they generally displayed a phenotype of CD133+/AFP+, and EpCAM protein expression was switched from pericentral to periportal maternal hepatocytes. In addition, we found that the Hippo/yes-associated protein (YAP) pathway does not respond to pregnancy. Yap1 gene deletion specifically in maternal hepatocytes did not affect maternal liver growth or metabolic zonation. However, the absence of Yap1 gene eliminated CD133 protein expression without interfering with Cd133 transcript expression in maternal livers. We demonstrated that maternal hepatocytes acquire heterogeneous and dynamic developmental phenotypes, resembling fetal hepatocytes, partially via YAP1 through a posttranscriptional mechanism. Moreover, maternal liver is a new source of AFP. In addition, maternal liver grows and maintains its metabolic zonation independent of the Hippo/YAP1 pathway. Our findings revealed a novel and gestation-dependent phenotypic plasticity in adult hepatocytes.NEW & NOTEWORTHY We found that maternal hepatocytes exhibit developmental phenotypes in a temporal and spatial manner, similarly to fetal hepatocytes. They acquire this new property partially via yes-associated protein 1.
Collapse
Affiliation(s)
- Shashank Manohar Nambiar
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Joonyong Lee
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Jennifer Abla Yanum
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Veronica Garcia
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Huaizhou Jiang
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Guoli Dai
- Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| |
Collapse
|
|
25
|
Ionescu RF, Enache RM, Cretoiu SM, Gaspar BS. Gut Microbiome Changes in Gestational Diabetes. Int J Mol Sci 2022; 23:12839. [PMID: 36361626 PMCID: PMC9654708 DOI: 10.3390/ijms232112839] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 08/27/2023] Open
Abstract
Gestational diabetes mellitus (GDM), one of the most common endocrine pathologies during pregnancy, is defined as any degree of glucose intolerance with onset or first discovery in the perinatal period. Physiological changes that occur in pregnant women can lead to inflammation, which promotes insulin resistance. In the general context of worldwide increasing obesity in young females of reproductive age, GDM follows the same ascending trend. Changes in the intestinal microbiome play a decisive role in obesity and the development of insulin resistance and chronic inflammation, especially in patients with type 2 diabetes mellitus (T2D). To date, various studies have also associated intestinal dysbiosis with metabolic changes in women with GDM. Although host metabolism in women with GDM has not been fully elucidated, it is of particular importance to analyze the available data and to discuss the actual knowledge regarding microbiome changes with potential impact on the health of pregnant women and newborns. We analyzed peer-reviewed journal articles available in online databases in order to summarize the most recent findings regarding how variations in diet and metabolic status of GDM patients can contribute to alteration of the gut microbiome, in the same way that changes of the gut microbiota can lead to GDM. The most frequently observed alteration in the microbiome of patients with GDM was either an increase of the Firmicutes phylum, respectively, or a decrease of the Bacteroidetes and Actinobacteria phyla. Gut dysbiosis was still present postpartum and can impact the development of the newborn, as shown in several studies. In the evolution of GDM, probiotic supplementation and regular physical activity have the strongest evidence of proper blood glucose control, favoring fetal development and a healthy outcome for the postpartum period. The current review aims to summarize and discuss the most recent findings regarding the correlation between GDM and dysbiosis, and current and future methods for prevention and treatment (lifestyle changes, pre- and probiotics administration). To conclude, by highlighting the role of the gut microbiota, one can change perspectives about the development and progression of GDM and open up new avenues for the development of innovative therapeutic targets in this disease.
Collapse
Affiliation(s)
- Ruxandra Florentina Ionescu
- Department of Cardiology I, Central Military Emergency Hospital “Dr Carol Davila”, 030167 Bucharest, Romania
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Robert Mihai Enache
- Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Sanda Maria Cretoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Bogdan Severus Gaspar
- Surgery Department, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Surgery Clinic, Bucharest Emergency Clinical Hospital, 014461 Bucharest, Romania
| |
Collapse
|
|
26
|
Oğlak SC, Yavuz A, Olmez F, Gedik Özköse Z, Süzen Çaypınar S. The reduced serum concentrations of β-arrestin-1 and β-arrestin-2 in pregnancies complicated with gestational diabetes mellitus. J Matern Fetal Neonatal Med 2022; 35:10017-10024. [PMID: 35674413 DOI: 10.1080/14767058.2022.2083495] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVE This study aimed to analyze maternal serum β-arrestin-1 and β-arrestin-2 concentrations in pregnant women complicated with gestational diabetes mellitus (GDM) and compare them with the normoglycemic uncomplicated healthy control group. METHODS A prospective case-control study was conducted, including pregnant women complicated with GDM between 15 February 2021, and 31 July 2021. We recorded serum β-arrestin-1 and β-arrestin-2 concentrations of the participants. Receiver operating characteristic (ROC) curves were used to describe and compare the performance of diagnostics value of variables β-arrestin-1, and β-arrestin-2. RESULTS The mean β-arrestin-1 and β-arrestin-2 levels were found to be significantly lower in the GDM group (41.0 ± 62.8 ng/mL, and 6.3 ± 9.9 ng/mL) than in the control group (93.1 ± 155.4 ng/mL, and 12.4 ± 17.7, respectively, p < .001). When we analyze the area under the ROC curve (AUC), maternal serum β-arrestin-1 and β-arrestin-2 levels can be considered a statistically significant parameter for diagnosing GDM. β-arrestin-1 had a significant negative correlation with fasting glucose (r = -0.551, p < .001), plasma insulin levels (r = -0.522, p < .001), HOMA-IR (r = -0.566, p < .001), and HbA1C (r = -0.465, p < .001). β-arrestin-2 was significantly negatively correlated with fasting glucose (r = -0.537, p < .001), plasma insulin levels (r = -0.515, p < .001), HOMA-IR (r = -0.550, p < .001), and HbA1C (r = -0.479, p < .001). CONCLUSION β-arrestin 1 and β-arrestin 2 could be utilized as biomarkers in the diagnosis of GDM. The novel therapeutic strategies targeting these β-arrestins may be designed for the GDM treatment.
Collapse
Affiliation(s)
- Süleyman Cemil Oğlak
- Department of Obstetrics and Gynecology, Health Sciences University, Gazi Yaşargil Training and Research Hospital, Diyarbakır, Turkey
| | - And Yavuz
- Department of Perinatology, Health Sciences University, Antalya Training and Research Hospital, Antalya, Turkey
| | - Fatma Olmez
- Department of Obstetrics and Gynecology, Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey
| | - Zeynep Gedik Özköse
- Department of Perinatology, Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey
| | - Sema Süzen Çaypınar
- Department of Perinatology, Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey
| |
Collapse
|
|
27
|
Sinzato YK, Paula VG, Gallego FQ, Moraes-Souza RQ, Corrente JE, Volpato GT, Damasceno DC. Maternal Diabetes and Postnatal High-Fat Diet on Pregnant Offspring. Front Cell Dev Biol 2022; 10:818621. [PMID: 35706903 PMCID: PMC9189289 DOI: 10.3389/fcell.2022.818621] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 04/12/2022] [Indexed: 12/22/2022] Open
Abstract
Maternal diabetes-induced fetal programming predisposes offspring to type 2 diabetes, cardiovascular disease, and obesity in adulthood. However, lifelong health and disease trajectories depend on several factors and nutrition is one of the main ones. We intend to understand the role of maternal diabetes-induced fetal programming and its association with a high-fat diet during lifelong in the female F1 generation focusing on reproductive outcomes and the possible changes in physiological systems during pregnancy as well as the repercussions on the F2 generation at birth. For this, we composed four groups: F1 female pups from control (OC) or from diabetic dams (OD) and fed with standard (SD) or high-fat diet from weaning to full-term pregnancy. During pregnancy, glucose intolerance and insulin sensitivity were evaluated. In a full-term pregnancy, the maternal blood and liver were collected to evaluate redox status markers. The maternal blood, placental tissue, and fetal blood (pool) were collected to evaluate adiponectin and leptin levels. Maternal reproductive parameters were evaluated as well. Maternal diabetes and high-fat diet consumption, in isolation, were both responsible for increased infertility rates and fasting glucose levels in the F1 generation and fetal growth restriction in the F2 generation. The association of both conditions showed, in addition to those, increased lipoperoxidation in maternal erythrocytes, regardless of the increased endogenous antioxidant enzyme activities, glucose intolerance, decreased number of implantation sites and live fetuses, decreased litter, fetal and placental weight, increased preimplantation losses, and increased fetal leptin serum levels. Thus, our findings show that fetal programming caused by maternal diabetes or lifelong high-fat diet consumption leads to similar repercussions in pregnant rats. In addition, the association of both conditions was responsible for glucose intolerance and oxidative stress in the first generation and increased fetal leptin levels in the second generation. Thus, our findings show both the F1 and F2 generations harmed health after maternal hyperglycemic intrauterine environment and exposure to a high-fat diet from weaning until the end of pregnancy.
Collapse
Affiliation(s)
- Yuri Karen Sinzato
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, Brazil
| | - Verônyca Gonçalves Paula
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, Brazil
| | - Franciane Quintanilha Gallego
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, Brazil
| | - Rafaianne Q. Moraes-Souza
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, Brazil
| | - José Eduardo Corrente
- Research Support Office, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, Brazil
| | - Gustavo Tadeu Volpato
- Laboratory of System Physiology and Reproductive Toxicology, Institute of Biological and Health Sciences, Federal University of Mato Grosso (UFMT), Barra do Garças, Brazil
| | - Débora Cristina Damasceno
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, Brazil
- *Correspondence: Débora Cristina Damasceno,
| |
Collapse
|
|
28
|
Gojnic M, Todorovic J, Stanisavljevic D, Jotic A, Lukic L, Milicic T, Lalic N, Lalic K, Stoiljkovic M, Stanisavljevic T, Stefanovic A, Stefanovic K, Vrzic-Petronijevic S, Petronijevic M, Terzic-Supic Z, Macura M, Perovic M, Babic S, Piperac P, Jovanovic M, Parapid B, Doklestic K, Cerovic R, Djurasevic S, Dugalic S. Maternal and Fetal Outcomes among Pregnant Women with Diabetes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:3684. [PMID: 35329371 PMCID: PMC8953700 DOI: 10.3390/ijerph19063684] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/12/2022] [Accepted: 03/15/2022] [Indexed: 02/08/2023]
Abstract
The aim of this study was to examine the differences in pregnancy complications, delivery characteristics, and neonatal outcomes between women with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). This study included all pregnant women with diabetes in pregnancy in Belgrade, Serbia, between 2010 and 2020. The total sample consisted of 6737 patients. In total, 1318 (19.6%) patients had T1DM, 138 (2.0%) had T2DM, and 5281 patients (78.4%) had GDM. Multivariate logistic regression with the type of diabetes as an outcome variable showed that patients with T1DM had a lower likelihood of vaginal delivery (OR: 0.73, 95% CI: 0.64-0.83), gestational hypertension (OR: 0.47, 95% CI: 0.36-0.62), higher likelihood of chronic hypertension (OR: 1.88, 95% CI: 1.55-2.29),and a higher likelihood ofgestational age at delivery before 37 weeks (OR: 1.38, 95% CI: 1.18-1.63) compared to women with GDM. Multivariate logistic regression showed that patients with T2DM had a lower likelihood ofgestational hypertension compared to women with GDM (OR: 0.37, 95% CI: 0.15-0.92).Our results indicate that the highest percentage of diabetes in pregnancy is GDM, and the existence of differences in pregnancy complications, childbirth characteristics, and neonatal outcomes are predominantly between women with GDM and women with T1DM.
Collapse
Affiliation(s)
- Miroslava Gojnic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Jovana Todorovic
- Institute of Social Medicine, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Dejana Stanisavljevic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Aleksandra Jotic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Ljiljana Lukic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Tanja Milicic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Nebojsa Lalic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Katarina Lalic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Milica Stoiljkovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | | | - Aleksandar Stefanovic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Katarina Stefanovic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Svetlana Vrzic-Petronijevic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milos Petronijevic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Zorica Terzic-Supic
- Institute of Social Medicine, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Maja Macura
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Milan Perovic
- Clinic for Gynecology and Obstetrics "NarodniFront", Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Sandra Babic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Pavle Piperac
- Department for Humanities, Faculty of Medicine, University of Belgrade, 11000 belgrade, Serbia
| | | | - Bijana Parapid
- Clinic for Cardiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Krisitna Doklestic
- Emergency Department, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Radmila Cerovic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | | | - Stefan Dugalic
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| |
Collapse
|
|
29
|
Lindsay KL, Gyllenhammer LE, Entringer S, Wadhwa PD. Rate of Gestational Weight Gain and Glucose-Insulin Metabolism Among Hispanic Pregnant Women With Overweight and Obesity. J Clin Endocrinol Metab 2022; 107:e734-e744. [PMID: 34468745 PMCID: PMC8764225 DOI: 10.1210/clinem/dgab655] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Indexed: 12/12/2022]
Abstract
CONTEXT Hispanic women are at elevated risk of gestational glucose intolerance and postpartum type 2 diabetes compared with non-Hispanic White women. Identification of potentially modifiable factors contributing to this trajectory of beta-cell dysfunction is warranted. OBJECTIVE We aimed to determine the association between rate of gestational weight gain (rGWG) and glucose-insulin metabolism in Hispanic pregnant women with overweight and obesity. METHODS This cross-sectional, observational study, conducted from 2018-2020 at the clinical research center at University of California, Irvine, included 33 nondiabetic Hispanic pregnant women at 28 to 30 weeks' gestation with pre-pregnancy body mass index (BMI) 25.0 to 34.9 kg/m2. Participants consumed a standardized liquid mixed meal after an overnight fast. Serial blood samples were collected at fasting and up to 2 hours postprandial. The glucose and insulin area under the curve (AUC), insulin sensitivity index (ISI) and insulin secretion sensitivity index (ISSI)-2 were computed. RESULTS Average rGWG (0.36 ± 0.22 kg/week) was classified as excessive in 60% of women. While rGWG was not associated with the glucose or insulin AUC or ISI, it accounted for 13.4% of the variance in ISSI-2 after controlling for covariates (maternal age, parity, and pre-pregnancy BMI); for each 1 unit increase in rGWG, ISSI-2 decreased 2.1 units (P = 0.015). CONCLUSION Even in the absence of gestational diabetes, rGWG was inversely associated with beta-cell function in a high-risk population of Hispanic pregnant women with overweight and obesity. Beta-cell decline is an established risk factor for transition to type 2 diabetes, and these cross-sectional findings highlight rGWG as a potentially modifiable contributor to this process.
Collapse
Affiliation(s)
- Karen L Lindsay
- Departments of Pediatrics, UCI School of Medicine, University of California, Irvine, CA 92697, USA
- Susan Samueli Integrative Health Institute, UCI College of Health Sciences, University of California, Irvine, CA 92617, USA
- Correspondence: Karen L Lindsay, PhD, RDN, 5141 California Ave, Suite 200B, University of California, Irvine, Irvine, CA 92617, USA.
| | - Lauren E Gyllenhammer
- Departments of Pediatrics, UCI School of Medicine, University of California, Irvine, CA 92697, USA
- UCI Development health and Disease Research Program, University of California, Irvine, CA 92868, USA
| | - Sonja Entringer
- Departments of Pediatrics, UCI School of Medicine, University of California, Irvine, CA 92697, USA
- UCI Development health and Disease Research Program, University of California, Irvine, CA 92868, USA
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, 10117 Berlin, Germany
| | - Pathik D Wadhwa
- UCI Development health and Disease Research Program, University of California, Irvine, CA 92868, USA
- Departments of Psychiatry and Human Behavior, UCI School of Medicine, University of California, Irvine, CA 92697, USA
| |
Collapse
|
|
30
|
Yin Y, Pan Y, He J, Zhong H, Wu Y, Ji C, Liu L, Cui X. The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus. Pharmacol Res 2022; 175:105987. [PMID: 34798268 DOI: 10.1016/j.phrs.2021.105987] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 01/29/2023]
Abstract
The most common complication during pregnancy, gestational diabetes mellitus (GDM), can cause adverse pregnancy outcomes and result in the mother and infant having a higher risk of developing type 2 diabetes after pregnancy. However, existing therapies for GDM remain scant, with the most common being lifestyle intervention and appropriate insulin treatment. MOTS-c, a mitochondrial-derived peptide, can target skeletal muscle and enhance glucose metabolism. Here, we demonstrate that MOTS-c can be an effective treatment for GDM. A GDM mouse model was established by short term high-fat diet combined with low-dose streptozotocin (STZ) treatment while MOTS-c was administrated daily during pregnancy. GDM symptoms such as blood glucose and insulin levels, glucose and insulin tolerance, as well as reproductive outcomes were investigated. MOTS-c significantly alleviated hyperglycemia, improved insulin sensitivity and glucose tolerance, and reduced birth weight and the death of offspring induced by GDM. Similar to a previous study, MOTS-c also could activate insulin sensitivity in the skeletal muscle of GDM mice and elevate glucose uptake in vitro. In addition, we found that MOTS-c protects pancreatic β-cell from STZ-mediated injury. Taken together, our findings demonstrate that MOTS-c could be a promising strategy for the treatment of GDM.
Collapse
Affiliation(s)
- Yadong Yin
- Department of Obstetrics and Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China; Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Yihui Pan
- Department of Obstetrics and Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Jin He
- Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Hong Zhong
- Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Yangyang Wu
- Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Chenbo Ji
- Department of Obstetrics and Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China; Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Lan Liu
- Department of Obstetrics and Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China; Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China.
| | - Xianwei Cui
- Department of Obstetrics and Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China; Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China.
| |
Collapse
|
|
31
|
Zhang Z, Piro AL, Dai FF, Wheeler MB. Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice. Front Endocrinol (Lausanne) 2022; 13:852149. [PMID: 35600586 PMCID: PMC9116578 DOI: 10.3389/fendo.2022.852149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Pregnancy is a dynamic state involving multiple metabolic adaptions in various tissues including the endocrine pancreas. However, a detailed characterization of the maternal islet metabolome in relation to islet function and the ambient circulating metabolome during pregnancy has not been established. METHODS A timed-pregnancy mouse model was studied, and age-matched non-pregnant mice were used as controls. Targeted metabolomics was applied to fasting plasma and purified islets during each trimester of pregnancy. Glucose homeostasis and islet function was assessed. Bioinformatic analyses were performed to reveal the metabolic adaptive changes in plasma and islets, and to identify key metabolic pathways associated with pregnancy. RESULTS Fasting glucose and insulin were found to be significantly lower in pregnant mice compared to non-pregnant controls, throughout the gestational period. Additionally, pregnant mice had superior glucose excursions and greater insulin response to an oral glucose tolerance test. Interestingly, both alpha and beta cell proliferation were significantly enhanced in early to mid-pregnancy, leading to significantly increased islet size seen in mid to late gestation. When comparing the plasma metabolome of pregnant and non-pregnant mice, phospholipid and fatty acid metabolism pathways were found to be upregulated throughout pregnancy, whereas amino acid metabolism initially decreased in early through mid pregnancy, but then increased in late pregnancy. Conversely, in islets, amino acid metabolism was consistently enriched throughout pregnancy, with glycerophospholid and fatty acid metabolism was only upregulated in late pregnancy. Specific amino acids (glutamate, valine) and lipids (acyl-alkyl-PC, diacyl-PC, and sphingomyelin) were found to be significantly differentially expressed in islets of the pregnant mice compared to controls, which was possibly linked to enhanced insulin secretion and islet proliferation. CONCLUSION Beta cell proliferation and function are elevated during pregnancy, and this is coupled to the enrichment of islet metabolites and metabolic pathways primarily associated with amino acid and glycerophospholipid metabolism. This study provides insight into metabolic adaptive changes in glucose homeostasis and islet function seen during pregnancy, which will provide a molecular rationale to further explore the regulation of maternal metabolism to avoid the onset of pregnancy disorders, including gestational diabetes.
Collapse
Affiliation(s)
- Ziyi Zhang
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Anthony L. Piro
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Feihan F. Dai
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- *Correspondence: Feihan F. Dai, ; Michael B. Wheeler,
| | - Michael B. Wheeler
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Metabolism Research Group, Division of Advanced Diagnostics, Toronto General Hospital Research Institute, Toronto, ON, Canada
- *Correspondence: Feihan F. Dai, ; Michael B. Wheeler,
| |
Collapse
|
|
32
|
Shashikadze B, Flenkenthaler F, Stöckl JB, Valla L, Renner S, Kemter E, Wolf E, Fröhlich T. Developmental Effects of (Pre-)Gestational Diabetes on Offspring: Systematic Screening Using Omics Approaches. Genes (Basel) 2021; 12:1991. [PMID: 34946940 PMCID: PMC8701487 DOI: 10.3390/genes12121991] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/27/2022] Open
Abstract
Worldwide, gestational diabetes affects 2-25% of pregnancies. Due to related disturbances of the maternal metabolism during the periconceptional period and pregnancy, children bear an increased risk for future diseases. It is well known that an aberrant intrauterine environment caused by elevated maternal glucose levels is related to elevated risks for increased birth weights and metabolic disorders in later life, such as obesity or type 2 diabetes. The complexity of disturbances induced by maternal diabetes, with multiple underlying mechanisms, makes early diagnosis or prevention a challenging task. Omics technologies allowing holistic quantification of several classes of molecules from biological fluids, cells, or tissues are powerful tools to systematically investigate the effects of maternal diabetes on the offspring in an unbiased manner. Differentially abundant molecules or distinct molecular profiles may serve as diagnostic biomarkers, which may also support the development of preventive and therapeutic strategies. In this review, we summarize key findings from state-of-the-art Omics studies addressing the impact of maternal diabetes on offspring health.
Collapse
Affiliation(s)
- Bachuki Shashikadze
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
| | - Florian Flenkenthaler
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
| | - Jan B. Stöckl
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
| | - Libera Valla
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
| | - Simone Renner
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
- Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Elisabeth Kemter
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
- Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Eckhard Wolf
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
- Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
| |
Collapse
|
|
33
|
Oppenländer L, Palit S, Stemmer K, Greisle T, Sterr M, Salinno C, Bastidas-Ponce A, Feuchtinger A, Böttcher A, Ansarullah, Theis FJ, Lickert H. Vertical sleeve gastrectomy triggers fast β-cell recovery upon overt diabetes. Mol Metab 2021; 54:101330. [PMID: 34500108 PMCID: PMC8487975 DOI: 10.1016/j.molmet.2021.101330] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/17/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The effectiveness of bariatric surgery in restoring β-cell function has been described in type-2 diabetes (T2D) patients and animal models for years, whereas the mechanistic underpinnings are largely unknown. The possibility of vertical sleeve gastrectomy (VSG) to rescue far-progressed, clinically-relevant T2D and to promote β-cell recovery has not been investigated on a single-cell level. Nevertheless, characterization of the heterogeneity and functional states of β-cells after VSG is a fundamental step to understand mechanisms of glycaemic recovery and to ultimately develop alternative, less-invasive therapies. METHODS We performed VSG in late-stage diabetic db/db mice and analyzed the islet transcriptome using single-cell RNA sequencing (scRNA-seq). Immunohistochemical analyses and quantification of β-cell area and proliferation complement our findings from scRNA-seq. RESULTS We report that VSG was superior to calorie restriction in late-stage T2D and rapidly restored normoglycaemia in morbidly obese and overt diabetic db/db mice. Single-cell profiling of islets of Langerhans showed that VSG induced distinct, intrinsic changes in the β-cell transcriptome, but not in that of α-, δ-, and PP-cells. VSG triggered fast β-cell redifferentiation and functional improvement within only two weeks of intervention, which is not seen upon calorie restriction. Furthermore, VSG expanded β-cell area by means of redifferentiation and by creating a proliferation competent β-cell state. CONCLUSION Collectively, our study reveals the superiority of VSG in the remission of far-progressed T2D and presents paths of β-cell regeneration and molecular pathways underlying the glycaemic benefits of VSG.
Collapse
Affiliation(s)
- Lena Oppenländer
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; Technical University of Munich, School of Medicine, 81675, Munich, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany
| | - Subarna Palit
- Institute of Computational Biology, Helmholtz Center Munich, 85764, Neuherberg, Germany; Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany
| | - Kerstin Stemmer
- Institute of Diabetes and Obesity, Helmholtz Center Munich, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany; Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, 35392, Giessen, Germany
| | - Tobias Greisle
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; Technical University of Munich, School of Medicine, 81675, Munich, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany
| | - Michael Sterr
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany
| | - Ciro Salinno
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; Technical University of Munich, School of Medicine, 81675, Munich, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany
| | - Aimée Bastidas-Ponce
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; Technical University of Munich, School of Medicine, 81675, Munich, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany
| | - Annette Feuchtinger
- Core Facility Pathology and Tissue Analytics, Helmholtz Center Munich, 85764, Neuherberg, Germany
| | - Anika Böttcher
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany
| | - Ansarullah
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
| | - Fabian J Theis
- Institute of Computational Biology, Helmholtz Center Munich, 85764, Neuherberg, Germany; Department of Mathematics, Technical University of Munich, 85748, Garching, Germany; Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany.
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, 85764, Neuherberg, Germany; Technical University of Munich, School of Medicine, 81675, Munich, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany; Department of Medicine, Technical University of Munich, 81675, Munich, Germany.
| |
Collapse
|
|
34
|
Ader M, Bergman RN. Hyperinsulinemic Compensation for Insulin Resistance Occurs Independent of Elevated Glycemia in Male Dogs. Endocrinology 2021; 162:6300300. [PMID: 34132779 PMCID: PMC8282122 DOI: 10.1210/endocr/bqab119] [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: 03/09/2021] [Indexed: 11/19/2022]
Abstract
Insulin resistance engenders a compensatory increase in plasma insulin. Inadequate compensation is a primary element in the pathogenesis of type 2 diabetes. The signal that heralds developing insulin resistance and initiates hyperinsulinemic compensation is not known. It has often been assumed to be increased glucose. We tested this assumption by determining whether development of fasting and/or glucose-stimulated hyperinsulinemia with diet-induced insulin resistance occurs because of concomitant elevation of glycemia. Male dogs (n = 58) were fed a hypercaloric, fat-supplemented diet for 6 weeks. Dogs underwent magnetic resonance imaging to quantify total and regional (visceral, subcutaneous) adiposity as well as euglycemic hyperinsulinemic clamps. A subset of animals also underwent an insulin-modified intravenous glucose tolerance test to assess insulin sensitivity, acute insulin response (AIRg), and glucose effectiveness. Fat feeding caused modest weight gain, increased visceral and subcutaneous fat, and insulin resistance at both peripheral and hepatic levels. Hyperinsulinemic compensation was observed in fasting levels as well as increased AIRg. However, we observed absolutely no increase in carefully measured fasting, evening (6 to 8 pm) or nocturnal glycemia (2 to 4 am). Insulin resistance and hyperinsulinemia occurred despite no elevation in 24-hour glucose. Compensatory development of hyperinsulinemia during diet-induced insulin resistance occurs without elevated fasting or 24-hour glycemia. These data refute the idea that glucose itself is a requisite signal for β-cell upregulation. Alternative feedback mechanisms need to be identified.
Collapse
Affiliation(s)
- Marilyn Ader
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Correspondence: Marilyn Ader, Ph.D., Associate Director, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, 116 N. Robertson Blvd, PACT 700.8V, Los Angeles, CA 90048, United States. E-mail:
| | - Richard N Bergman
- Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| |
Collapse
|
|
35
|
Olmos-Ortiz A, Flores-Espinosa P, Díaz L, Velázquez P, Ramírez-Isarraraz C, Zaga-Clavellina V. Immunoendocrine Dysregulation during Gestational Diabetes Mellitus: The Central Role of the Placenta. Int J Mol Sci 2021; 22:8087. [PMID: 34360849 PMCID: PMC8348825 DOI: 10.3390/ijms22158087] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/15/2021] [Accepted: 07/26/2021] [Indexed: 02/07/2023] Open
Abstract
Gestational Diabetes Mellitus (GDM) is a transitory metabolic condition caused by dysregulation triggered by intolerance to carbohydrates, dysfunction of beta-pancreatic and endothelial cells, and insulin resistance during pregnancy. However, this disease includes not only changes related to metabolic distress but also placental immunoendocrine adaptations, resulting in harmful effects to the mother and fetus. In this review, we focus on the placenta as an immuno-endocrine organ that can recognize and respond to the hyperglycemic environment. It synthesizes diverse chemicals that play a role in inflammation, innate defense, endocrine response, oxidative stress, and angiogenesis, all associated with different perinatal outcomes.
Collapse
Affiliation(s)
- Andrea Olmos-Ortiz
- Departamento de Inmunobioquímica, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes (INPer), Ciudad de México 11000, Mexico; (A.O.-O.); (P.F.-E.)
| | - Pilar Flores-Espinosa
- Departamento de Inmunobioquímica, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes (INPer), Ciudad de México 11000, Mexico; (A.O.-O.); (P.F.-E.)
| | - Lorenza Díaz
- Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México 14080, Mexico;
| | - Pilar Velázquez
- Departamento de Ginecología y Obstetricia, Hospital Ángeles México, Ciudad de México 11800, Mexico;
| | - Carlos Ramírez-Isarraraz
- Clínica de Urología Ginecológica, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes (INPer), Ciudad de México 11000, Mexico;
| | - Verónica Zaga-Clavellina
- Departamento de Fisiología y Desarrollo Celular, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes (INPer), Ciudad de México 11000, Mexico
| |
Collapse
|
|
36
|
Associations between insulin resistance and adverse pregnancy outcomes in women with gestational diabetes mellitus: a retrospective study. BMC Pregnancy Childbirth 2021; 21:526. [PMID: 34301212 PMCID: PMC8306365 DOI: 10.1186/s12884-021-04006-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 07/02/2021] [Indexed: 11/28/2022] Open
Abstract
Background This study aimed to explore the relationship between insulin resistance (IR) and adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM), and to determine the risk factors for IR in women with GDM. Methods This study employed a retrospective survey of 710 women diagnosed with GDM. Serum lipids, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), and serum protein were measured in the first trimester (6–12 weeks), and OGTT and fasting insulin tests were performed in the second trimester (24–28 weeks). These results were then used to evaluate IR by homeostasis model assessment (HOMA). When HOMA-IR ≥ 2.0, IR was diagnosed. The relationship between HOMA-IR and adverse pregnancy outcomes was analyzed by a logistic regression model, and multiple stepwise regression was used to analyze the risk factors of IR. Results IR significantly increasd the risk of the hypertensive disorders of pregnancy and large for gestational age (LGA) (OR = 5.31,95%CI:1.87,15.10; OR = 1.65,95%CI:1.10, 2.48, respectively) in women with GDM, but not for cesarean section, premature delivery, premature rupture of membranes, postpartum hemorrhage, macrosomia and SGA. Compared to normal groups, greater body mass index (BMI) before pregnancy category (overweight or obesity group) were associated with higher risk of IR in the second trimester, the OR (95% CI) were 4.09 (2.65, 6.30) and 6.52 (2.99, 14.20). And higher level of FPG (OR = 1.63, 95%CI: 1.11, 2.40), TG (OR = 1.32, 95%CI: 1.08, 1.63) and weight gain before diagnosis of GDM (OR = 1.08, 95%CI: 1.02, 1.15) were also associated with higher risk of IR in the second trimester in women with GDM, while age (OR = 0.94, 95%CI: 0.90, 0.98)was the weak protective factor for IR. Conclusion GDM with IR in the second trimester increased adverse pregnancy outcomes, especially the risk of hypertensive disorders of pregnancy and LGA. In addition, FPG, HbA1c, and TG in early pregnancy, pre-pregnant BMI and weight gain before diagnosis of GDM were all independent risk factors for IR.
Collapse
|
|
37
|
Gu P, Lin Y, Wan Q, Su D, Shu Q. Oxytocin signal contributes to the adaptative growth of islets during gestation. Endocr Connect 2021; 10:694-706. [PMID: 34077390 PMCID: PMC8240721 DOI: 10.1530/ec-21-0043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/02/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy. METHODS The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells. RESULTS The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A 3-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells. CONCLUSIONS These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and the lack of oxytocin could be associated with the risk of GDM.
Collapse
Affiliation(s)
- Ping Gu
- Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuege Lin
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Qi Wan
- Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Correspondence should be addressed to Q Shu or D Su or Q Wan: or or
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China
- Correspondence should be addressed to Q Shu or D Su or Q Wan: or or
| | - Qun Shu
- Department of Obstetrics, Shanghai First Maternity and Infant Health Hospital, School of Medicine, Tongji University, Shanghai, China
- Correspondence should be addressed to Q Shu or D Su or Q Wan: or or
| |
Collapse
|
|
38
|
Liu ZN, Jiang Y, Liu XQ, Yang MM, Chen C, Zhao BH, Huang HF, Luo Q. MiRNAs in Gestational Diabetes Mellitus: Potential Mechanisms and Clinical Applications. J Diabetes Res 2021; 2021:4632745. [PMID: 34869778 PMCID: PMC8635917 DOI: 10.1155/2021/4632745] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/08/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a common pregnancy complication which is normally diagnosed in the second trimester of gestation. With an increasing incidence, GDM poses a significant threat to maternal and offspring health. Therefore, we need a deeper understanding of GDM pathophysiology and novel investigation on the diagnosis and treatment for GDM. MicroRNAs (miRNAs), a class of endogenic small noncoding RNAs with a length of approximately 19-24 nucleotides, have been reported to exert their function in gene expression by binding to proteins or being enclosed in membranous vesicles, such as exosomes. Studies have investigated the roles of miRNAs in the pathophysiological mechanism of GDM and their potential as noninvasive biological candidates for the management of GDM, including diagnosis and treatment. This review is aimed at summarizing the pathophysiological significance of miRNAs in GDM development and their potential function in GDM clinical diagnosis and therapeutic approach. In this review, we summarized an integrated expressional profile and the pathophysiological significance of placental exosomes and associated miRNAs, as well as other plasma miRNAs such as exo-AT. Furthermore, we also discussed the practical application of exosomes in GDM postpartum outcomes and the potential function of several miRNAs as therapeutic target in the GDM pathological pathway, thus providing a novel clinical insight of these biological signatures into GDM therapeutic approach.
Collapse
Affiliation(s)
- Zhao-Nan Liu
- Department of Reproductive Genetics, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Ying Jiang
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - Xuan-Qi Liu
- Department of Reproductive Genetics, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Meng-Meng Yang
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - Cheng Chen
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - Bai-Hui Zhao
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| | - He-Feng Huang
- Department of Reproductive Genetics, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Qiong Luo
- Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, China
| |
Collapse
|
|
39
|
Rosselot C, Baumel-Alterzon S, Li Y, Brill G, Lambertini L, Katz LS, Lu G, Garcia-Ocaña A, Scott DK. The many lives of Myc in the pancreatic β-cell. J Biol Chem 2021; 296:100122. [PMID: 33239359 PMCID: PMC7949031 DOI: 10.1074/jbc.rev120.011149] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/20/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
Diabetes results from insufficient numbers of functional pancreatic β-cells. Thus, increasing the number of available functional β-cells ex vivo for transplantation, or regenerating them in situ in diabetic patients, is a major focus of diabetes research. The transcription factor, Myc, discovered decades ago lies at the nexus of most, if not all, known proliferative pathways. Based on this, many studies in the 1990s and early 2000s explored the potential of harnessing Myc expression to expand β-cells for diabetes treatment. Nearly all these studies in β-cells used pathophysiological or supraphysiological levels of Myc and reported enhanced β-cell death, dedifferentiation, or the formation of insulinomas if cooverexpressed with Bcl-xL, an inhibitor of apoptosis. This obviously reduced the enthusiasm for Myc as a therapeutic target for β-cell regeneration. However, recent studies indicate that "gentle" induction of Myc expression enhances β-cell replication without induction of cell death or loss of insulin secretion, suggesting that appropriate levels of Myc could have therapeutic potential for β-cell regeneration. Furthermore, although it has been known for decades that Myc is induced by glucose in β-cells, very little is known about how this essential anabolic transcription factor perceives and responds to nutrients and increased insulin demand in vivo. Here we summarize the previous and recent knowledge of Myc in the β-cell, its potential for β-cell regeneration, and its physiological importance for neonatal and adaptive β-cell expansion.
Collapse
Affiliation(s)
- Carolina Rosselot
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sharon Baumel-Alterzon
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yansui Li
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gabriel Brill
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Luca Lambertini
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Liora S Katz
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Geming Lu
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Adolfo Garcia-Ocaña
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.
| | - Donald K Scott
- Diabetes Obesity Metabolism Institute, and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
40
|
Guzman-Ortiz E, Bueno-Hernandez N, Melendez-Mier G, Roldan-Valadez E. Quantitative systematic review: Methods used for the in vivo measurement of body composition in pregnancy. J Adv Nurs 2020; 77:537-549. [PMID: 33058345 DOI: 10.1111/jan.14594] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/04/2020] [Accepted: 08/27/2020] [Indexed: 02/05/2023]
Abstract
AIMS Because of the increased overall prevalence of pre-pregnancy obesity among racial-ethnic groups, we conducted a review of published methods for body composition measurement during pregnancy considering at present there is no consensus on the best practices and type of study design that researchers should use for this purpose. DESIGN Quantitative systematic review. DATA SOURCES PubMed, EMBASE, Scopus, Web of Science, and Virtual Library of Health. Search dates from 1997-2016. REVIEW METHODS Search of articles indexed in selected databases from 1997-2016. Studies were published in English, Spanish, and Portuguese. Graphs were carried out using data visualization software. RESULTS From the 112 included studies, 70 were prospective cohorts, 30 cross-sectional studies, 10 randomized controlled trial, and two retrospective studies. Cross-sectional studies and randomized controlled trial depicted a positive correlation with significant trend. CONCLUSIONS Although several methods for body composition measurement exist, only bioelectrical impedance analysis, displacement plethysmography, and displacement plethysmography show a significant growing trend. Use of data visualization allows understanding various associations among categorical variables, with a graphical display of their multidimensional behaviour. IMPACT Public and private health-care institution evaluating pregnancy women. Health-care personnel, including nursing professional, dealing with measurements of body composition during pregnancy will find reading this manuscript beneficial.
Collapse
Affiliation(s)
| | - Nallely Bueno-Hernandez
- Laboratory for Proteomics and Metabolomics, Research Division, General Hospital of Mexico, Mexico City, Mexico
| | | | - Ernesto Roldan-Valadez
- Directorate of Research, Hospital General de Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico.,Department of Radiology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| |
Collapse
|
|
41
|
Yefet E, Schwartz N, Sliman B, Nachum Z. One elevated oral glucose tolerance test value in pregnancy increases the risk for future diabetes mellitus type 2. Arch Gynecol Obstet 2020; 303:933-941. [PMID: 33057771 DOI: 10.1007/s00404-020-05827-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 09/26/2020] [Indexed: 01/01/2023]
Abstract
PURPOSE Women with only one elevated 100 g OGTT value are not considered as having gestational diabetes mellitus (GDM) and therefore there are no recommendations to address this population as a risk group for type 2 diabetes mellitus (T2DM). We aimed to elucidate whether one elevated OGTT value increases the risk for T2DM. METHODS A retrospective population-based cohort study of women with a first diagnosis of GDM who delivered between 1991 and 2011 was conducted. Women were divided according to GDM diagnosis criteria into three groups: (1) at least two elevated values of Carpenter and Coustan criteria (C&C; N = 209), (2) At least two elevated values of the National Diabetes Data Group (NDDG) criteria (NDDG2; N = 290) and (3) only one elevated value of the NDDG criteria (NDDG1; N = 226). A fourth group comprising women without GDM was included (control; N = 352). The primary outcome was the development of T2DM. RESULTS The mean follow-up was 12.4 ± 5.3 years and the mean age at follow-up was 43.0 ± 5.7 years. The rate of T2DM in the control, C&C, NDDG1 and NDDG2 groups were 5%, 18%, 19% and 31%, respectively. All GDM diagnoses were independent risk factors for T2DM in multivariable Cox regression when compared to controls, adjusted hazard ratio and 95% CI: C&C 7.8 [95% CI 3.7-16.4], NDDG1 5.5 [2.6-11.6], and NDDG2 10.5 [5.2-21.4]. Additional independent risk factors were parity, fasting and 1-h post-glucose load of the OGTT and insulin use. CONCLUSIONS Women with one elevated OGTT value using the NDDG criteria are at increased risk for T2DM. Further studies are needed to decide whether those women should be considered a focus group for long-term surveillance and T2DM prevention interventions.
Collapse
Affiliation(s)
- Enav Yefet
- Department of Obstetrics and Gynecology, Emek Medical Center, Afula, Israel. .,Department of Obstetrics and Gynecology, Baruch Padeh Medical Center Poriya, Tiberias, Israel. .,Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
| | | | - Basma Sliman
- Department of Obstetrics and Gynecology, Emek Medical Center, Afula, Israel
| | - Zohar Nachum
- Department of Obstetrics and Gynecology, Emek Medical Center, Afula, Israel.,Rappaport Faculty of Medicine, Technion, Haifa, Israel
| |
Collapse
|
|
42
|
Sun YY, Juan J, Xu QQ, Su RN, Hirst JE, Yang HX. Increasing insulin resistance predicts adverse pregnancy outcomes in women with gestational diabetes mellitus. J Diabetes 2020; 12:438-446. [PMID: 31808991 DOI: 10.1111/1753-0407.13013] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/07/2019] [Accepted: 12/02/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND This study aimed to investigate the association between maternal insulin resistance (IR) in the late second trimester and pregnancy outcomes, as well as to identify risk factors of IR among women with gestational diabetes mellitus (GDM). METHODS A retrospective study was conducted among 2647 women diagnosed with GDM. IR was evaluated using the homeostasis model assessment method for IR (HOMA-IR) in the late second trimester (between 24 and 28 weeks), and the lipid profiles were measured at the same time. Patients were divided into groups based on quartiles of HOMA-IR. The information on pregnancy outcomes and risk factors was extracted from the medical records of all participants and entered electronically. Logistic regression models were used to analyze the associations between HOMA-IR and pregnancy outcomes, as well as the associations between risk factors and HOMA-IR. RESULTS Greater IR was associated with cesarean delivery, preterm delivery, macrosomia, and large for gestational age newborns, but only significantly associated with preterm delivery after adjustment for potential confounders (P < .001). Prepregnancy body mass index (BMI), weight gain before diagnosis of GDM, and triglycerides were significantly related with IR in the late second trimester (P < .001). Besides, the total area under the curve of the diagnostic 75-g oral glucose tolerance test and glycosylated hemoglobin A1c increased from the lowest to the highest HOMA-IR groups. CONCLUSIONS Increasing IR in the late second trimester predicts adverse pregnancy outcomes especially for preterm delivery in women with GDM. Additionally, prepregnancy BMI and weight gain before diagnosis of GDM are independent risk factors for the development of IR.
Collapse
Affiliation(s)
- Yi-Ying Sun
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Juan Juan
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Qian-Qian Xu
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Ri-Na Su
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Jane E Hirst
- Nuffield Department of Women's and Reproductive Health and the George Institute for Global Health, University of Oxford, Oxford, UK
| | - Hui-Xia Yang
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| |
Collapse
|
|
43
|
Sferruzzi-Perri AN, Lopez-Tello J, Napso T, Yong HEJ. Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models. Placenta 2020; 98:43-51. [PMID: 33039031 DOI: 10.1016/j.placenta.2020.01.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/20/2020] [Accepted: 01/29/2020] [Indexed: 02/07/2023]
Abstract
Pregnancy is a remarkable physiological state, during which the metabolic system of the mother adapts to ensure that nutrients are made available for transfer to the fetus for growth and development. Adaptations of maternal metabolism during pregnancy are influenced by the metabolic and nutritional status of the mother and the production of endocrine factors by the placenta that exert metabolic effects. Insufficient or inappropriate adaptations in maternal metabolism during pregnancy may lead to pregnancy complications with important short- and long-term effects for both the health of the child and mother. This is very evident in gestational diabetes, which is marked by greater glucose intolerance and insulin resistance above that expected of a normal pregnancy. Gestational diabetes is associated with increased fetal weight and/or increased adiposity, higher instrumented delivery rates and greater risks for both mother and child of developing type 2 diabetes in the long-term. However, despite the negative health impacts of such metabolic imbalances during pregnancy, the precise mechanisms responsible for orchestrating these changes remain largely unknown. The present review describes the dynamic pregnancy-specific changes that occur in the metabolic system of the mother during pregnancy. It also discusses findings using surgical, pharmacological, genetic and dietary methods in experimental animals that highlight the role of pathways in maternal tissues that lead to metabolic dysfunction, with a particular focus on gestational diabetes. Finally, it summarises the work largely employing gene targeting and hormone administration in rodents that have illuminated the involvement of placental endocrine function in driving maternal metabolic adaptations. While current animal models may not fully replicate what is observed in humans, these have been instrumental in showing that there is a dynamic interplay between changes in maternal metabolic physiology and the placental production of endocrine factors that govern the availability of nutrients to the growing fetus. However, more work is required to specifically identify the placenta-driven changes in maternal metabolic physiology that ensure the appropriate level of insulin production and action during pregnancy. In doing so, these studies may pave the way to understanding the development of pregnancy complications like gestational diabetes, as well as further our understanding of type-2 diabetes and the control of metabolic physiology more broadly.
Collapse
Affiliation(s)
- Amanda N Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Downing Street, University of Cambridge, Cambridge, CB2 3EG, UK.
| | - Jorge Lopez-Tello
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Downing Street, University of Cambridge, Cambridge, CB2 3EG, UK
| | - Tina Napso
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Downing Street, University of Cambridge, Cambridge, CB2 3EG, UK
| | - Hannah E J Yong
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Downing Street, University of Cambridge, Cambridge, CB2 3EG, UK
| |
Collapse
|
|
44
|
Mugahid D, Kalocsay M, Liu X, Gruver JS, Peshkin L, Kirschner MW. YAP regulates cell size and growth dynamics via non-cell autonomous mediators. eLife 2020; 9:53404. [PMID: 31913124 PMCID: PMC6989120 DOI: 10.7554/elife.53404] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 12/16/2019] [Indexed: 12/18/2022] Open
Abstract
The Hippo pathway regulates organ size, regeneration, and cell growth by controlling the stability of the transcription factor, YAP (Yorkie in Drosophila). When there is tissue damage, YAP is activated allowing the restoration of homeostatic tissue size. The exact signals by which YAP is activated are still not fully understood, but its activation is known to affect both cell size and cell number. Here we used cultured cells to examine the coordinated regulation of cell size and number under the control of YAP. Our experiments in isogenic HEK293 cells reveal that YAP can affect cell size and number by independent circuits. Some of these effects are cell autonomous, such as proliferation, while others are mediated by secreted signals. In particular CYR61, a known secreted YAP target, is a non-cell autonomous mediator of cell survival, while another unidentified secreted factor controls cell size.
Collapse
Affiliation(s)
- Douaa Mugahid
- Department of Systems Biology, Harvard Medical School, Boston, United States
| | - Marian Kalocsay
- Department of Systems Biology, Harvard Medical School, Boston, United States
| | - Xili Liu
- Department of Systems Biology, Harvard Medical School, Boston, United States
| | | | - Leonid Peshkin
- Department of Systems Biology, Harvard Medical School, Boston, United States
| | - Marc W Kirschner
- Department of Systems Biology, Harvard Medical School, Boston, United States
| |
Collapse
|
|
45
|
Sun K, Lin D, Feng Q, Li F, Qi Y, Huang C, Feng W, Yang C, Yan L, Ren M. Parity is associated with albuminuria and chronic kidney disease: a population-based study. Aging (Albany NY) 2019; 11:11030-11039. [PMID: 31790364 PMCID: PMC6932874 DOI: 10.18632/aging.102507] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 11/18/2019] [Indexed: 01/05/2023]
Abstract
Background and aims: Epidemiological studies have shown that increasing parity is associated with risk of hypertension and diabetes in parous women. However, the relationship between the parity degree with chronic kidney disease (CKD) is still unknown. Results: Parous women with higher parity had increased age, body mass index, waist circumference, systolic blood pressure, fasting plasma glucose, fasting insulin and decreased high-density lipoprotein cholesterol, eGFR and education levels. Compared with women with one-child birth, those with more than two-child births had greater prevalence of increased urinary albumin excretion (odds ratios [ORs] 1.53, 95% confidence intervals [CI], 1.03 - 2.28) and CKD (ORs 1.79, 95% CI, 1.24 - 2.58) after multiple adjustments. In dose-response analysis, a nonlinear relationship of parity degree with albuminuria and CKD was detected. Conclusion: Parity is associated with higher prevalence of albuminuria and CKD in middle-aged and elderly Chinese women. Methods: We conducted a community-based study in 6,946 women to investigate the association of parity with albuminuria and CKD. Increased urinary albumin excretion was defined as albumin-to-creatinine ratio (ACR) greater or equal than 30 mg/g. CKD was defined as estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or presence of albuminuria.
Collapse
Affiliation(s)
- Kan Sun
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Diaozhu Lin
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Qiling Feng
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Feng Li
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Yiqin Qi
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Chulin Huang
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Wanting Feng
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Chuan Yang
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Li Yan
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Meng Ren
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| |
Collapse
|
|
46
|
Sun K, Lin D, Qiling F, Li F, Qi Y, Feng W, Ren M, Yan L, Liu D. Number of parity is associated with low-grade albuminuria in middle-aged and elderly Chinese women. BMC WOMENS HEALTH 2019; 19:117. [PMID: 31590639 PMCID: PMC6781324 DOI: 10.1186/s12905-019-0814-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 09/06/2019] [Indexed: 01/13/2023]
Abstract
Background Women with a higher number of pregnancies have a higher risk of developing cardiovascular diseases. Subtle fluctuations in albumin excretion could be related to pathophysiologic changes in the vascular system. We aimed to investigate the possible association of parity with low-grade albuminuria. Methods We conducted a community-based study in 6495 women aged 40 years or older. Low-grade albuminuria was defined according to the highest quartile of urine albumin-to-creatinine ratio in participants free of micro- or macro-albuminuria. Results Parous women with a higher number of pregnancies had increased age, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), fasting plasma glucose (FPG), and fasting insulin, as well as decreased high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR) levels, and proportion of menopause. The prevalence of low-grade albuminuria in parous women gradually increased with parity number. Compared with women with one childbirth, those with more than two childbirths were independently associated with a higher prevalent low-grade albuminuria (odds ratios [ORs] 1.41, 95% confidence interval [CI], 1.09–1.81) after multiple adjustments. In subgroup analysis after multiple adjustments, significant relation between parity number and prevalent low-grade albuminuria was detected in subjects age 55 years or older. Conclusion Number of parity is associated with prevalent low-grade albuminuria in middle-aged and elderly Chinese women without micro- or macro-albuminuria.
Collapse
Affiliation(s)
- Kan Sun
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
| | - Diaozhu Lin
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
| | - Feng Qiling
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
| | - Feng Li
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
| | - Yiqin Qi
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
| | - Wanting Feng
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
| | - Meng Ren
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
| | - Li Yan
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China.
| | - Dan Liu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No.107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China.
| |
Collapse
|
|
47
|
Wu SY, Liang J, Yang BC, Leung PS. SIRT1 Activation Promotes β-Cell Regeneration by Activating Endocrine Progenitor Cells via AMPK Signaling-Mediated Fatty Acid Oxidation. Stem Cells 2019; 37:1416-1428. [PMID: 31400234 DOI: 10.1002/stem.3073] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 07/04/2019] [Accepted: 07/21/2019] [Indexed: 12/26/2022]
Abstract
Induction of β-cell regeneration from endogenous cells represents a highly promising strategy in stem cell-based treatment for patients with diabetes. Recently, calorie restriction has been shown to affect the regulation of tissue and cell regeneration, including β cells, via metabolic related mechanisms. Here, we examined the potential utility of sirtuin 1 (SIRT1), a calorie restriction mimetic, for stimulating β-cell regeneration and the underlying mechanisms of such stimulation. The present results showed that SIRT1 activation with SRT1720 promoted β-cell regeneration in streptozotocin (STZ)-induced β-cell-deficient neonatal rats. This beneficial effect involved enhanced activation of neurogenin3 (NGN3)-positive endocrine progenitors from pancreatic ductal cells, rather than an expansion of residual β cells. A dynamic expression profile of SIRT1 was observed in endocrine progenitors both during β-cell regeneration in neonatal rats and in the second transition phase of mouse pancreas development. Consistently, SRT1720 treatment upregulated endocrine progenitor differentiation in cultured pancreatic rudiments. Upregulation of NGN3 by SIRT1 activation was through stimulating AMP-activated protein kinase (AMPK) signaling-mediated fatty acid oxidation (FAO) in human pancreatic progenitor cells; AMPK inhibition abolished these effects. The present findings demonstrate a promotional effect of SIRT1 activation on β-cell restoration and endocrine progenitor differentiation that involves regulation of AMPK signaling-mediated FAO. Stem Cells 2019;37:1416-1428.
Collapse
Affiliation(s)
- Shang Ying Wu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Juan Liang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Bao Chen Yang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Po Sing Leung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.,Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
48
|
Enhanced PDGF signaling in gestational diabetes mellitus is involved in pancreatic β-cell dysfunction. Biochem Biophys Res Commun 2019; 516:402-407. [PMID: 31217075 DOI: 10.1016/j.bbrc.2019.06.048] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 06/09/2019] [Indexed: 12/13/2022]
Abstract
Gestational diabetes mellitus (GDM) is often accompanied by the development of hyperinsulinemia as an adaptation to increased insulin demand, but this subsequently causes insulin resistance. Loss of function in pancreatic β-cells further aggravates the development of GDM. The level of serum platelet-derived growth factor (PDGF) reportedly increases in GDM patients. The present study investigated whether enhanced PDGF signaling directly causes β-cell dysfunction during gestation. Serum PDGF levels were negatively correlated with β-cell function in GDM patients. Administration of PDGF-BB disrupted glucose tolerance and β-cell function without inducing apoptosis in gestational mice but had no similar effect in non-gestational mice. The β-cell-specific genes encoding insulin synthesis proteins were decreased in the islets of PDGF-BB-treated gestational mice. In vitro experiments using INS1 insulinoma cells showed that PDGF-BB promoted cell proliferation, whereas it downregulated β-cell-specific genes. Taken together, these findings suggested that PDGF reduces β-cell function during gestation possibly through β-cell dedifferentiation.
Collapse
|
|
49
|
Herrera-Van Oostdam AS, Salgado-Bustamante M, López JA, Herrera-Van Oostdam DA, López-Hernández Y. Placental exosomes viewed from an 'omics' perspective: implications for gestational diabetes biomarkers identification. Biomark Med 2019; 13:675-684. [PMID: 31157549 DOI: 10.2217/bmm-2018-0468] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Exosomes are defined as extracellular vesicles that are released from cells upon fusion of an intermediate endocytic compartment - the multivesicular body - with the plasma membrane. Recently, placenta-derived exosomes have gained special attention, since they play a crucial role in the communication between the mother and fetus. It is known that the concentration of placenta-derived exosomes in the maternal bloodstream is higher in patients with preeclampsia or gestational diabetes mellitus. However, their composition in terms of the content of proteins, nucleic acids or lipids is uncertain. In this work, we reviewed the recent advances in placental exosomes characterization through omics-based methods, and their potential to predict gestational diabetes mellitus.
Collapse
Affiliation(s)
- Ana S Herrera-Van Oostdam
- Department of Biochemistry, Medicine Faculty, Universidad Autónoma de San Luis Potosí, San Luis Potosí, PC 78210, Mexico
| | - Mariana Salgado-Bustamante
- Department of Biochemistry, Medicine Faculty, Universidad Autónoma de San Luis Potosí, San Luis Potosí, PC 78210, Mexico
| | - Jesús Adrián López
- MicroRNAs Laboratory, Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Zacatecas, PC 98610, Mexico
| | - David A Herrera-Van Oostdam
- Department of Rheumatology & Pathology, Hospital Central 'Dr. Ignacio Morones Prieto,' Universidad Autónoma de San Luis Potosí, San Luis Potosí, PC 78210, Mexico
| | - Yamilé López-Hernández
- CONACyT-Universidad Autónoma de Zacatecas, Unidad Académica de Ciencias Biológicas, Zacatecas, PC 98610, Mexico
| |
Collapse
|
|
50
|
Dirice E, De Jesus DF, Kahraman S, Basile G, Ng RW, El Ouaamari A, Teo AKK, Bhatt S, Hu J, Kulkarni RN. Human duct cells contribute to β cell compensation in insulin resistance. JCI Insight 2019; 4:99576. [PMID: 30996131 PMCID: PMC6538348 DOI: 10.1172/jci.insight.99576] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 03/05/2019] [Indexed: 12/19/2022] Open
Abstract
The identification of new sources of β cells is an important endeavor with therapeutic implications for diabetes. Insulin resistance, in physiological states such as pregnancy or in pathological states such as type 2 diabetes (T2D), is characterized by a compensatory increase in β cell mass. To explore the existence of a dynamic β cell reserve, we superimposed pregnancy on the liver-specific insulin receptor-KO (LIRKO) model of insulin resistance that already exhibits β cell hyperplasia and used lineage tracing to track the source of new β cells. Although both control and LIRKO mice displayed increased β cell mass in response to the relative insulin resistance of pregnancy, the further increase in mass in the latter supported a dynamic source that could be traced to pancreatic ducts. Two observations support the translational significance of these findings. First, NOD/SCID-γ LIRKO mice that became pregnant following cotransplantation of human islets and human ducts under the kidney capsule showed enhanced β cell proliferation and an increase in ductal cells positive for transcription factors expressed during β cell development. Second, we identified duct cells positive for immature β cell markers in pancreas sections from pregnant humans and in individuals with T2D. Taken together, during increased insulin demand, ductal cells contribute to the compensatory β cell pool by differentiation/neogenesis.
Collapse
Affiliation(s)
- Ercument Dirice
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Dario F. De Jesus
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
- Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal
| | - Sevim Kahraman
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Giorgio Basile
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Raymond W.S. Ng
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Abdelfattah El Ouaamari
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Adrian Kee Keong Teo
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Shweta Bhatt
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Jiang Hu
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
| | - Rohit N. Kulkarni
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. USA
- Harvard Stem Cell Institute, Boston, Massachusetts, USA
| |
Collapse
|