|
1
|
Dudzik D, Atanasova V, Barbas C, Bartha JL. First-trimester metabolic profiling of gestational diabetes mellitus: insights into early-onset and late-onset cases compared with healthy controls. Front Mol Biosci 2025; 11:1452312. [PMID: 39881810 PMCID: PMC11774710 DOI: 10.3389/fmolb.2024.1452312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 12/30/2024] [Indexed: 01/31/2025] Open
Abstract
Introduction Gestational diabetes mellitus (GDM) is a global health concern with significant short and long-term complications for both mother and baby. Early prediction of GDM, particularly late-onset, is crucial for implementing timely interventions to mitigate adverse outcomes. In this study, we conducted a comprehensive metabolomic analysis to explore potential biomarkers for early GDM prediction. Methods Plasma samples were collected during the first trimester from 60 women: 20 with early-onset GDM, 20 with late-onset GDM, and 20 with normal glucose tolerance. Using advanced analytical techniques, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS), we profiled over 150 lipid species and central carbon metabolism intermediates. Results Significant metabolic alterations were observed in both early- and late-onset GDM groups compared to healthy controls, with a specific focus on glycerolipids, fatty acids, and glucose metabolism. Key findings revealed a 4.0-fold increase in TG(44:0), TG(46:0), TG(46:1) with p-values <0.001 and TG(46:2) with 4.7-fold increase and p-value <0.0001 as well as changes in several phospholipids as PC(38:3), PC(40:4) with 1.4-fold increase, p < 0.001 and PE(34:1), PE(34:2) and PE(36:2) with 1.5-fold change, p < 0.001 in late-onset GDM. Discussion Observed lipid changes highlight disruptions in energy metabolism and inflammatory pathways. It is suggested that lipid profiles with distinct fatty acid chain lengths and degrees of unsaturation can serve as early biomarkers of GDM risk. These findings underline the importance of integrating metabolomic insights with clinical data to develop predictive models for GDM. Such models could enable early risk stratification, allowing for timely dietary, lifestyle, or medical interventions aimed at optimizing glucose regulation and preventing complications such as preeclampsia, macrosomia, and neonatal metabolic disorders. By focusing on metabolic disruptions evident in the first trimester, this approach addresses a critical window for improving maternal and fetal outcomes. Our study demonstrates the value of metabolomics in understanding the metabolic perturbations associated with GDM. Future research is needed to validate these biomarkers in larger cohorts and assess their integration into clinical workflows for personalized pregnancy care.
Collapse
Affiliation(s)
- Danuta Dudzik
- Department of Biopharmaceutics and Pharmacodynamics, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland
| | - Vangeliya Atanasova
- Division of Maternal and Fetal Medicine, Fundación Para la Investigación Biomédica, La Paz University Hospital, Madrid, Spain
| | - Coral Barbas
- Department of Chemistry and Biochemistry, Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Jose Luis Bartha
- Division of Maternal and Fetal Medicine, Fundación Para la Investigación Biomédica, La Paz University Hospital, Madrid, Spain
| |
Collapse
|
|
2
|
Zhang D, Zhu J, Wewer Albrechtsen NJ, Rayner CK, Saffery R, Zhang H, Chen C, Wu T. Impairments of insulin and glucagon sensitivity in Chinese women with gestational diabetes mellitus. Diabetes Obes Metab 2024; 26:3926-3934. [PMID: 38957925 DOI: 10.1111/dom.15740] [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: 01/16/2024] [Revised: 06/06/2024] [Accepted: 06/08/2024] [Indexed: 07/04/2024]
Abstract
AIM To evaluate insulin and glucagon sensitivity in Han Chinese women with and without gestational diabetes mellitus (GDM). METHODS In total, 81 women with GDM and 81 age-matched healthy controls were evaluated with a 75 g oral glucose tolerance test (OGTT) at gestational weeks 24-28. Plasma glucose concentrations were measured at fasting and 1 h and 2 h post-OGTT. Fasting plasma insulin, glucagon and amino acids were also measured. Insulin and glucagon sensitivity were assessed by the homeostatic model assessment of insulin resistance (HOMA-IR) and glucagon-alanine index, respectively. RESULTS As expected, plasma glucose concentrations were higher at fasting and 1 h and 2 h post-OGTT in GDM participants (p < .001 each). Both the HOMA-IR and the glucagon-alanine index were higher in GDM participants. There was a weak positive correlation between HOMA-IR and glucagon-alanine index (r = 0.24, p = .0024). Combining the HOMA-IR and the glucagon-alanine index yielded better capacity (area under the curve = 0.878) than either alone (area under the curve = 0.828 for HOMA-IR and 0.751 for glucagon-alanine index, respectively) in differentiating GDM from healthy participants. While the majority of GDM participants (64%) exhibited both reduced insulin and glucagon sensitivity, a third of them presented either reduced insulin (20%) or glucagon (14%) sensitivity alone. HOMA-IR and glucagon-alanine index correlated differentially with fasting glucose, triglycerides, low-density lipoprotein cholesterol, sum of amino acids and hepatic steatosis index. CONCLUSIONS Impairments of both insulin and glucagon sensitivity occur frequently in Chinese women with GDM, which may, individually or together, drive metabolic derangements in GDM. These observations provide new insights into the pathophysiology of GDM and support the need to target insulin or glucagon resistance, or both, in the management of GDM.
Collapse
Affiliation(s)
- Dan Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianan Zhu
- Laboratory Medicine Centre, Department of Transfusion Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | | | - Christopher K Rayner
- Centre for Research Excellence in Translating Nutritional Sciences to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
| | - Richard Saffery
- Molecular Immunity, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia
| | - Hua Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chang Chen
- Institute of Life Sciences, College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Tongzhi Wu
- Centre for Research Excellence in Translating Nutritional Sciences to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
| |
Collapse
|
|
3
|
Francis EC, Powe CE, Lowe WL, White SL, Scholtens DM, Yang J, Zhu Y, Zhang C, Hivert MF, Kwak SH, Sweeting A. Refining the diagnosis of gestational diabetes mellitus: a systematic review and meta-analysis. COMMUNICATIONS MEDICINE 2023; 3:185. [PMID: 38110524 PMCID: PMC10728189 DOI: 10.1038/s43856-023-00393-8] [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: 05/16/2023] [Accepted: 10/25/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Perinatal outcomes vary for women with gestational diabetes mellitus (GDM). The precise factors beyond glycemic status that may refine GDM diagnosis remain unclear. We conducted a systematic review and meta-analysis of potential precision markers for GDM. METHODS Systematic literature searches were performed in PubMed and EMBASE from inception to March 2022 for studies comparing perinatal outcomes among women with GDM. We searched for precision markers in the following categories: maternal anthropometrics, clinical/sociocultural factors, non-glycemic biochemical markers, genetics/genomics or other -omics, and fetal biometry. We conducted post-hoc meta-analyses of a subset of studies with data on the association of maternal body mass index (BMI, kg/m2) with offspring macrosomia or large-for-gestational age (LGA). RESULTS A total of 5905 titles/abstracts were screened, 775 full-texts reviewed, and 137 studies synthesized. Maternal anthropometrics were the most frequent risk marker. Meta-analysis demonstrated that women with GDM and overweight/obesity vs. GDM with normal range BMI are at higher risk of offspring macrosomia (13 studies [n = 28,763]; odds ratio [OR] 2.65; 95% Confidence Interval [CI] 1.91, 3.68), and LGA (10 studies [n = 20,070]; OR 2.23; 95% CI 2.00, 2.49). Lipids and insulin resistance/secretion indices were the most studied non-glycemic biochemical markers, with increased triglycerides and insulin resistance generally associated with greater risk of offspring macrosomia or LGA. Studies evaluating other markers had inconsistent findings as to whether they could be used as precision markers. CONCLUSIONS Maternal overweight/obesity is associated with greater risk of offspring macrosomia or LGA in women with GDM. Pregnancy insulin resistance or hypertriglyceridemia may be useful in GDM risk stratification. Future studies examining non-glycemic biochemical, genetic, other -omic, or sociocultural precision markers among women with GDM are warranted.
Collapse
Affiliation(s)
- Ellen C Francis
- Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA.
| | - Camille E Powe
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - William L Lowe
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Sara L White
- Department of Women and Children's Health, King's College London, London, UK
| | - Denise M Scholtens
- Department of Preventive Medicine, Division of Biostatistics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jiaxi Yang
- Global Center for Asian Women's Health (GloW), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Bia-Echo Asia Centre for Reproductive Longevity & Equality (ACRLE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yeyi Zhu
- Kaiser Permanente Northern California Division of Research, Oakland, CA, USA
| | - Cuilin Zhang
- Global Center for Asian Women's Health (GloW), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Bia-Echo Asia Centre for Reproductive Longevity & Equality (ACRLE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Marie-France Hivert
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Arianne Sweeting
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
4
|
Merrill AK, Sobolewski M, Susiarjo M. Exposure to endocrine disrupting chemicals impacts immunological and metabolic status of women during pregnancy. Mol Cell Endocrinol 2023; 577:112031. [PMID: 37506868 PMCID: PMC10592265 DOI: 10.1016/j.mce.2023.112031] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/12/2023] [Accepted: 07/24/2023] [Indexed: 07/30/2023]
Affiliation(s)
- Alyssa K Merrill
- Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA
| | - Marissa Sobolewski
- Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA
| | - Martha Susiarjo
- Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA.
| |
Collapse
|
|
5
|
Guevara-Ramírez P, Paz-Cruz E, Cadena-Ullauri S, Ruiz-Pozo VA, Tamayo-Trujillo R, Felix ML, Simancas-Racines D, Zambrano AK. Molecular pathways and nutrigenomic review of insulin resistance development in gestational diabetes mellitus. Front Nutr 2023; 10:1228703. [PMID: 37799768 PMCID: PMC10548225 DOI: 10.3389/fnut.2023.1228703] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/01/2023] [Indexed: 10/07/2023] Open
Abstract
Gestational diabetes mellitus is a condition marked by raised blood sugar levels and insulin resistance that usually occurs during the second or third trimester of pregnancy. According to the World Health Organization, hyperglycemia affects 16.9% of pregnancies worldwide. Dietary changes are the primarily alternative treatment for gestational diabetes mellitus. This paper aims to perform an exhaustive overview of the interaction between diet, gene expression, and the metabolic pathways related to insulin resistance. The intake of foods rich in carbohydrates can influence the gene expression of glycolysis, as well as foods rich in fat, can disrupt the beta-oxidation and ketogenesis pathways. Furthermore, vitamins and minerals are related to inflammatory processes regulated by the TLR4/NF-κB and one carbon metabolic pathways. We indicate that diet regulated gene expression of PPARα, NOS, CREB3L3, IRS, and CPT I, altering cellular physiological mechanisms and thus increasing or decreasing the risk of gestational diabetes. The alteration of gene expression can cause inflammation, inhibition of fatty acid transport, or on the contrary help in the modulation of ketogenesis, improve insulin sensitivity, attenuate the effects of glucotoxicity, and others. Therefore, it is critical to comprehend the metabolic changes of pregnant women with gestational diabetes mellitus, to determine nutrients that help in the prevention and treatment of insulin resistance and its long-term consequences.
Collapse
Affiliation(s)
- Patricia Guevara-Ramírez
- Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigación Genética y Genómica, Universidad UTE, Quito, Ecuador
| | - Elius Paz-Cruz
- Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigación Genética y Genómica, Universidad UTE, Quito, Ecuador
| | - Santiago Cadena-Ullauri
- Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigación Genética y Genómica, Universidad UTE, Quito, Ecuador
| | - Viviana A. Ruiz-Pozo
- Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigación Genética y Genómica, Universidad UTE, Quito, Ecuador
| | - Rafael Tamayo-Trujillo
- Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigación Genética y Genómica, Universidad UTE, Quito, Ecuador
| | - Maria L. Felix
- Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Daniel Simancas-Racines
- Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Universidad UTE, Quito, Ecuador
| | - Ana Karina Zambrano
- Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigación Genética y Genómica, Universidad UTE, Quito, Ecuador
| |
Collapse
|
|
6
|
Dessì A, Bosco A, Cesare Marincola F, Pintus R, Paci G, Atzori L, Fanos V, Piras C. Sardinian Infants of Diabetic Mothers: A Metabolomics Observational Study. Int J Mol Sci 2023; 24:13724. [PMID: 37762025 PMCID: PMC10530546 DOI: 10.3390/ijms241813724] [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: 07/29/2023] [Revised: 08/29/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is a condition characterized by glucose intolerance, with hyperglycemia of varying severity with onset during pregnancy. An uncontrolled GDM can lead to an increased risk of morbidity in the fetus and newborn, and an increased risk of obesity or developing type 2 diabetes, hypertension or neurocognitive developmental impairment in adulthood. In this study, we used nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (GS-MS) to analyze the urinary metabolomic profile of newborns of diabetic mothers (NDMs) with the aim of identifying biomarkers useful for the monitoring of NDMs and for early diagnosis of predisposition to develop related chronic diseases. A total of 26 newborns were recruited: 21 children of diabetic mothers, comprising 13 in diet therapy (NDM-diet) and 8 in insulin therapy (NDM-insulin), and 5 control children of non-diabetic mothers (CTR). Urine samples were collected at five time points: at birth (T1), on the third day of life (T2), one week (T3), one month (T4) and six months postpartum (T5). At T1, variations were observed in the levels of seven potential biomarkers (acetate, lactate, glycylproline/proline, isocitrate, N,N-dimethylglycine, N-acetylglucosamine and N-carbamoyl-aspartate) in NMD-insulin infants compared to NDM-diet and CTR infants. In particular, the altered metabolites were found to be involved in several metabolic pathways such as citrate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, amino sugar and nucleotide sugar metabolism, and pyruvate metabolism. In contrast, these changes were not visible at subsequent sampling times. The impact of early nutrition (maternal and formula milk) on the metabolomic profile was considered as a potential contributing factor to this finding.
Collapse
Affiliation(s)
- Angelica Dessì
- Department of Surgical Sciences, University of Cagliari and Neonatal Intensive Care Unit, AOU Cagliari, 09042 Cagliari, Italy; (A.B.); (R.P.); (V.F.)
| | - Alice Bosco
- Department of Surgical Sciences, University of Cagliari and Neonatal Intensive Care Unit, AOU Cagliari, 09042 Cagliari, Italy; (A.B.); (R.P.); (V.F.)
| | - Flaminia Cesare Marincola
- Department of Chemical and Geological Sciences, University of Cagliari, Cittadella Universitaria, SS 554, km 4.5, Monserrato, 09042 Cagliari, Italy;
| | - Roberta Pintus
- Department of Surgical Sciences, University of Cagliari and Neonatal Intensive Care Unit, AOU Cagliari, 09042 Cagliari, Italy; (A.B.); (R.P.); (V.F.)
| | - Giulia Paci
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, SS 554, km 4.5, Monserrato, 09042 Cagliari, Italy; (G.P.); (L.A.); (C.P.)
| | - Luigi Atzori
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, SS 554, km 4.5, Monserrato, 09042 Cagliari, Italy; (G.P.); (L.A.); (C.P.)
| | - Vassilios Fanos
- Department of Surgical Sciences, University of Cagliari and Neonatal Intensive Care Unit, AOU Cagliari, 09042 Cagliari, Italy; (A.B.); (R.P.); (V.F.)
| | - Cristina Piras
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, SS 554, km 4.5, Monserrato, 09042 Cagliari, Italy; (G.P.); (L.A.); (C.P.)
| |
Collapse
|
|
7
|
Li L, Li L, Shao Y, Du R, Li L, Shi X, Bai Y. Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses. Mol Med 2023; 29:82. [PMID: 37386367 DOI: 10.1186/s10020-023-00669-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 05/24/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) is an important determinant of glucose metabolic disturbance and placental dysplasia in gestational diabetes mellitus (GDM). Calcium/calmodulin dependent protein kinase IV (CAMK4) improves insulin IR induced by a high-fat diet (HFD). The current study sought to elucidate the role and potential mechanism of CAMK4 in GDM. METHODS A GDM model was established in female C57BL/6J mice via HFD feeding for one week before mating and throughout gestation. The IR was elicited by 10-6 M insulin treatment for 48 h in HTR-8/SVneo cells and mouse primary trophoblast cells. The function of CAMK4 was investigated by transfection of overexpression plasmid in HTR-8/SVneo cells and infection of lentivirus loaded with CAMK4 encoding sequence in primary trophoblast cells. Real-time PCR, western blot, cell counting kit-8, transwell, wound healing, dual-luciferase reporter assay, and liquid chromatography/mass spectrometry-based untargeted metabolomics were performed to confirm the effects of CAMK4 on trophoblast cells. RESULTS Decreased CAMK4 expression was found in the placenta of GDM mice. CAMK4 overexpression ameliorated IR-induced viability impairment, migratory and invasive capacity inhibition, autophagy blocking, insulin signaling inactivation and glucose uptake disorder in trophoblast cells. CAMK4 also transcriptionally activated orphan nuclear receptor NUR77, and the effects of CAMK4 were abrogated by silencing of NUR77. Metabolomics analysis revealed that CAMK4 overexpression caused alterations of amino acid, lipid and carbohydrate metabolism, which were important in GDM. CONCLUSION Our results indicated that CAMK4/NUR77 axis may provide novel potential targets in GDM treatment.
Collapse
Affiliation(s)
- Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China
| | - Li Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China
| | - Ying Shao
- Department of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China
| | - Runyu Du
- Department of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China
| | - Xiaoguang Shi
- Department of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China.
| | - Yu Bai
- Department of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China.
| |
Collapse
|
|
8
|
Bianco ME, Vu MH, Bain JR, Muehlbauer MJ, Ilkayeva OR, Scholtens DM, Josefson J, Lowe WL. Maternal and Cord Blood Serum Metabolite Associations with Childhood Adiposity and Body Composition Outcomes. Metabolites 2023; 13:749. [PMID: 37367907 PMCID: PMC10302619 DOI: 10.3390/metabo13060749] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/01/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023] Open
Abstract
Maternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during pregnancy with childhood adiposity, and cord blood metabolites with childhood adiposity using phenotype and metabolomic data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study. The maternal metabolites analyses included 2324 mother-offspring pairs, while the cord blood metabolites analyses included 937 offspring. Multiple logistic and linear regression were used to examine associations between primary predictors, maternal or cord blood metabolites, and childhood adiposity outcomes. Multiple maternal fasting and 1 hr metabolites were significantly associated with childhood adiposity outcomes in Model 1 but were no longer significant after adjusting for maternal BMI and/or maternal glycemia. In the fully adjusted model, fasting lactose levels were negatively associated with child BMI z-scores and waist circumference, while fasting urea levels were positively associated with waist circumference. One-hour methionine was positively associated with fat-free mass. There were no significant associations between cord blood metabolites and childhood adiposity outcomes. Few metabolites were associated with childhood adiposity outcomes after adjusting for maternal BMI and glucose, suggesting that maternal BMI accounts for the association between maternal metabolites and childhood adiposity.
Collapse
Affiliation(s)
- Monica E. Bianco
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (M.E.B.); (J.J.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - My H. Vu
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.H.V.); (D.M.S.)
| | - James R. Bain
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; (J.R.B.); (M.J.M.); (O.R.I.)
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine, Durham, NC 27710, USA
| | - Michael J. Muehlbauer
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; (J.R.B.); (M.J.M.); (O.R.I.)
| | - Olga R. Ilkayeva
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; (J.R.B.); (M.J.M.); (O.R.I.)
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine, Durham, NC 27710, USA
| | - Denise M. Scholtens
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.H.V.); (D.M.S.)
| | - Jami Josefson
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (M.E.B.); (J.J.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - William L. Lowe
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| |
Collapse
|
|
9
|
Gleason B, Kuang A, Bain JR, Muehlbauer MJ, Ilkayeva OR, Scholtens DM, Lowe WL. Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort. Metabolites 2023; 13:505. [PMID: 37110162 PMCID: PMC10145069 DOI: 10.3390/metabo13040505] [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: 03/07/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother-newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24-32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity.
Collapse
Affiliation(s)
- Brooke Gleason
- Feinberg School of Medicine, Northwestern University, Chicago, IL 60091, USA
| | - Alan Kuang
- Feinberg School of Medicine, Northwestern University, Chicago, IL 60091, USA
| | - James R. Bain
- Duke Molecular Physiology Institute, Durham, NC 27701, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Michael J. Muehlbauer
- Duke Molecular Physiology Institute, Durham, NC 27701, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Olga R. Ilkayeva
- Duke Molecular Physiology Institute, Durham, NC 27701, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Denise M. Scholtens
- Feinberg School of Medicine, Northwestern University, Chicago, IL 60091, USA
| | - William L. Lowe
- Feinberg School of Medicine, Northwestern University, Chicago, IL 60091, USA
| |
Collapse
|
|
10
|
Buyukozkan M, Benedetti E, Krumsiek J. rox: A Statistical Model for Regression with Missing Values. Metabolites 2023; 13:metabo13010127. [PMID: 36677052 PMCID: PMC9861384 DOI: 10.3390/metabo13010127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 01/18/2023] Open
Abstract
High-dimensional omics datasets frequently contain missing data points, which typically occur due to concentrations below the limit of detection (LOD) of the profiling platform. The presence of such missing values significantly limits downstream statistical analysis and result interpretation. Two common techniques to deal with this issue include the removal of samples with missing values and imputation approaches that substitute the missing measurements with reasonable estimates. Both approaches, however, suffer from various shortcomings and pitfalls. In this paper, we present "rox", a novel statistical model for the analysis of omics data with missing values without the need for imputation. The model directly incorporates missing values as "low" concentrations into the calculation. We show the superiority of rox over common approaches on simulated data and on six metabolomics datasets. Fully leveraging the information contained in LOD-based missing values, rox provides a powerful tool for the statistical analysis of omics data.
Collapse
|
|
11
|
Zhai X, Liu J, Yu M, Zhang Q, Li M, Zhao N, Liu J, Song Y, Ma L, Li R, Qiao Z, Zhao G, Wang R, Xiao X. Nontargeted metabolomics reveals the potential mechanism underlying the association between birthweight and metabolic disturbances. BMC Pregnancy Childbirth 2023; 23:14. [PMID: 36624413 PMCID: PMC9830726 DOI: 10.1186/s12884-023-05346-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
AIMS The aim of this study was to characterize the metabolites associated with small- and large-gestational-age newborns in maternal and cord blood, and to investigate potential mechanisms underlying the association between birthweight and metabolic disturbances. RESEARCH DESIGN AND METHODS We recorded detailed anthropometric data of mother-offspring dyads. Untargeted metabolomic assays were performed on 67 pairs of cord blood and maternal fasting plasma samples including 16 pairs of small-for-gestational (SGA, < 10th percentile) dyads, 28 pairs of appropriate-for-gestational (AGA, approximate 50 percentile) dyads, and 23 pairs of large-for-gestational (LGA, > 90th percentile) dyads. The association of metabolites with newborn birthweight was conducted to screen for metabolites with U-shaped and line-shaped distributions. The association of metabolites with maternal and fetal phenotypes was also performed. RESULTS We found 2 types of metabolites that changed in different patterns according to newborn birthweight. One type of metabolite exhibited a "U-shaped" trend of abundance fluctuation in the SGA-AGA-LGA groups. The results demonstrated that cuminaldehyde level was lower in the SGA and LGA groups, and its abundance in cord blood was negatively correlated with maternal BMI (r = -0.352 p = 0.009) and weight gain (r = -0.267 p = 0.043). 2-Methoxy-estradiol-17b 3-glucuronide, which showed enrichment in the SGA and LGA groups, was positively correlated with homocysteine (r = 0.44, p < 0.001) and free fatty acid (r = 0.42, p < 0.001) in maternal blood. Serotonin and 13(S)-HODE were the second type of metabolites, denoted as "line-shaped", which both showed increasing trends in the SGA-AGA-LGA groups in both maternal and cord blood and were both significantly positively correlated with maternal BMI before pregnancy. Moreover, cuminaldehyde, serotonin, 13(S)-HODE and some lipid metabolites showed a strong correlation between maternal and cord blood. CONCLUSIONS These investigations demonstrate broad-scale metabolomic differences associated with newborn birthweight in both pregnant women and their newborns. The U-shaped metabolites associated with both the SGA and LGA groups might explain the U-shaped association between birthweight and metabolic dysregulation. The line-shaped metabolites might participate in intrauterine growth regulation. These observations might help to provide new insights into the insulin resistance and the risk of metabolic disturbance of SGA and LGA babies in adulthood and might identify potential new markers for adverse newborn outcomes in pregnant women.
Collapse
Affiliation(s)
- Xiao Zhai
- grid.413106.10000 0000 9889 6335Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Jieying Liu
- grid.413106.10000 0000 9889 6335Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China ,grid.413106.10000 0000 9889 6335Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Miao Yu
- grid.413106.10000 0000 9889 6335Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Qian Zhang
- grid.413106.10000 0000 9889 6335Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Ming Li
- grid.413106.10000 0000 9889 6335Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Nan Zhao
- grid.413106.10000 0000 9889 6335Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Juntao Liu
- grid.413106.10000 0000 9889 6335Department of Obstetrics & Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Yingna Song
- grid.413106.10000 0000 9889 6335Department of Obstetrics & Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Liangkun Ma
- grid.413106.10000 0000 9889 6335Department of Obstetrics & Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Rongrong Li
- grid.413106.10000 0000 9889 6335Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| | - Zongxu Qiao
- grid.478131.80000 0004 9334 6499Department of Obstetrics & Gynecology, Xingtai People’s Hospital, Xingtai, Hebei 054000 People’s Republic of China
| | - Guifen Zhao
- grid.478131.80000 0004 9334 6499Department of Obstetrics & Gynecology, Xingtai People’s Hospital, Xingtai, Hebei 054000 People’s Republic of China
| | - Ruiping Wang
- grid.478131.80000 0004 9334 6499Department of Obstetrics & Gynecology, Xingtai People’s Hospital, Xingtai, Hebei 054000 People’s Republic of China
| | - Xinhua Xiao
- grid.413106.10000 0000 9889 6335Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China
| |
Collapse
|
|
12
|
A Study of the Metabolic Pathways Affected by Gestational Diabetes Mellitus: Comparison with Type 2 Diabetes. Diagnostics (Basel) 2022; 12:diagnostics12112881. [PMID: 36428943 PMCID: PMC9689375 DOI: 10.3390/diagnostics12112881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) remains incompletely understood and increases the risk of developing Diabetes mellitus type 2 (DM2). Metabolomics provides insights etiology and pathogenesis of disease and discovery biomarkers for accurate detection. Nuclear magnetic resonance (NMR) spectroscopy is a key platform defining metabolic signatures in intact serum/plasma. In the present study, we used NMR-based analysis of macromolecules free-serum to accurately characterize the altered metabolic pathways of GDM and assessing their similarities to DM2. Our findings could contribute to the understanding of the pathophysiology of GDM and help in the identification of metabolomic markers of the disease. METHODS Sixty-two women with GDM matched with seventy-seven women without GDM (control group). 1H NMR serum spectra were acquired on an 11.7 T Bruker Avance DRX NMR spectrometer. RESULTS We identified 55 metabolites in both groups, 25 of which were significantly altered in the GDM group. GDM group showed elevated levels of ketone bodies, 2-hydroxybutyrate and of some metabolic intermediates of branched-chain amino acids (BCAAs) and significantly lower levels of metabolites of one-carbon metabolism, energy production, purine metabolism, certain amino acids, 3-methyl-2-oxovalerate, ornithine, 2-aminobutyrate, taurine and trimethylamine N-oxide. CONCLUSION Metabolic pathways affected in GDM were beta-oxidation, ketone bodies metabolism, one-carbon metabolism, arginine and ornithine metabolism likewise in DM2, whereas BCAAs catabolism and aromatic amino acids metabolism were affected, but otherwise than in DM2.
Collapse
|
|
13
|
Quotah OF, Poston L, Flynn AC, White SL. Metabolic Profiling of Pregnant Women with Obesity: An Exploratory Study in Women at Greater Risk of Gestational Diabetes. Metabolites 2022; 12:metabo12100922. [PMID: 36295825 PMCID: PMC9612230 DOI: 10.3390/metabo12100922] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most prevalent obstetric conditions, particularly among women with obesity. Pathways to hyperglycaemia remain obscure and a better understanding of the pathophysiology would facilitate early detection and targeted intervention. Among obese women from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), we aimed to compare metabolic profiles early and mid-pregnancy in women identified as high-risk of developing GDM, stratified by GDM diagnosis. Using a GDM prediction model combining maternal age, mid-arm circumference, systolic blood pressure, glucose, triglycerides and HbA1c, 231 women were identified as being at higher-risk, of whom 119 women developed GDM. Analyte data (nuclear magnetic resonance and conventional) were compared between higher-risk women who developed GDM and those who did not at timepoint 1 (15+0−18+6 weeks) and at timepoint 2 (23+2−30+0 weeks). The adjusted regression analyses revealed some differences in the early second trimester between those who developed GDM and those who did not, including lower adiponectin and glutamine concentrations, and higher C-peptide concentrations (FDR-adjusted p < 0.005, < 0.05, < 0.05 respectively). More differences were evident at the time of GDM diagnosis (timepoint 2) including greater impairment in β-cell function (as assessed by HOMA2-%B), an increase in the glycolysis-intermediate pyruvate (FDR-adjusted p < 0.001, < 0.05 respectively) and differing lipid profiles. The liver function marker γ-glutamyl transferase was higher at both timepoints (FDR-adjusted p < 0.05). This exploratory study underlines the difficulty in early prediction of GDM development in high-risk women but adds to the evidence that among pregnant women with obesity, insulin secretory dysfunction may be an important discriminator for those who develop GDM.
Collapse
Affiliation(s)
- Ola F. Quotah
- Department of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, 10th Floor North Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK
- Department of Clinical Nutrition, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 999088, Saudi Arabia
| | - Lucilla Poston
- Department of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, 10th Floor North Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK
| | - Angela C. Flynn
- Department of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, 10th Floor North Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK
- Department of Nutritional Sciences, School of Life Course and Population Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK
| | - Sara L. White
- Department of Women and Children’s Health, School of Life Course and Population Sciences, King’s College London, 10th Floor North Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK
- Correspondence:
| |
Collapse
|
|
14
|
UHPLC-MS/MS-Based Metabolomics and Clinical Phenotypes Analysis Reveal Broad-Scale Perturbations in Early Pregnancy Related to Gestational Diabetes Mellitus. DISEASE MARKERS 2022; 2022:4231031. [PMID: 36061360 PMCID: PMC9433254 DOI: 10.1155/2022/4231031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/20/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022]
Abstract
Gestational diabetes mellitus (GDM) is the most common metabolic disturbance during pregnancy, with adverse effects on both mother and fetus. The establishment of early diagnosis and risk assessment model is of great significance for preventing and reducing adverse outcomes of GDM. In this study, the broad-scale perturbations related to GDM were explored through the integration analysis of metabolic and clinical phenotypes. Maternal serum samples from the first trimester were collected for targeted metabolomics analysis by using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Statistical analysis was conducted based on the levels of the 184 metabolites and 76 clinical indicators from GDM women (
=60) and matched healthy controls (
=90). Metabolomics analysis revealed the down-regulation of fatty acid oxidation in the first trimester of GDM women, which was supposed to be related to the low serum level of dehydroepiandrosterone.While the significantly altered clinical phenotypes were mainly related to the increased risk of cardiovascular disease, abnormal iron metabolism, and inflammation. A phenotype panel established from the significantly changed serum indicators can be used for the early prediction of GDM, with the area under the receiver-operating characteristic curve (ROC) 0.83. High serum uric acid and C-reaction protein levels were risk factors for GDM independent of body mass indexes, with ORs 4.76 (95% CI: 2.08-10.90) and 3.10 (95% CI: 1.38-6.96), respectively. Predictive phenotype panel of GDM, together with the risk factors of GDM, will provide novel perspectives for the early clinical warning and diagnosis of GDM.
Collapse
|
|
15
|
Gao B, Shen Q, Wu Y, Cao M, Zhang Q, Chen L. Branched-chain and aromatic amino acid levels response to an oral glucose load associated with gestational diabetes mellitus. Sci Rep 2022; 12:12257. [PMID: 35851317 PMCID: PMC9293928 DOI: 10.1038/s41598-022-16539-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 07/12/2022] [Indexed: 11/18/2022] Open
Abstract
Serum branched chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with obesity, insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the levels of these amino acids in women with gestational diabetes mellitus (GDM) and examined their changes in response to an oral glucose tolerance test (OGTT). 110 women were enrolled and underwent a 75-g OGTT during their second trimester; 43 women were diagnosed with GDM and 67 women did not have GDM (non-GDM women). During the OGTT, fasting, 1-h, and 2-h blood samples were obtained. BCAA and AAA levels were measured by liquid chromatography-tandem mass spectrometry. The differences in BCAA and AAA levels between GDM and non-GDM women were not evident during fasting but became significant after glucose loading. Glucose ingestion decreased the levels of BCAAs and AAAs in both groups. Notably, GDM women showed a delayed and blunted decrease in these amino acids compared to non-GDM women. The risks of 2-h changes in BCAAs and AAAs for GDM women were significant. We identified that the differences in BCAA and AAA levels between GDM women and controls, which were not evident during fasting, could be provoked by performing an OGTT.
Collapse
Affiliation(s)
- BeiBei Gao
- Department of Endocrinology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, China
| | - Qiong Shen
- Department of Endocrinology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, China
| | - Ying Wu
- Department of Endocrinology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, China
| | - MengDie Cao
- Department of Endocrinology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, China
| | - QiWu Zhang
- Department of Endocrinology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, China
| | - Lei Chen
- Department of Endocrinology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, China.
| |
Collapse
|
|
16
|
Mandò C, Abati S, Anelli GM, Favero C, Serati A, Dioni L, Zambon M, Albetti B, Bollati V, Cetin I. Epigenetic Profiling in the Saliva of Obese Pregnant Women. Nutrients 2022; 14:2122. [PMID: 35631263 PMCID: PMC9146705 DOI: 10.3390/nu14102122] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 02/06/2023] Open
Abstract
Maternal obesity is associated with inflammation and oxidative stress, strongly impacting the intrauterine environment with detrimental consequences for both mother and offspring. The saliva is a non-invasive biofluid reflecting both local and systemic health status. This observational study aimed to profile the epigenetic signature in the saliva of Obese (OB) and Normal-Weight (NW) pregnant women. Sixteen NW and sixteen OB Caucasian women with singleton spontaneous pregnancies were enrolled. microRNAs were quantified by the OpenArray Platform. The promoter region methylation of Suppressor of Cytokine Signaling 3 (SOCS3) and Transforming Growth Factor Beta 1 (TGF-Beta1) was assessed by pyrosequencing. There were 754 microRNAs evaluated: 20 microRNAs resulted in being differentially expressed between OB and NW. microRNA pathway enrichment analysis showed a significant association with the TGF-Beta signaling pathway (miTALOS) and with fatty acids biosynthesis/metabolism, lysine degradation, and ECM-receptor interaction pathways (DIANA-miRPath). Both SOCS3 and TGF-Beta1 were significantly down-methylated in OB vs. NW. These results help to clarify impaired mechanisms involved in obesity and pave the way for the understanding of specific damaged pathways. The characterization of the epigenetic profile in saliva of pregnant women can represent a promising tool for the identification of obesity-related altered mechanisms and of possible biomarkers for early diagnosis and treatment of pregnancy-adverse conditions.
Collapse
Affiliation(s)
- Chiara Mandò
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157 Milan, Italy; (G.M.A.); (A.S.); (I.C.)
| | - Silvio Abati
- Department of Dentistry, University Vita-Salute San Raffaele, 20132 Milan, Italy;
| | - Gaia Maria Anelli
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157 Milan, Italy; (G.M.A.); (A.S.); (I.C.)
| | - Chiara Favero
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (C.F.); (L.D.); (B.A.); (V.B.)
| | - Anaïs Serati
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157 Milan, Italy; (G.M.A.); (A.S.); (I.C.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20054 Segrate, Italy
| | - Laura Dioni
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (C.F.); (L.D.); (B.A.); (V.B.)
| | - Marta Zambon
- Department of Woman, Mother and Child, Luigi Sacco and Vittore Buzzi Children Hospital, ASST Fatebenefratelli-Sacco, 20154 Milan, Italy;
| | - Benedetta Albetti
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (C.F.); (L.D.); (B.A.); (V.B.)
| | - Valentina Bollati
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (C.F.); (L.D.); (B.A.); (V.B.)
- Occupational Health Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Irene Cetin
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157 Milan, Italy; (G.M.A.); (A.S.); (I.C.)
- Department of Woman, Mother and Child, Luigi Sacco and Vittore Buzzi Children Hospital, ASST Fatebenefratelli-Sacco, 20154 Milan, Italy;
| |
Collapse
|
|
17
|
Dimou A, Tsimihodimos V, Bairaktari E. The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology. Int J Mol Sci 2022; 23:ijms23074022. [PMID: 35409380 PMCID: PMC8999875 DOI: 10.3390/ijms23074022] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 12/26/2022] Open
Abstract
Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.
Collapse
Affiliation(s)
- Aikaterini Dimou
- Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Vasilis Tsimihodimos
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Eleni Bairaktari
- Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
- Correspondence: ; Tel.: +30-26510-07620
| |
Collapse
|
|
18
|
Azab SM, de Souza RJ, Ly R, Teo KK, Atkinson SA, Morrison KM, Anand SS, Britz-McKibbin P. Non-esterified fatty acids as biomarkers of diet and glucose homeostasis in pregnancy: The impact of fatty acid reporting methods: NEFA reporting methods affect dietary and cardiometabolic endpoints. Prostaglandins Leukot Essent Fatty Acids 2022; 176:102378. [PMID: 34871861 DOI: 10.1016/j.plefa.2021.102378] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Sparse data exists on the utility of individual serum non-esterified fatty acids (NEFAs) as clinical and dietary biomarkers and how reporting methods could affect these associations. We investigated the associations of 19 serum NEFAs expressed as µM or mol%, with self-reported dietary intake data, and cardiometabolic health indicators in pregnant women. METHODS In this cross-sectional study, 273 pregnant women in their second trimester each completed a semi-quantitative food-frequency questionnaire and provided fasting serum samples. Comprehensive serum NEFA analysis was performed by multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry. We evaluated the associations of NEFAs using two different reporting methods, with diet quality, specific foods intake, and measures of adiposity and glucose homeostasis. RESULTS Consistently stronger dietary correlations were observed when expressed as mol%. Serum ω-3 NEFAs were associated with diet quality and fish/fish oil daily servings (DHA mol%, r= 0.37; p = 4.8e-10), and odd-chain NEFAs were associated with full-fat dairy intake (15:0 mol%, r = 0.23; p = 9.0e-5). Glucose intolerance was positively associated with odd chain NEFAs as expressed in µM (r = 0.21; p= 0.001) but inversely associated when expressed as mol% (r = -0.31; p= 2.2e-7). In contrast, monounsaturated NEFAs (µM and mol%) had robust positive associations with pre-pregnancy BMI, second trimester skin-fold thickness, glycated hemoglobin, fasting glucose, and glucose intolerance. CONCLUSIONS This study demonstrates the utility of specific NEFAs and their sub-classes as viable dietary and clinical biomarkers when reported as their relative proportions. More research is needed to investigate inconsistencies between absolute concentrations and relative proportions when reporting fatty acids.
Collapse
Affiliation(s)
- Sandi M Azab
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Pharmacognosy, Alexandria University, Alexandria, Egypt.
| | - Russell J de Souza
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada
| | - Ritchie Ly
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Koon K Teo
- Department of Medicine, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada
| | | | - Katherine M Morrison
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada; Department of Pediatrics, McMaster University, Hamilton, ON, Canada
| | - Sonia S Anand
- Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada
| | - Philip Britz-McKibbin
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| |
Collapse
|
|
19
|
Raczkowska BA, Mojsak P, Rojo D, Telejko B, Paczkowska-Abdulsalam M, Hryniewicka J, Zielinska-Maciulewska A, Szelachowska M, Gorska M, Barbas C, Kretowski A, Ciborowski M. Gas Chromatography-Mass Spectroscopy-Based Metabolomics Analysis Reveals Potential Biochemical Markers for Diagnosis of Gestational Diabetes Mellitus. Front Pharmacol 2021; 12:770240. [PMID: 34867398 PMCID: PMC8640240 DOI: 10.3389/fphar.2021.770240] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022] Open
Abstract
Due to many adverse effects of gestational diabetes mellitus (GDM) on the mother and fetus, its diagnosis is crucial. The presence of GDM can be confirmed by an abnormal fasting plasma glucose level (aFPG) and/or oral glucose tolerance test (OGTT) performed mostly between 24 and 28 gestational week. Both aFPG and abnormal glucose tolerance (aGT) are used to diagnose GDM. In comparison to measurement of FPG, OGTT is time-consuming, usually inconvenient for the patient, and very often needs to be repeated. Therefore, it is necessary to seek tests that will be helpful and convenient to diagnose GDM. For this reason, we investigated the differences in fasting serum metabolites between GDM women with abnGM and normal FPG (aGT-GDM group), with aFPG and normal glucose metabolism (aFPG-GDM group) as well as pregnant women with normal glucose tolerance (NGT) being a control group. Serum metabolites were measured by an untargeted approach using gas chromatography–mass spectrometry (GC–MS). In the discovery phase, fasting serum samples collected from 79 pregnant women (aFPG-GDM, n = 24; aGT-GDM, n = 26; NGT, n = 29) between 24 and 28 weeks of gestation (gwk) were fingerprinted. A set of metabolites (α–hydroxybutyric acid (α–HB), β–hydroxybutyric acid (β–HB), and several fatty acids) significant in aGT-GDM vs NGT but not significant in aFPG-GDM vs NGT comparison in the discovery phase was selected for validation. These metabolites were quantified by a targeted GC–MS method in a validation cohort consisted of 163 pregnant women (aFPG-GDM, n = 51; aGT-GDM, n = 44; and NGT, n = 68). Targeted analyses were also performed on the serum collected from 92 healthy women in the first trimester (8–14 gwk) who were NGT at this time, but in the second trimester (24–28 gwk) they were diagnosed with GDM. It was found that α–HB, β–HB, and several fatty acids were associated with aGT-GDM. A combination of α–HB, β–HB, and myristic acid was found highly specific and sensitive for the diagnosis of GDM manifested by aGT-GDM (AUC = 0.828) or to select women at a risk of aGT-GDM in the first trimester (AUC = 0.791). Our findings provide new potential markers of GDM and may have implications for its early diagnosis.
Collapse
Affiliation(s)
- Beata A Raczkowska
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Patrycja Mojsak
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - David Rojo
- Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Campus Montepríncipe, Madrid, Spain
| | - Beata Telejko
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | | | - Justyna Hryniewicka
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Anna Zielinska-Maciulewska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Malgorzata Szelachowska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Maria Gorska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Coral Barbas
- Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Campus Montepríncipe, Madrid, Spain
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland.,Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Michal Ciborowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| |
Collapse
|
|
20
|
Wang QY, You LH, Xiang LL, Zhu YT, Zeng Y. Current progress in metabolomics of gestational diabetes mellitus. World J Diabetes 2021; 12:1164-1186. [PMID: 34512885 PMCID: PMC8394228 DOI: 10.4239/wjd.v12.i8.1164] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/20/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common metabolic disorders of pregnancy and can cause short- and long-term adverse effects in both pregnant women and their offspring. However, the etiology and pathogenesis of GDM are still unclear. As a metabolic disease, GDM is well suited to metabolomics study, which can monitor the changes in small molecular metabolites induced by maternal stimuli or perturbations in real time. The application of metabolomics in GDM can be used to discover diagnostic biomarkers, evaluate the prognosis of the disease, guide the application of diet or drugs, evaluate the curative effect, and explore the mechanism. This review provides comprehensive documentation of metabolomics research methods and techniques as well as the current progress in GDM research. We anticipate that the review will contribute to identifying gaps in the current knowledge or metabolomics technology, provide evidence-based information, and inform future research directions in GDM.
Collapse
Affiliation(s)
- Qian-Yi Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 21000, Jiangsu Province, China
| | - Liang-Hui You
- Nanjing Maternity and Child Health Care Institute, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 21000, Jiangsu Province, China
| | - Lan-Lan Xiang
- Department of Clinical Laboratory, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 21000, Jiangsu Province, China
| | - Yi-Tian Zhu
- Department of Clinical Laboratory, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 21000, Jiangsu Province, China
| | - Yu Zeng
- Department of Clinical Laboratory, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 21000, Jiangsu Province, China
| |
Collapse
|
|
21
|
Delgadillo-Velázquez JA, Nambo-Venegas R, Patiño N, Meraz-Cruz N, Razo-Azamar M, Guevara-Cruz M, Fonseca M, Pale Montero LE, Ibarra-González I, Vela-Amieva M, Vadillo-Ortega F, Palacios-González B. Metabolic flexibility during normal pregnancy allows appropriate adaptation during gestation independently of BMI. Clin Nutr ESPEN 2021; 44:254-262. [PMID: 34330475 DOI: 10.1016/j.clnesp.2021.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 02/22/2021] [Accepted: 06/08/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND & AIMS Overweight and obesity in reproductive-age women hasten the development of insulin resistance and increase risk for deterioration of pregnancy metabolism. These pregnancy-associated metabolic changes are similar to those of the metabolic syndrome. Thus, some metabolic flexibility must allow appropriate adaptation to the metabolic load that pregnancy imposes. We evaluated metabolic flexibility during uncomplicated pregnancy in women with pre-gestational normal weight or overweight. METHODS In 20 women with singleton pregnancies, pre-pregnancy BMI was categorized as normal-weight (Nw) or overweight (Ow). The women were seen quarterly, and fasting and postprandial blood samples were collected at each visit. Indirect fasting and/postprandial calorimetry was performed to evaluate metabolic flexibility (Δrespiratory quotient (RQ) = RQpostprandial - RQfasting). RESULTS In the first trimester, metabolic flexibility was lower in the Ow group compared to the Nw group (0.031 ± 0.0131 vs 0.077 ± 0.018, respectively) without a statistically significant difference (p = 0.053). In the second trimester, the Ow group was significantly more flexible than the Nw group (0.190 ± 0.016 vs 0.077 ± 0.015, respectively (p = 0.004)). For the third trimester, the Ow and Nw groups did not differ in metabolic flexibility (0.074 ± 0.013 vs 0.087 ± 0.021, respectively) (p = 0.40). The most influential variables for metabolic flexibility during pregnancy were lactate, leptin, β-hydroxybutyrate, glycerol, aromatic amino acids, medium and long chain acylcarnitine's. CONCLUSIONS Our findings indicate that metabolic flexibility changes throughout pregnancy, independently of pre-pregnancy BMI. These changes maintain metabolic homeostasis between the mother and foetus, allowing for appropriate adjustments during pregnancy.
Collapse
Affiliation(s)
- Jaime A Delgadillo-Velázquez
- Unidad de Vinculación Científica de La Facultad de Medicina UNAM-INMEGEN, Instituto Nacional de Medicina Genómica, Mexico City, Mexico; Facultad de Química, Universidad Nacional Autónoma de México, México City, Mexico
| | - Rafael Nambo-Venegas
- Laboratorio de Bioquímica de Enfermedades Crónicas, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Nayelli Patiño
- Unidad de Vinculación Científica de La Facultad de Medicina UNAM-INMEGEN, Instituto Nacional de Medicina Genómica, Mexico City, Mexico; Escuela de Dietética y Nutrición Del ISSSTE, Mexico City, Mexico
| | - Noemí Meraz-Cruz
- Unidad de Vinculación Científica de La Facultad de Medicina UNAM-INMEGEN, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Melissa Razo-Azamar
- Unidad de Vinculación Científica de La Facultad de Medicina UNAM-INMEGEN, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Martha Guevara-Cruz
- Fisiología de La Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - Mayali Fonseca
- Escuela de Dietética y Nutrición Del ISSSTE, Mexico City, Mexico
| | | | | | - Marcela Vela-Amieva
- Laboratorio de Errores Innatos Del Metabolismo, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Felipe Vadillo-Ortega
- Unidad de Vinculación Científica de La Facultad de Medicina UNAM-INMEGEN, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Berenice Palacios-González
- Unidad de Vinculación Científica de La Facultad de Medicina UNAM-INMEGEN, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
| |
Collapse
|
|
22
|
Nakano H, Fajardo VM, Nakano A. The role of glucose in physiological and pathological heart formation. Dev Biol 2021; 475:222-233. [PMID: 33577830 PMCID: PMC8107118 DOI: 10.1016/j.ydbio.2021.01.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/30/2020] [Accepted: 01/29/2021] [Indexed: 02/08/2023]
Abstract
Cells display distinct metabolic characteristics depending on its differentiation stage. The fuel type of the cells serves not only as a source of energy but also as a driver of differentiation. Glucose, the primary nutrient to the cells, is a critical regulator of rapidly growing embryos. This metabolic change is a consequence as well as a cause of changes in genetic program. Disturbance of fetal glucose metabolism such as in diabetic pregnancy is associated with congenital heart disease. In utero hyperglycemia impacts the left-right axis establishment, migration of cardiac neural crest cells, conotruncal formation and mesenchymal formation of the cardiac cushion during early embryogenesis and causes cardiac hypertrophy in late fetal stages. In this review, we focus on the role of glucose in cardiogenesis and the molecular mechanisms underlying heart diseases associated with hyperglycemia.
Collapse
Affiliation(s)
- Haruko Nakano
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Viviana M Fajardo
- Department of Pediatrics, Division of Neonatology and Developmental Biology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Atsushi Nakano
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA 90095, USA.
| |
Collapse
|
|
23
|
Meng X, Zhu B, Liu Y, Fang L, Yin B, Sun Y, Ma M, Huang Y, Zhu Y, Zhang Y. Unique Biomarker Characteristics in Gestational Diabetes Mellitus Identified by LC-MS-Based Metabolic Profiling. J Diabetes Res 2021; 2021:6689414. [PMID: 34212051 PMCID: PMC8211500 DOI: 10.1155/2021/6689414] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 02/18/2021] [Accepted: 05/15/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a type of glucose intolerance disorder that first occurs during women's pregnancy. The main diagnostic method for GDM is based on the midpregnancy oral glucose tolerance test. The rise of metabolomics has expanded the opportunity to better identify early diagnostic biomarkers and explore possible pathogenesis. METHODS We collected blood serum from 34 GDM patients and 34 normal controls for a LC-MS-based metabolomics study. RESULTS 184 metabolites were increased and 86 metabolites were decreased in the positive ion mode, and 65 metabolites were increased and 71 were decreased in the negative ion mode. Also, it was found that the unsaturated fatty acid metabolism was disordered in GDM. Ten metabolites with the most significant differences were selected for follow-up studies. Since the diagnostic specificity and sensitivity of a single differential metabolite are not definitive, we combined these metabolites to prepare a ROC curve. We found a set of metabolite combination with the highest sensitivity and specificity, which included eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, arachidonic acid, citric acid, α-ketoglutaric acid, and genistein. The area under the curves (AUC) value of those metabolites was 0.984 between the GDM and control group. CONCLUSIONS Our results provide a direction for the mechanism of GDM research and demonstrate the feasibility of developing a diagnostic test that can distinguish between GDM and normal controls clearly. Our findings were helpful to develop novel biomarkers for precision or personalized diagnosis for GDM. In addition, we provide a critical insight into the pathological and biological mechanisms for GDM.
Collapse
Affiliation(s)
- Xingjun Meng
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
- Institute of Laboratory Medicine, Zhejiang University, Hangzhou 310006, China
| | - Bo Zhu
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
- Institute of Laboratory Medicine, Zhejiang University, Hangzhou 310006, China
| | - Yan Liu
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China
| | - Lei Fang
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
- Institute of Laboratory Medicine, Zhejiang University, Hangzhou 310006, China
| | - Binbin Yin
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
- Institute of Laboratory Medicine, Zhejiang University, Hangzhou 310006, China
| | - Yanni Sun
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
- Institute of Laboratory Medicine, Zhejiang University, Hangzhou 310006, China
| | - Mengni Ma
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
- Institute of Laboratory Medicine, Zhejiang University, Hangzhou 310006, China
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, China
| | - Yuning Zhu
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
- Institute of Laboratory Medicine, Zhejiang University, Hangzhou 310006, China
| | - Yunlong Zhang
- Key Laboratory of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| |
Collapse
|
|
24
|
Alesi S, Ghelani D, Rassie K, Mousa A. Metabolomic Biomarkers in Gestational Diabetes Mellitus: A Review of the Evidence. Int J Mol Sci 2021; 22:ijms22115512. [PMID: 34073737 PMCID: PMC8197243 DOI: 10.3390/ijms22115512] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/20/2021] [Accepted: 05/20/2021] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is the fastest growing type of diabetes, affecting between 2 to 38% of pregnancies worldwide, varying considerably depending on diagnostic criteria used and sample population studied. Adverse obstetric outcomes include an increased risk of macrosomia, and higher rates of stillbirth, instrumental delivery, and birth trauma. Metabolomics, which is a platform used to analyse and characterise a large number of metabolites, is increasingly used to explore the pathophysiology of cardiometabolic conditions such as GDM. This review aims to summarise metabolomics studies in GDM (from inception to January 2021) in order to highlight prospective biomarkers for diagnosis, and to better understand the dysfunctional metabolic pathways underlying the condition. We found that the most commonly deranged pathways in GDM include amino acids (glutathione, alanine, valine, and serine), carbohydrates (2-hydroxybutyrate and 1,5-anhydroglucitol), and lipids (phosphatidylcholines and lysophosphatidylcholines). We also highlight the possibility of using certain metabolites as predictive markers for developing GDM, with the use of highly stratified modelling techniques. Limitations for metabolomic research are evaluated, and future directions for the field are suggested to aid in the integration of these findings into clinical practice.
Collapse
Affiliation(s)
- Simon Alesi
- Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne 3168, Australia; (S.A.); (D.G.); (K.R.)
| | - Drishti Ghelani
- Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne 3168, Australia; (S.A.); (D.G.); (K.R.)
| | - Kate Rassie
- Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne 3168, Australia; (S.A.); (D.G.); (K.R.)
- Department of Diabetes, Monash Health, Melbourne 3168, Australia
| | - Aya Mousa
- Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne 3168, Australia; (S.A.); (D.G.); (K.R.)
- Correspondence:
| |
Collapse
|
|
25
|
Shearer J, Klein MS, Vogel HJ, Mohammad S, Bainbridge S, Adamo KB. Maternal and Cord Blood Metabolite Associations with Gestational Weight Gain and Pregnancy Health Outcomes. J Proteome Res 2021; 20:1630-1638. [PMID: 33529033 DOI: 10.1021/acs.jproteome.0c00854] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Pre-pregnancy obesity and excessive gestational weight gain (GWG) are risk factors for future maternal and childhood obesity. Maternal obesity is potentially communicated to the fetus in part by the metabolome, altering the child's metabolic program in early development. Fasting maternal blood samples from 37 singleton pregnancies at 25-28 weeks of gestation were obtained from mothers with pre-pregnancy body mass indexes (BMIs) between 18 and 40 kg/m2. Various health measures including GWG, diet, and physical activity were also assessed. At term (37-42 weeks), a venous umbilical cord sample was obtained. Serum metabolomic profiles were measured using nuclear magnetic resonance spectroscopy as well as a gut and metabolic hormone panel. Maternal and cord serum metabolites were tested for associations with pre-pregnancy BMI, GWG, health outcomes, and gut and metabolic hormones. While cord blood metabolites showed no significant correlation to maternal obesity status or other measured health outcomes, maternal serum metabolites showed distinct profiles for lean, overweight, and obese women. Additionally, four serum metabolites, namely, glutamate, lysine, pyruvate, and valine, allowed prediction of excessive GWG when pre-pregnancy BMI was controlled. Metabolic biomarkers predictive of GWG are reported and, if validated, could aid in the guidance of prenatal weight management plans as the majority of pregnancy weight gain occurs in the third trimester.
Collapse
Affiliation(s)
- Jane Shearer
- Department of Biochemistry and Molecular Biology. Faculty of Kinesiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Matthias S Klein
- Department of Food Science and Technology, The Ohio State University, Columbus, Ohio 43210, United States.,Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Hans J Vogel
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Shuhiba Mohammad
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
| | - Shannon Bainbridge
- Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
| | - Kristi B Adamo
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.,Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
| |
Collapse
|
|
26
|
Bowman CE, Arany Z, Wolfgang MJ. Regulation of maternal-fetal metabolic communication. Cell Mol Life Sci 2020; 78:1455-1486. [PMID: 33084944 DOI: 10.1007/s00018-020-03674-w] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/23/2020] [Accepted: 10/05/2020] [Indexed: 02/08/2023]
Abstract
Pregnancy may be the most nutritionally sensitive stage in the life cycle, and improved metabolic health during gestation and early postnatal life can reduce the risk of chronic disease in adulthood. Successful pregnancy requires coordinated metabolic, hormonal, and immunological communication. In this review, maternal-fetal metabolic communication is defined as the bidirectional communication of nutritional status and metabolic demand by various modes including circulating metabolites, endocrine molecules, and other secreted factors. Emphasis is placed on metabolites as a means of maternal-fetal communication by synthesizing findings from studies in humans, non-human primates, domestic animals, rabbits, and rodents. In this review, fetal, placental, and maternal metabolic adaptations are discussed in turn. (1) Fetal macronutrient needs are summarized in terms of the physiological adaptations in place to ensure their proper allocation. (2) Placental metabolite transport and maternal physiological adaptations during gestation, including changes in energy budget, are also discussed. (3) Maternal nutrient limitation and metabolic disorders of pregnancy serve as case studies of the dynamic nature of maternal-fetal metabolic communication. The review concludes with a summary of recent research efforts to identify metabolites, endocrine molecules, and other secreted factors that mediate this communication, with particular emphasis on serum/plasma metabolomics in humans, non-human primates, and rodents. A better understanding of maternal-fetal metabolic communication in health and disease may reveal novel biomarkers and therapeutic targets for metabolic disorders of pregnancy.
Collapse
Affiliation(s)
- Caitlyn E Bowman
- Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Zoltan Arany
- Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael J Wolfgang
- Department of Biological Chemistry, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
27
|
Mokkala K, Vahlberg T, Houttu N, Koivuniemi E, Laitinen K. Distinct Metabolomic Profile Because of Gestational Diabetes and its Treatment Mode in Women with Overweight and Obesity. Obesity (Silver Spring) 2020; 28:1637-1644. [PMID: 32705820 DOI: 10.1002/oby.22882] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/18/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Whether the presence of gestational diabetes (GDM) and its treatment mode influence the serum metabolic profile in women with overweight or obesity was studied. METHODS The serum metabolic profiles of 352 women with overweight or obesity participating in a mother-infant clinical study were analyzed with a targeted NMR approach (at 35.1 median gestational weeks). GDM was diagnosed with a 2-hour 75-g oral glucose tolerance test. RESULTS The metabolomic profile of the women with GDM (n = 100) deviated from that of women without GDM (n = 252). Differences were seen in 70 lipid variables, particularly higher concentrations of very low-density lipoprotein particles and serum triglycerides were related to GDM. Furthermore, levels of branched-chain amino acids and glycoprotein acetylation, a marker of low-grade inflammation, were higher in women with GDM. Compared with women with GDM treated with diet only, the women treated with medication (n = 19) had higher concentrations of severalizes of VLDL particles and their components, leucine, and isoleucine, as well as glycoprotein acetylation. CONCLUSIONS A clearly distinct metabolic profile was detected in GDM, which deviated even more if the patient was receiving medical treatment. This suggests a need for more intense follow-up and therapy for women with GDM during pregnancy and postpartum to reduce their long-term adverse health risks.
Collapse
Affiliation(s)
- Kati Mokkala
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Tero Vahlberg
- Department of Clinical Medicine, Biostatistics, University of Turku, Turku, Finland
| | - Noora Houttu
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Ella Koivuniemi
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Kirsi Laitinen
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
- Turku University Hospital, Turku, Finland
| |
Collapse
|
|
28
|
Liu Y, Kuang A, Talbot O, Bain JR, Muehlbauer MJ, Hayes MG, Ilkayeva OR, Lowe LP, Metzger BE, Newgard CB, Scholtens DM, Lowe WL. Metabolomic and genetic associations with insulin resistance in pregnancy. Diabetologia 2020; 63:1783-1795. [PMID: 32556615 PMCID: PMC7416451 DOI: 10.1007/s00125-020-05198-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 05/01/2020] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Our study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance. METHODS Fasting and 1 h serum samples were collected from women in the Hyperglycemia and Adverse Pregnancy Outcome study who underwent an OGTT at ∼28 weeks' gestation. We obtained targeted and non-targeted metabolomics and genome-wide association data from 1600 and 4528 mothers, respectively, in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai); 1412 of the women had both metabolomics and genome-wide association data. Insulin sensitivity was calculated using a modified insulin sensitivity index that included fasting and 1 h glucose and C-peptide levels after a 75 g glucose load. RESULTS Per-metabolite and network analyses across the four ancestries identified numerous metabolites associated with maternal insulin sensitivity before and 1 h after a glucose load, ranging from amino acids and carbohydrates to fatty acids and lipids. Genome-wide association analyses identified 12 genetic variants in the glucokinase regulatory protein gene locus that were significantly associated with maternal insulin sensitivity, including a common functional missense mutation, rs1260326 (β = -0.2004, p = 4.67 × 10-12 in a meta-analysis across the four ancestries). This SNP was also significantly associated with multiple fasting and 1 h metabolites during pregnancy, including fasting and 1 h triacylglycerols and 2-hydroxybutyrate and 1 h lactate, 2-ketoleucine/ketoisoleucine and palmitoleic acid. Mediation analysis suggested that 1 h palmitoleic acid contributes, in part, to the association of rs1260326 with maternal insulin sensitivity, explaining 13.7% (95% CI 4.0%, 23.3%) of the total effect. CONCLUSIONS/INTERPRETATION The present study demonstrates commonalities between metabolites and genetic variants associated with insulin sensitivity in the gravid and non-gravid states and provides insights into mechanisms underlying pregnancy-induced insulin resistance. Graphical abstract.
Collapse
Affiliation(s)
- Yu Liu
- Department of Medicine, Northwestern University Feinberg School of Medicine, Rubloff 12, 420 E. Superior St, Chicago, IL, 60611, USA
- Department of Endocrinology, South Campus, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Alan Kuang
- Department of Preventive Medicine (Biostatistics), Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, 60611, USA
| | - Octavious Talbot
- Department of Preventive Medicine (Biostatistics), Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, 60611, USA
| | - James R Bain
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Michael J Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
| | - M Geoffrey Hayes
- Department of Medicine, Northwestern University Feinberg School of Medicine, Rubloff 12, 420 E. Superior St, Chicago, IL, 60611, USA
| | - Olga R Ilkayeva
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
| | - Lynn P Lowe
- Department of Preventive Medicine (Biostatistics), Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, 60611, USA
| | - Boyd E Metzger
- Department of Medicine, Northwestern University Feinberg School of Medicine, Rubloff 12, 420 E. Superior St, Chicago, IL, 60611, USA
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Denise M Scholtens
- Department of Preventive Medicine (Biostatistics), Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, 60611, USA.
| | - William L Lowe
- Department of Medicine, Northwestern University Feinberg School of Medicine, Rubloff 12, 420 E. Superior St, Chicago, IL, 60611, USA.
| | | |
Collapse
|
|
29
|
LaBarre JL, Puttabyatappa M, Song PXK, Goodrich JM, Zhou L, Rajendiran TM, Soni T, Domino SE, Treadwell MC, Dolinoy DC, Padmanabhan V, Burant CF. Maternal lipid levels across pregnancy impact the umbilical cord blood lipidome and infant birth weight. Sci Rep 2020; 10:14209. [PMID: 32848180 PMCID: PMC7449968 DOI: 10.1038/s41598-020-71081-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 07/20/2020] [Indexed: 12/14/2022] Open
Abstract
Major alterations in metabolism occur during pregnancy enabling the mother to provide adequate nutrients to support infant development, affecting birth weight (BW) and potentially long-term risk of obesity and cardiometabolic disease. We classified dynamic changes in the maternal lipidome during pregnancy and identified lipids associated with Fenton BW z-score and the umbilical cord blood (CB) lipidome. Lipidomics was performed on first trimester maternal plasma (M1), delivery maternal plasma (M3), and CB plasma in 106 mother-infant dyads. Shifts in the maternal and CB lipidome were consistent with the selective transport of long-chain polyunsaturated fatty acids (PUFA) as well as lysophosphatidylcholine (LysoPC) and lysophosphatidylethanolamine (LysoPE) species into CB. Partial correlation networks demonstrated fluctuations in correlations between lipid groups at M1, M3, and CB, signifying differences in lipid metabolism. Using linear models, LysoPC and LysoPE groups in CB were positively associated with BW. M1 PUFA containing triglycerides (TG) and phospholipids were correlated with CB LysoPC and LysoPE species and total CB polyunsaturated TGs. These results indicate that early gestational maternal lipid levels influence the CB lipidome and its relationship with BW, suggesting an opportunity to modulate maternal diet and improve long-term offspring cardiometabolic health.
Collapse
Affiliation(s)
- Jennifer L LaBarre
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | | | - Peter X K Song
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Jaclyn M Goodrich
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Ling Zhou
- Center of Statistical Research, Southwestern University of Finance and Economics, Chengdu, Sichuan, China
| | - Thekkelnaycke M Rajendiran
- Michigan Regional Comprehensive Metabolomics Resource Core, Ann Arbor, MI, USA.,Department of Pathology, Michigan Regional Comprehensive Metabolomics Resource Core, Ann Arbor, MI, USA
| | - Tanu Soni
- Michigan Regional Comprehensive Metabolomics Resource Core, Ann Arbor, MI, USA
| | - Steven E Domino
- Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Marjorie C Treadwell
- Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Dana C Dolinoy
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Vasantha Padmanabhan
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.,Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.,Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Charles F Burant
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA. .,Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
| |
Collapse
|
|
30
|
Zhang YZ, Zhou L, Tian L, Li X, Zhang G, Qin JY, Zhang DD, Fang H. A mid-pregnancy risk prediction model for gestational diabetes mellitus based on the maternal status in combination with ultrasound and serological findings. Exp Ther Med 2020; 20:293-300. [PMID: 32536997 PMCID: PMC7282073 DOI: 10.3892/etm.2020.8690] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 02/28/2020] [Indexed: 12/11/2022] Open
Abstract
Although previous studies have proposed predictive models of gestational diabetes mellitus (GDM) based on maternal status, they do not always provide reliable results. The present study aimed to create a novel model that included ultrasound data of maternal fat distribution and serum inflammatory factors. The clinical data of 1,158 pregnant women treated at Tangshan Gongren Hospital and eight other flagship hospitals in Tangshan, including the First Hospital of Tangshan Gongren Hospital group, Ninth Hospital of Tangshan Gongren Hospital group, Tangshan Gongren Hospital group rehabilitation hospital, Tangshan railway central hospital, Tangshan Gongren Hospital group Fengnan hospital, Tangshan Gongren Hospital group Qianan Yanshan hospital, Tangshan Gongren Hospital group Qianxi Kangli hospital and Tangshan Gongren Hospital group Jidong Sub-hospital, were analyzed following the division of subjects into GDM and non-GDM groups according to their diagnostic results at 24-28 weeks of pregnancy. Univariate analysis was performed to investigate the significance of the maternal clinical parameters for GDM diagnosis and a GDM prediction model was established using stepwise regression analysis. The predictive value of the model was evaluated using a Homer-Lemeshow goodness-of-fit test and a receiver operating characteristic curve (ROC). The model demonstrated that age, pre-pregnancy body mass index, a family history of diabetes mellitus, polycystic ovary syndrome, a history of GDM, high systolic pressures, glycosylated hemoglobin levels, triglyceride levels, total cholesterol levels, low-density lipoprotein cholesterol levels, serum hypersensitive C-reactive protein, increased subcutaneous fat thickness and visceral fat thickness were all correlated with an increased GDM risk (all P<0.01). The area under the curve value was 0.911 (95% CI, 0.893-0.930). Overall, the results indicated that the current model, which included ultrasound and serological data, may be a more effective predictor of GDM compared with other single predictor models. In conclusion, the present study developed a tool to determine the risk of GDM in pregnant women during the second trimester. This prediction model, based on various risk factors, demonstrated a high predictive value for the GDM occurrence in pregnant women in China and may prove useful in guiding future clinical practice.
Collapse
Affiliation(s)
- Ya-Zhong Zhang
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Lei Zhou
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Luobing Tian
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Xin Li
- Department of Imaging, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Guyue Zhang
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Jiang-Yuan Qin
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Dan-Dan Zhang
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Hui Fang
- Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| |
Collapse
|
|
31
|
Lindsay KL, Entringer S, Buss C, Wadhwa PD. Intergenerational transmission of the effects of maternal exposure to childhood maltreatment on offspring obesity risk: A fetal programming perspective. Psychoneuroendocrinology 2020; 116:104659. [PMID: 32240906 PMCID: PMC7293953 DOI: 10.1016/j.psyneuen.2020.104659] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 03/12/2020] [Accepted: 03/19/2020] [Indexed: 12/19/2022]
Abstract
Childhood obesity constitutes a major global public health challenge. A substantial body of evidence suggests that conditions and states experienced by the embryo/fetus in utero can result in structural and functional changes in cells, tissues, organ systems and homeostatic set points related to obesity. Furthermore, growing evidence suggests that maternal conditions and states experienced prior to conception, such as stress, obesity and metabolic dysfunction, may spill over into pregnancy and influence those key aspects of gestational biology that program offspring obesity risk. In this narrative review, we advance a novel hypothesis and life-span framework to propose that maternal exposure to childhood maltreatment may constitute an important and as-yet-underappreciated risk factor implicated in developmental programming of offspring obesity risk via the long-term psychological, biological and behavioral sequelae of childhood maltreatment exposure. In this context, our framework considers the key role of maternal-placental-fetal endocrine, immune and metabolic pathways and also other processes including epigenetics, oocyte mitochondrial biology, and the maternal and infant microbiomes. Finally, our paper discusses future research directions required to elucidate the nature and mechanisms of the intergenerational transmission of the effects of maternal childhood maltreatment on offspring obesity risk.
Collapse
Affiliation(s)
- Karen L Lindsay
- Department of Pediatrics, University of California, Irvine, School of Medicine, California 92697, U.S.A,Departments of Development, Health and Disease Research Program, University of California, Irvine, School of Medicine, California 92697, U.S.A
| | - Sonja Entringer
- Department of Pediatrics, University of California, Irvine, School of Medicine, California 92697, U.S.A,Departments of Development, Health and Disease Research Program, University of California, Irvine, School of Medicine, California 92697, U.S.A,Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology
| | - Claudia Buss
- Department of Pediatrics, University of California, Irvine, School of Medicine, California 92697, U.S.A,Departments of Development, Health and Disease Research Program, University of California, Irvine, School of Medicine, California 92697, U.S.A,Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology
| | - Pathik D Wadhwa
- Department of Pediatrics, University of California, Irvine, School of Medicine, CA 92697, USA; Department of Psychiatry and Human Behavior, University of California, Irvine, School of Medicine, CA 92697, USA; Department of Obstetrics and Gynecology, University of California, Irvine, School of Medicine, CA 92697, USA; Department of Epidemiology, University of California, Irvine, School of Medicine, CA 92697, USA; UCI Development, Health and Disease Research Program, University of California, Irvine, School of Medicine, CA 92697, USA.
| |
Collapse
|
|
32
|
Helle E, Priest JR. Maternal Obesity and Diabetes Mellitus as Risk Factors for Congenital Heart Disease in the Offspring. J Am Heart Assoc 2020; 9:e011541. [PMID: 32308111 PMCID: PMC7428516 DOI: 10.1161/jaha.119.011541] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Congenital heart disease (CHD) is the most common anatomical malformation occurring live‐born infants and an increasing cause of morbidity and mortality across the lifespan and throughout the world. Population‐based observations have long described associations between maternal cardiometabolic disorders and the risk of CHD in the offspring. Here we review the epidemiological evidence and clinical observations relating maternal obesity and diabetes mellitus to the risk of CHD offspring with particular attention to mechanistic models of maternal‐fetal risk transmission and first trimester disturbances of fetal cardiac development. A deeper understanding of maternal risk factors holds the potential to improve both prenatal detection of CHD by identifying at‐risk pregnancies, along with primary prevention of disease by improving preconception and prenatal treatment of at‐risk mothers.
Collapse
Affiliation(s)
- Emmi Helle
- Stem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki Helsinki Finland.,Pediatric Cardiology Children's Hospital, and Pediatric Research Center Helsinki University Hospital University of Helsinki Helsinki Finland
| | - James R Priest
- Department of Pediatrics (Cardiology) Stanford University School of Medicine Stanford CA.,Chan-Zuckerberg Biohub San Francisco CA
| |
Collapse
|
|
33
|
Cao M, Li C, Liu Y, Cai K, Chen L, Yuan C, Zhao Z, Zhang B, Hou R, Zhou X. Assessing Urinary Metabolomics in Giant Pandas Using Chromatography/Mass Spectrometry: Pregnancy-Related Changes in the Metabolome. Front Endocrinol (Lausanne) 2020; 11:215. [PMID: 32373070 PMCID: PMC7176934 DOI: 10.3389/fendo.2020.00215] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/25/2020] [Indexed: 01/05/2023] Open
Abstract
Giant pandas represent one of the most endangered species worldwide, and their reproductive capacity is extremely low. They have a relatively long gestational period, mainly because embryo implantation is delayed. Giant panda cubs comprise only a small proportion of the mother's body weight, making it difficult to determine whether a giant panda is pregnant. Timely determination of pregnancy contributes to the efficient breeding and management of giant pandas. Meanwhile, metabolomics studies the metabolic composition of biological samples, which can reflect metabolic functions in cells, tissues, and organisms. This work explored the urinary metabolites of giant pandas during pregnancy. A sample of 8 female pandas was selected. Differences in metabolite levels in giant panda urine samples were analyzed via ultra-high-performance liquid chromatography/mass spectrometry comparing pregnancy to anoestrus. Pattern recognition techniques, including partial least squares-discriminant analysis and orthogonal partial least squares-discriminant analysis, were used to analyze multiple parameters of the data. Compared with the results during anoestrus, multivariate statistical analysis of results obtained from the same pandas being pregnant identified 16 differential metabolites in the positive-ion mode and 43 differential metabolites in the negative-ion mode. The levels of tryptophan, choline, kynurenic acid, uric acid, indole-3-acetaldehyde, taurine, and betaine were higher in samples during pregnancy, whereas those of xanthurenic acid and S-adenosylhomocysteine were lower. Amino acid metabolism, lipid metabolism, and organic acid production differed significantly between anoestrus and pregnancy. Our results provide new insights into metabolic changes in the urine of giant pandas during pregnancy, and the differential levels of metabolites in urine provide a basis for determining pregnancy in giant pandas. Understanding these metabolic changes could be helpful for managing pregnant pandas to provide proper nutrients to their fetuses.
Collapse
Affiliation(s)
- Maosheng Cao
- College of Animal Sciences, Jilin University, Changchun, China
| | - Chunjin Li
- College of Animal Sciences, Jilin University, Changchun, China
| | - Yuliang Liu
- Chengdu Research Base of Giant Panda Breeding, Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Sichuan Academy of Giant Panda, Chengdu, China
| | - Kailai Cai
- Chengdu Research Base of Giant Panda Breeding, Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Sichuan Academy of Giant Panda, Chengdu, China
| | - Lu Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Chenfeng Yuan
- College of Animal Sciences, Jilin University, Changchun, China
| | - Zijiao Zhao
- College of Animal Sciences, Jilin University, Changchun, China
| | - Boqi Zhang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Rong Hou
- Chengdu Research Base of Giant Panda Breeding, Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Sichuan Academy of Giant Panda, Chengdu, China
| | - Xu Zhou
- College of Animal Sciences, Jilin University, Changchun, China
| |
Collapse
|
|
34
|
Guillemette L, Dart A, Wicklow B, Dolinsky VW, Cheung D, Jassal DS, Sellers EAC, Gelinas J, Eves ND, Balshaw R, Agarwal P, Duhamel TA, Gordon JW, McGavock JM. Cardiac structure and function in youth with type 2 diabetes in the iCARE cohort study: Cross-sectional associations with prenatal exposure to diabetes and metabolomic profiles. Pediatr Diabetes 2020; 21:233-242. [PMID: 31802590 DOI: 10.1111/pedi.12954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/25/2019] [Accepted: 12/02/2019] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE This study aimed to determine the degree of left ventricular (LV) dysfunction and its determinants in adolescents with type 2 diabetes (T2D). We hypothesized that adolescents with T2D would display impaired LV diastolic function and that these cardiovascular complications would be exacerbated in youth exposed to maternal diabetes in utero. METHODS Left ventricular structure and function, carotid artery intima media thickness and strain, and serum metabolomic profiles were compared between adolescents with T2D (n = 121) and controls (n = 34). Sub-group analyses examined the role of exposure to maternal diabetes as a determinant of LV or carotid artery structure and function among adolescents with T2D. RESULTS Adolescents with T2D were 15.1 ± 2.5 years old, (65% female, 99% Indigenous), had lived with diabetes for 2.7 ± 2.2 years, had suboptimal glycemic control (HbA1c = 9.4 ± 2.6%) and 58% (n = 69) were exposed to diabetes in utero. Compared to controls, adolescents with T2D displayed lower LV diastolic filling (early diastole/atrial filling rate ratio [E/A] = 1.9 ± 0.6 vs 2.2 ± 0.6, P = 0.012), lower LV relaxation and carotid strain (0.12 ± 0.05 vs 0.17 ± 0.05, P = .03) and elevated levels of leucine, isoleucine and valine. Among adolescents with T2D, exposure to diabetes in utero was not associated with differences in LV diastolic filling, LV relaxation, carotid strain or branched chain amino acids. CONCLUSIONS Adolescents with T2D display LV diastolic dysfunction, carotid artery stiffness, and elevated levels of select branch chain amino acids; differences were not associated with exposure to maternal diabetes in utero.
Collapse
Affiliation(s)
- Laetitia Guillemette
- Department of Pediatrics and Child Health, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.,Diabetes Research Envisioned and Accomplished in Manitoba Research Theme, Winnipeg, Manitoba, Canada
| | - Allison Dart
- Department of Pediatrics and Child Health, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.,Diabetes Research Envisioned and Accomplished in Manitoba Research Theme, Winnipeg, Manitoba, Canada
| | - Brandy Wicklow
- Department of Pediatrics and Child Health, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.,Diabetes Research Envisioned and Accomplished in Manitoba Research Theme, Winnipeg, Manitoba, Canada
| | - Vernon W Dolinsky
- Diabetes Research Envisioned and Accomplished in Manitoba Research Theme, Winnipeg, Manitoba, Canada.,Department of Pharmacology, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - David Cheung
- St. Boniface Cardiovascular Research Centre, Winnipeg, Manitoba, Canada.,Division of Cardiology, St. Boniface Hospital, Winnipeg, Manitoba, Canada
| | - Davinder S Jassal
- St. Boniface Cardiovascular Research Centre, Winnipeg, Manitoba, Canada.,Division of Cardiology, St. Boniface Hospital, Winnipeg, Manitoba, Canada
| | - Elizabeth A C Sellers
- Department of Pediatrics and Child Health, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.,Diabetes Research Envisioned and Accomplished in Manitoba Research Theme, Winnipeg, Manitoba, Canada
| | - Jinelle Gelinas
- School of Health and Exercise Sciences, Faculty of health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Neil D Eves
- School of Health and Exercise Sciences, Faculty of health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Robert Balshaw
- Biostatistical Consulting Unit, George and Fay Yee Centre for Health Care Innovation, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Prasoon Agarwal
- Diabetes Research Envisioned and Accomplished in Manitoba Research Theme, Winnipeg, Manitoba, Canada.,Department of Pharmacology, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Todd A Duhamel
- Faculty of Kinesiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Joseph W Gordon
- Faculty of Nursing, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jonathan M McGavock
- Department of Pediatrics and Child Health, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.,Diabetes Research Envisioned and Accomplished in Manitoba Research Theme, Winnipeg, Manitoba, Canada.,Faculty of Kinesiology, University of Manitoba, Winnipeg, Manitoba, Canada
| |
Collapse
|
|
35
|
Khan MW, Layden BT. Gestational Glucose Metabolism: Focus on the Role and Mechanisms of Insulin Resistance. MATERNAL-FETAL AND NEONATAL ENDOCRINOLOGY 2020:75-90. [DOI: 10.1016/b978-0-12-814823-5.00006-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
36
|
Satheesh G, Ramachandran S, Jaleel A. Metabolomics-Based Prospective Studies and Prediction of Type 2 Diabetes Mellitus Risks. Metab Syndr Relat Disord 2019; 18:1-9. [PMID: 31634052 DOI: 10.1089/met.2019.0047] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The preceding decade has witnessed an intense upsurge in the diabetic population across the world making type 2 diabetes mellitus (T2DM) more of an epidemic than a lifestyle disease. Metabolic disorders are often latent for a while before becoming clinically evident, thus reinforcing the pursuit of early biomarkers of metabolic alterations. A prospective study along with metabolic profiling is the most appropriate way to detect the early pathophysiological changes in metabolic diseases such as T2DM. The aim of this review was to summarize the different potential biomarkers of T2DM identified in prospective studies, which used tools of metabolomics. The review also demonstrates on how metabolomic profiling-based prospective studies can be used to address a concern like population-specific disease mechanism. We performed a literature search on metabolomics-based prospective studies on T2DM using the key words "metabolomics," "Type 2 diabetes," "diabetes mellitus", "metabolite profiling," "prospective study," "metabolism," and "biomarker." Additional articles that were obtained from the reference lists of the articles obtained using the above key words were also examined. Articles on dietary intake, type 1 diabetes mellitus, and gestational diabetes were excluded. The review revealed that many studies showed a direct association of branched-chain amino acids and an inverse association of glycine with T2DM. Majority of the prospective studies conducted were targeted metabolomics-based, with Caucasians as their study cohort. The whole disease risk in populations, including Asians, could therefore not be identified. This review proposes the utility of prospective studies in conjunction with metabolomics platform to unravel the altered metabolic pathways that contribute to the risk of T2DM.
Collapse
Affiliation(s)
- Gopika Satheesh
- Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | | | - Abdul Jaleel
- Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| |
Collapse
|
|
37
|
Kadakia R, Talbot O, Kuang A, Bain JR, Muehlbauer MJ, Stevens RD, Ilkayeva OR, Lowe LP, Metzger BE, Newgard CB, Scholtens DM, Lowe WL. Cord Blood Metabolomics: Association With Newborn Anthropometrics and C-Peptide Across Ancestries. J Clin Endocrinol Metab 2019; 104:4459-4472. [PMID: 31498869 PMCID: PMC6735762 DOI: 10.1210/jc.2019-00238] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 06/28/2019] [Indexed: 12/18/2022]
Abstract
CONTEXT Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance. OBJECTIVE To determine the association of cord blood metabolites with newborn adiposity and hyperinsulinemia in a multiethnic cohort of newborns. DESIGN Cross-sectional, observational study. SETTING Hyperglycemia and Adverse Pregnancy Outcome study. PARTICIPANTS One thousand six hundred multiethnic mother-newborn pairs. MAIN OUTCOME MEASURE Cord blood C-peptide, birthweight, and newborn sum of skinfolds. RESULTS Meta-analyses across four ancestry groups (Afro-Caribbean, Northern European, Thai, and Mexican American) demonstrated significant associations of cord blood metabolites with cord blood C-peptide, birthweight, and newborn sum of skinfolds. Several metabolites, including branched-chain amino acids (BCAAs), medium- and long-chain acylcarnitines, nonesterified fatty acids, and triglycerides were negatively associated with cord C-peptide but positively associated with birthweight and/or sum of skinfolds. 1,5-Anhydroglucitol, an inverse marker of recent maternal glycemia, was significantly inversely associated with birthweight and sum of skinfolds. Network analyses revealed groups of interrelated amino acid, acylcarnitine, and fatty acid metabolites associated with all three newborn outcomes. CONCLUSIONS Cord blood metabolites are associated with newborn size and cord blood C-peptide levels after adjustment for maternal body mass index and glucose during pregnancy. Negative associations of metabolites with C-peptide at birth were observed. 1,5-Anhydroglucitol appears to be a marker of adiposity in newborns. BCAAs were individually associated with birthweight and demonstrated possible associations with newborn adiposity in network analyses.
Collapse
Affiliation(s)
- Rachel Kadakia
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
- Correspondence and Reprint Requests: William L. Lowe, Jr., MD, Feinberg School of Medicine, Northwestern University, Rubloff Building, 12th Floor, 420 East Superior Street, Chicago, Ilinois 60611.
| | - Octavious Talbot
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Alan Kuang
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - James R Bain
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina
- Duke Molecular Physiology Institute, Durham, North Carolina
- Duke University School of Medicine, Durham, North Carolina
| | - Michael J Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina
- Duke Molecular Physiology Institute, Durham, North Carolina
- Duke University School of Medicine, Durham, North Carolina
| | - Robert D Stevens
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina
- Duke Molecular Physiology Institute, Durham, North Carolina
- Duke University School of Medicine, Durham, North Carolina
| | - Olga R Ilkayeva
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina
- Duke Molecular Physiology Institute, Durham, North Carolina
- Duke University School of Medicine, Durham, North Carolina
| | - Lynn P Lowe
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Boyd E Metzger
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina
- Duke Molecular Physiology Institute, Durham, North Carolina
- Duke University School of Medicine, Durham, North Carolina
| | | | - William L Lowe
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | | |
Collapse
|
|
38
|
Perng W, Oken E, Dabelea D. Developmental overnutrition and obesity and type 2 diabetes in offspring. Diabetologia 2019; 62:1779-1788. [PMID: 31451868 DOI: 10.1007/s00125-019-4914-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/01/2019] [Indexed: 01/01/2023]
Abstract
Childhood obesity has reached pandemic proportions, and youth-onset type 2 diabetes is following suit. This review summarises the literature on the influence of developmental overnutrition, resulting from maternal diabetes, obesity, maternal dietary intake during pregnancy, excess gestational weight gain, and infant feeding practices, on the aetiology of obesity and type 2 diabetes risk during childhood and adolescence. Key goals of this review are: (1) to summarise evidence to date on consequences of developmental overnutrition; (2) describe shared and distinct biological pathways that may link developmental overnutrition to childhood obesity and youth-onset type 2 diabetes; and (3) to translate current knowledge into clinical and public health strategies that not only target primary prevention in youth, but also encourage primordial prevention during the perinatal period, with the aim of breaking the intergenerational cycle of obesity and diabetes.
Collapse
Affiliation(s)
- Wei Perng
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Center, Aurora, CO, USA
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, 13001 East 17th Ave, Box B119, Room W3110, Aurora, CO, 80045, USA
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Emily Oken
- Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School/Harvard Pilgrim Health Care Institute, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Dana Dabelea
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, 13001 East 17th Ave, Box B119, Room W3110, Aurora, CO, 80045, USA.
- Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
| |
Collapse
|
|
39
|
Nahavandi S, Price S, Sumithran P, Ekinci EI. Exploration of the shared pathophysiological mechanisms of gestational diabetes and large for gestational age offspring. World J Diabetes 2019; 10:333-340. [PMID: 31231456 PMCID: PMC6571486 DOI: 10.4239/wjd.v10.i6.333] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 05/13/2019] [Accepted: 05/23/2019] [Indexed: 02/05/2023] Open
Abstract
Gestational diabetes mellitus (GDM) and large for gestational age (LGA) offspring are two common pregnancy complications. Connections also exist between the two conditions, including mutual maternal risk factors for the conditions and an increased prevalence of LGA offspring amongst pregnancies affected by GDM. Thus, it is important to elucidate potential shared underlying mechanisms of both LGA and GDM. One potential mechanistic link relates to macronutrient metabolism. Indeed, derangement of carbohydrate and lipid metabolism is present in GDM, and maternal biomarkers of glucose and lipid control are associated with LGA neonates in such pregnancies. The aim of this paper is therefore to reflect on the existing nutritional guidelines for GDM in light of our understanding of the pathophysiological mechanisms of GDM and LGA offspring. Lifestyle modification is first line treatment for GDM, and while there is some promise that nutritional interventions may favourably impact outcomes, there is a lack of definitive evidence that changing the macronutrient composition of the diet reduces the incidence of either GDM or LGA offspring. The quality of the available evidence is a major issue, and rigorous trials are needed to inform evidence-based treatment guidelines.
Collapse
Affiliation(s)
- Sofia Nahavandi
- The Royal Children’s Hospital Melbourne, Parkville, VIC 3052, Australia
| | - Sarah Price
- Department of Endocrinology, Austin Health, Repatriation Campus Heidelberg West, Melbourne, VIC 3081, Australia
- Department of Medicine, Austin Health and the University of Melbourne (Austin Campus), Parkville, Melbourne, VIC 3084, Australia
| | - Priya Sumithran
- Department of Endocrinology, Austin Health, Repatriation Campus Heidelberg West, Melbourne, VIC 3081, Australia
- Department of Medicine, Austin Health and the University of Melbourne (Austin Campus), Parkville, Melbourne, VIC 3084, Australia
| | - Elif Ilhan Ekinci
- Department of Endocrinology, Austin Health, Repatriation Campus Heidelberg West, Melbourne, VIC 3081, Australia
- Department of Medicine, Austin Health and the University of Melbourne (Austin Campus), Parkville, Melbourne, VIC 3084, Australia
| |
Collapse
|
|
40
|
Disrupted Maturation of the Microbiota and Metabolome among Extremely Preterm Infants with Postnatal Growth Failure. Sci Rep 2019; 9:8167. [PMID: 31160673 PMCID: PMC6546715 DOI: 10.1038/s41598-019-44547-y] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 05/15/2019] [Indexed: 01/05/2023] Open
Abstract
Growth failure during infancy is a major global problem that has adverse effects on long-term health and neurodevelopment. Preterm infants are disproportionately affected by growth failure and its effects. Herein we found that extremely preterm infants with postnatal growth failure have disrupted maturation of the intestinal microbiota, characterized by persistently low diversity, dominance of pathogenic bacteria within the Enterobacteriaceae family, and a paucity of strictly anaerobic taxa including Veillonella relative to infants with appropriate postnatal growth. Metabolomic profiling of infants with growth failure demonstrated elevated serum acylcarnitines, fatty acids, and other byproducts of lipolysis and fatty acid oxidation. Machine learning algorithms for normal maturation of the microbiota and metabolome among infants with appropriate growth revealed a pattern of delayed maturation of the microbiota and metabolome among infants with growth failure. Collectively, we identified novel microbial and metabolic features of growth failure in preterm infants and potentially modifiable targets for intervention.
Collapse
|
|
41
|
The influence of maternal and infant nutrition on cardiometabolic traits: novel findings and future research directions from four Canadian birth cohort studies. Proc Nutr Soc 2019; 78:351-361. [PMID: 31140389 DOI: 10.1017/s0029665119000612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A mother's nutritional choices while pregnant may have a great influence on her baby's development in the womb and during infancy. There is evidence that what a mother eats during pregnancy interacts with her genes to affect her child's susceptibility to poor health outcomes including childhood obesity, pre-diabetes, allergy and asthma. Furthermore, after what an infant eats can change his or her intestinal bacteria, which can further influence the development of these poor outcomes. In the present paper, we review the importance of birth cohorts, the formation and early findings from a multi-ethnic birth cohort alliance in Canada and summarise our future research directions for this birth cohort alliance. We summarise a method for harmonising collection and analysis of self-reported dietary data across multiple cohorts and provide examples of how this birth cohort alliance has contributed to our understanding of gestational diabetes risk; ethnic and diet-influences differences in the healthy infant microbiome; and the interplay between diet, ethnicity and birth weight. Ongoing work in this birth cohort alliance will focus on the use of metabolomic profiling to measure dietary intake, discovery of unique diet-gene and diet-epigenome interactions, and qualitative interviews with families of children at risk of metabolic syndrome. Our findings to-date and future areas of research will advance the evidence base that informs dietary guidelines in pregnancy, infancy and childhood, and will be relevant to diverse and high-risk populations of Canada and other high-income countries.
Collapse
|
|
42
|
Shokry E, Marchioro L, Uhl O, Bermúdez MG, García-Santos JA, Segura MT, Campoy C, Koletzko B. Impact of maternal BMI and gestational diabetes mellitus on maternal and cord blood metabolome: results from the PREOBE cohort study. Acta Diabetol 2019; 56:421-430. [PMID: 30725264 DOI: 10.1007/s00592-019-01291-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 01/18/2019] [Indexed: 12/15/2022]
Abstract
AIMS Maternal obesity and gestational diabetes mellitus (GDM) were frequently reported to be risk factors for obesity and diabetes in offspring. Our goal was to study the impact of maternal prepregnancy BMI (pBMI) and GDM on both maternal and cord blood metabolic profiles. METHODS We used LC-MS/MS to measure 201 metabolites comprising phospholipids (PL), amino acids, non-esterified fatty acids (NEFA), organic acids, acyl carnitines (AC), and Krebs cycle metabolites in maternal plasma at delivery and cord plasma obtained from 325 PREOBE study participants. RESULTS Several metabolites were associated with pBMI/GDM in both maternal and cord blood (p < 0.05), while others were specific to either blood sources. BMI was positively associated with leucine, isoleucine, and inflammation markers in both mother and offspring, while β-hydroxybutyric acid was positively associated only in cord blood. GDM showed elevated levels of sum of hexoses, a characteristic finding in both maternal and cord blood. Uniquely in cord blood of offspring born to GDM mothers, free carnitine was significantly lower with the same tendency observed for AC, long-chain NEFA, PL, specific Krebs cycle metabolites, and β-oxidation markers. CONCLUSIONS Maternal BMI and GDM are associated with maternal and cord blood metabolites supporting the hypothesis of transgenerational cycle of obesity and diabetes.
Collapse
Affiliation(s)
- Engy Shokry
- Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, LMU-Ludwig-Maximilians-Universität München, University of Munich Medical Centre, Campus Innenstadt, Lindwurmstr. 4, 80337, Munich, Germany
| | - Linda Marchioro
- Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, LMU-Ludwig-Maximilians-Universität München, University of Munich Medical Centre, Campus Innenstadt, Lindwurmstr. 4, 80337, Munich, Germany
| | - Olaf Uhl
- Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, LMU-Ludwig-Maximilians-Universität München, University of Munich Medical Centre, Campus Innenstadt, Lindwurmstr. 4, 80337, Munich, Germany
| | - Mercedes G Bermúdez
- Department of Paediatrics, School of Medicine, EURISTIKOS Excellence Centre for Paediatric Research, University of Granada, Avenida de la Investigación 11, 18016, Granada, Spain
| | - Jose Antonio García-Santos
- Department of Paediatrics, School of Medicine, EURISTIKOS Excellence Centre for Paediatric Research, University of Granada, Avenida de la Investigación 11, 18016, Granada, Spain
| | - Mª Teresa Segura
- Department of Paediatrics, School of Medicine, EURISTIKOS Excellence Centre for Paediatric Research, University of Granada, Avenida de la Investigación 11, 18016, Granada, Spain
| | - Cristina Campoy
- Department of Paediatrics, School of Medicine, EURISTIKOS Excellence Centre for Paediatric Research, University of Granada, Avenida de la Investigación 11, 18016, Granada, Spain
| | - Berthold Koletzko
- Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, LMU-Ludwig-Maximilians-Universität München, University of Munich Medical Centre, Campus Innenstadt, Lindwurmstr. 4, 80337, Munich, Germany.
| |
Collapse
|
|
43
|
Kadakia R, Nodzenski M, Talbot O, Kuang A, Bain JR, Muehlbauer MJ, Stevens RD, Ilkayeva OR, O'Neal SK, Lowe LP, Metzger BE, Newgard CB, Scholtens DM, Lowe WL. Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries. Diabetologia 2019; 62:473-484. [PMID: 30483859 PMCID: PMC6374187 DOI: 10.1007/s00125-018-4781-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/26/2018] [Indexed: 12/30/2022]
Abstract
AIMS/HYPOTHESIS We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother-newborn dyads. METHODS Targeted and non-targeted metabolomics assays were performed on fasting and 1 h serum samples from a total of 1600 mothers in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, underwent an OGTT at ~28 weeks gestation and whose newborns had anthropometric measurements at birth. RESULTS In this observational study, meta-analyses demonstrated significant associations of maternal fasting and 1 h metabolites with birthweight, cord C-peptide and/or sum of skinfolds across ancestry groups. In particular, maternal fasting triacylglycerols were associated with newborn sum of skinfolds. At 1 h, several amino acids, fatty acids and lipid metabolites were associated with one or more newborn outcomes. Network analyses revealed clusters of fasting acylcarnitines, amino acids, lipids and fatty acid metabolites associated with cord C-peptide and sum of skinfolds, with the addition of branched-chain and aromatic amino acids at 1 h. CONCLUSIONS/INTERPRETATION The maternal metabolome during pregnancy is associated with newborn outcomes. Maternal levels of amino acids, acylcarnitines, lipids and fatty acids and their metabolites during pregnancy relate to fetal growth, adiposity and cord C-peptide, independent of maternal BMI and blood glucose levels.
Collapse
Affiliation(s)
- Rachel Kadakia
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
- Ann and Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Avenue, Box 54, Chicago, IL, 60611, USA.
| | - Michael Nodzenski
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Octavious Talbot
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Alan Kuang
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - James R Bain
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | - Michael J Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | - Robert D Stevens
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | - Olga R Ilkayeva
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | - Sara K O'Neal
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | - Lynn P Lowe
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Boyd E Metzger
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
- Duke University School of Medicine, Durham, NC, USA
| | | | - William L Lowe
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | | |
Collapse
|
|
44
|
The Role of Inflammation in the Development of GDM and the Use of Markers of Inflammation in GDM Screening. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:217-242. [PMID: 30919340 DOI: 10.1007/978-3-030-12668-1_12] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gestational diabetes mellitus is a hyperglycaemic state first recognised in pregnancy. GDM affects both mother and child. Women with GDM and their new-borns are at risk of developing type 2 diabetes in the future. The screening and diagnostic criteria for GDM are inconsistent and thus novel biomarkers of GDM are required to strengthen the screening and diagnostic processes in GDM. Chronic low-grade inflammation is linked to the majority of the well-established risk factors of GDM such as old age, obesity and PCOS. This review provides an overview of the present knowledge on the pathology of GDM, the screening criteria applied, the role of inflammation in the development of GDM and the use of markers of inflammation namely cytokines, oxidative stress markers, lipids, amino acids and iron markers in screening and diagnosis of GDM.
Collapse
|
|
45
|
Gestational Diabetes Alters the Metabolomic Profile in 2nd Trimester Amniotic Fluid in a Sex-Specific Manner. Int J Mol Sci 2018; 19:ijms19092696. [PMID: 30201937 PMCID: PMC6165183 DOI: 10.3390/ijms19092696] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/02/2018] [Accepted: 09/06/2018] [Indexed: 01/06/2023] Open
Abstract
Maternal diabetes and obesity induce marked abnormalities in glucose homeostasis and insulin secretion in the fetus, and are linked to obesity, diabetes, and metabolic disease in the offspring, with specific metabolic characterization based on offspring sex. Gestational diabetes (GDM) has profound effects on the intrauterine milieu, which may reflect and/or modulate the function of the maternal–fetal unit. In order to characterize metabolic factors that affect offspring development, we profiled the metabolome of second trimester amniotic fluid (AF) from women who were subsequently diagnosed with gestational diabetes (GDM) using a targeted metabolomics approach, profiling 459 known biochemicals through gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) assays. Using a nested case-control study design, we identified 69 total biochemicals altered by GDM exposure, while sex-specific analysis identified 44 and 58 metabolites in male and female offspring, respectively. The most significant changes were in glucose, amino acid, glutathione, fatty acid, sphingolipid, and bile acid metabolism with specific changes identified based on the offspring sex. Targeted isotope dilution LC/MS confirmatory assays measured significant changes in docosahexaenoic acid and arachidonic acid. We conclude that the sex-specific alterations in GDM maternal–fetal metabolism may begin to explain the sex-specific metabolic outcomes seen in offspring exposed to GDM in utero.
Collapse
|
|
46
|
Chen Q, Francis E, Hu G, Chen L. Metabolomic profiling of women with gestational diabetes mellitus and their offspring: Review of metabolomics studies. J Diabetes Complications 2018; 32:512-523. [PMID: 29506818 DOI: 10.1016/j.jdiacomp.2018.01.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 01/10/2018] [Accepted: 01/12/2018] [Indexed: 01/22/2023]
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) reflects an increased risk of developing type 2 diabetes (T2D) after pregnancy in women. Offspring born to mothers with GDM are at an elevated risk of obesity and T2D at a young age. Currently, there are lack of ways for identifying women in early pregnancy who are at risk of developing GDM. As a result, both mothers and fetus are not treated until late in the second trimester when GDM is diagnosed. The recent advance in metabolomics, a new approach of systematic investigation of the metabolites, provides an opportunity for early detection of GDM, and classifying the risk of subsequent chronic diseases among women and their offspring. METHODS We reviewed the literatures published in the past 20 years on studies using high-throughput metabolomics technologies to investigate women with GDM and their offspring. CONCLUSIONS Despite the inconsistent results, previous studies have identified biomarkers that involved in specific metabolite groups and several pathways, including amino acid metabolism, steroid hormone biosynthesis, glycerophospholipid metabolism, and fatty acid metabolism. However, most studies have small sample sizes. Further research is warranted to determine if metabolomics will result in new indicators for the diagnosis, management, and prognosis of GDM and related complications.
Collapse
Affiliation(s)
- Qian Chen
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangdong, China.
| | - Ellen Francis
- Department of Public Health Sciences, Clemson University, Clemson, SC, United States.
| | - Gang Hu
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States.
| | - Liwei Chen
- Department of Public Health Sciences, Clemson University, Clemson, SC, United States.
| |
Collapse
|
|
47
|
Abstract
Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and cardiac-specific metabolism that occur across a spectrum of cardiovascular disease states. Findings from metabolomics studies have contributed to better understanding of the metabolic changes that occur in heart failure and ischemic heart disease and have identified new cardiovascular disease biomarkers. As technologies advance, the metabolomics field continues to evolve rapidly. In this review, we will discuss the current state of metabolomics technologies, including consideration of various metabolomics platforms and elements of study design; the emerging utility of stable isotopes for metabolic flux studies; and the use of metabolomics to better understand specific cardiovascular diseases, with an emphasis on recent advances in the field.
Collapse
Affiliation(s)
- Robert W McGarrah
- From the Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute (R.W.M., S.B.C., G.F.Z., S.H.S., C.B.N.)
- Division of Cardiology (R.W.M., S.H.S.)
- Department of Medicine (R.W.M., G.F.Z., S.H.S., C.B.N.)
| | - Scott B Crown
- From the Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute (R.W.M., S.B.C., G.F.Z., S.H.S., C.B.N.)
| | - Guo-Fang Zhang
- From the Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute (R.W.M., S.B.C., G.F.Z., S.H.S., C.B.N.)
- Division of Endocrinology (G.F.Z., C.B.N.)
- Department of Medicine (R.W.M., G.F.Z., S.H.S., C.B.N.)
| | - Svati H Shah
- From the Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute (R.W.M., S.B.C., G.F.Z., S.H.S., C.B.N.)
- Division of Cardiology (R.W.M., S.H.S.)
- Department of Medicine (R.W.M., G.F.Z., S.H.S., C.B.N.)
| | - Christopher B Newgard
- From the Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute (R.W.M., S.B.C., G.F.Z., S.H.S., C.B.N.)
- Division of Endocrinology (G.F.Z., C.B.N.)
- Department of Medicine (R.W.M., G.F.Z., S.H.S., C.B.N.)
- Departments of Pharmacology and Cancer Biology (C.B.N.), Duke University Medical Center, Durham, NC
| |
Collapse
|
|
48
|
Fattuoni C, Mandò C, Palmas F, Anelli GM, Novielli C, Parejo Laudicina E, Savasi VM, Barberini L, Dessì A, Pintus R, Fanos V, Noto A, Cetin I. Preliminary metabolomics analysis of placenta in maternal obesity. Placenta 2017; 61:89-95. [PMID: 29277276 DOI: 10.1016/j.placenta.2017.11.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 11/23/2017] [Accepted: 11/27/2017] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Metabolomics identifies phenotypical groups with specific metabolic profiles, being increasingly applied to several pregnancy conditions. This is the first preliminary study analyzing placental metabolomics in normal weight (NW) and obese (OB) pregnancies. METHODS Twenty NW (18.5 ≤ BMI< 25 kg/m2) and eighteen OB (BMI≥ 30 kg/m2) pregnancies were studied. Placental biopsies were collected at elective caesarean section. Metabolites extraction method was optimized for hydrophilic and lipophilic phases, then analyzed with GC-MS. Univariate and PLS-DA multivariate analysis were applied. RESULTS Univariate analysis showed increased uracil levels while multivariate PLS-DA analysis revealed lower levels of LC-PUFA derivatives in the lipophilic phase and several metabolites with significantly different levels in the hydrophilic phase of OB vs NW. DISCUSSION Placental metabolome analysis of obese pregnancies showed differences in metabolites involved in antioxidant defenses, nucleotide production, as well as lipid synthesis and energy production, supporting a shift towards higher placental metabolism. OB placentas also showed a specific fatty acids profile suggesting a disruption of LC-PUFA biomagnification. This study can lay the foundation to further metabolomic placental characterization in maternal obesity. Metabolic signatures in obese placentas may reflect changes occurring in the intrauterine metabolic environment, which may affect the development of adult diseases.
Collapse
Affiliation(s)
- Claudia Fattuoni
- Department of Chemical and Geological Sciences, University of Cagliari, Italy
| | - Chiara Mandò
- Unit of Obstetrics and Gynecology, Hospital "L. Sacco" and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Italy
| | - Francesco Palmas
- Department of Chemical and Geological Sciences, University of Cagliari, Italy
| | - Gaia Maria Anelli
- Unit of Obstetrics and Gynecology, Hospital "L. Sacco" and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Italy
| | - Chiara Novielli
- Unit of Obstetrics and Gynecology, Hospital "L. Sacco" and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Italy
| | - Estefanìa Parejo Laudicina
- Centre of Excellence for Pediatric Research EURISTIKOS and Department of Pediatrics, School of Medicine, University of Granada, Granada, Spain
| | - Valeria Maria Savasi
- Unit of Obstetrics and Gynecology, Hospital "L. Sacco" and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Italy
| | - Luigi Barberini
- Department of Medical Sciences and Public Health, University of Cagliari, Italy
| | - Angelica Dessì
- Maternal-Neonatal Department, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOUCA University Hospital of Cagliari, Italy
| | - Roberta Pintus
- Maternal-Neonatal Department, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOUCA University Hospital of Cagliari, Italy
| | - Vassilios Fanos
- Maternal-Neonatal Department, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOUCA University Hospital of Cagliari, Italy
| | - Antonio Noto
- Maternal-Neonatal Department, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOUCA University Hospital of Cagliari, Italy
| | - Irene Cetin
- Unit of Obstetrics and Gynecology, Hospital "L. Sacco" and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Italy.
| |
Collapse
|
|
49
|
Metabolomics in gestational diabetes. Clin Chim Acta 2017; 475:116-127. [DOI: 10.1016/j.cca.2017.10.019] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 10/19/2017] [Accepted: 10/20/2017] [Indexed: 12/21/2022]
|
|
50
|
Perng W, Rifas-Shiman SL, McCulloch S, Chatzi L, Mantzoros C, Hivert MF, Oken E. Associations of cord blood metabolites with perinatal characteristics, newborn anthropometry, and cord blood hormones in project viva. Metabolism 2017; 76:11-22. [PMID: 28987236 PMCID: PMC5675164 DOI: 10.1016/j.metabol.2017.07.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 07/05/2017] [Accepted: 07/07/2017] [Indexed: 01/23/2023]
Abstract
CONTEXT Metabolomics has emerged as a powerful tool to characterize biomarkers and elucidate physiological processes underlying adverse health outcomes. Little is known of these relationships during gestation and infancy, which are critical period for development of metabolic disease risk. OBJECTIVES To identify cord blood metabolite patterns associated with birth size; and to investigate relations of the birth size-associated metabolite patterns, and a branched chain amino acid (BCAA) metabolite pattern with a range of newborn and perinatal characteristics. METHODS Using untargeted mass-spectrometry, we quantified metabolites in cord blood of 126 mother-child pairs. After excluding 103 xenobiotics, we used principal components analysis (PCA) to consolidate the remaining 606 metabolites into principal components ("factors"). Next, we identified factors associated with gestational age-and sex-standardized birthweight z-score (BW/GA) and examined associations of the BW/GA-associated pattern(s) and the BCAA pattern with cord blood insulin, leptin, adiponectin, insulin-like growth factor (IGF)-1, IGF-2, and IGF binding protein 3 (IGFBP-3) using multivariable linear regression. Finally, we examined associations of maternal/perinatal characteristics with the cord blood metabolite patterns. RESULTS Mean BW/GA z-score was 0.27±0.98 units. About half of the infants were male (52.4%) and white (57.1%). Of the 6 factors identified from PCA, one was associated with higher BW/GA: Factor 5, which comprised metabolites involved in energy production (malate, succinate, fumarate) and nucleotide turnover (inosine 5-monophosphate, adenosine 5-monophosphate, cytidine 5-monophosphate) pathways. In multivariable analysis, Factor 5 was related to higher cord blood leptin (1.64 [95% CI: 0.42, 2.87] ng/mL) and IGF-1 even after adjusting for IGFBP-3 (3.35 [0.25, 6.44] ng/mL). The BCAA pattern was associated with higher BW/GA (0.20 [0.03, 0.36] z-scores) and IGFBP-3 (106.5 [44.7, 168.2] ng/mL). No maternal characteristics were associated with either metabolite pattern; however, infants born via Cesarean delivery exhibited a higher score for Factor 5, and gestation length was inversely associated with the BCAA pattern. CONCLUSIONS Metabolites in energy production and DNA/RNA turnover pathways in cord blood are associated with larger size at birth, and higher leptin and IGF-1. Similarly, the BCAA pattern was associated with larger birth size and IGFBP-3.
Collapse
Affiliation(s)
- Wei Perng
- Department of Nutritional Sciences, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
| | - Sheryl L Rifas-Shiman
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School/Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | | | - Leda Chatzi
- Department of Social Medicine, Faculty of Medicine University of Crete, Heraklion, Greece; Department of Preventive Medicine, Keck School of Medicine, University of South California, Los Angeles, CA, USA; Department of Genetics & Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
| | - Christos Mantzoros
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Marie-France Hivert
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School/Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Emily Oken
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School/Harvard Pilgrim Health Care Institute, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| |
Collapse
|