|
1
|
Bobin P, Mitanchez D, Castellano B, Grit I, Moyon T, Raux A, Vambergue A, Winer N, Darmaun D, Michel C, Le Drean G, Alexandre-Gouabau MC. A specific metabolomic and lipidomic signature reveals the postpartum resolution of gestational diabetes mellitus or its evolution to type 2 diabetes in rat. Am J Physiol Endocrinol Metab 2025; 328:E493-E512. [PMID: 39947887 DOI: 10.1152/ajpendo.00396.2024] [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: 10/10/2024] [Revised: 11/11/2024] [Accepted: 02/01/2025] [Indexed: 04/01/2025]
Abstract
Gestational diabetes mellitus (GDM) represents a major public health concern due to adverse maternal postpartum and long-term outcomes. Current strategies to manage GDM fail to reduce the maternal risk to develop later impaired glucose tolerance (IGT) and type 2 diabetes (T2D). In a rodent model of diet-induced GDM without obesity, we explored the perinatal metabolic adaptations in dams with gestational IGT followed by either persistent or resolved postpartum IGT. Female Sprague-Dawley rats were fed a high-fat high-sucrose (HFHS) or a chow [control group (CTL)] diet, 1 wk before mating and throughout gestation (G). Following parturition, HFHS dams were randomized to two subgroups: one switched to a chow diet and the other one maintained on an HFHS diet throughout lactation (L). Oral glucose tolerance tests (OGTTs) were performed, and plasma metabolome-lipidome were characterized at G12 and L12. We found that 1) in GDM-pregnant dams, IGT was associated with incomplete fatty acid oxidation (FAO), enhanced gluconeogenesis, altered insulin signaling, and oxidative stress; 2) improved glucose tolerance postpartum seemed to restore complete FAO along with elevation of nervonic acid-containing sphingomyelins, assumed to impart β-cell protection; and 3) persistence of IGT after delivery was associated with metabolites known to predict the early onset of insulin and leptin resistance, with maintained liver dysfunction. Our findings shed light on the impact of postpartum IGT evolution on maternal metabolic outcome after an episode of GDM. They suggest innovative strategies, implemented shortly after delivery and targeted on these biomarkers, should be explored to curb or delay the transition from GDM to T2D in these mothers.NEW & NOTEWORTHY Specific metabolomic/lipidomic features are associated with GDM postpartum outcomes. GDM-pregnant dams exhibit partial fatty acid oxidation and boosted gluconeogenesis. Resolution of postpartum IGT relies on nervonic acid-sphingomyelin, a β-cell protector. Postpartum IGT persistence suggests muscle insulin resistance and liver dysfunction.
Collapse
Affiliation(s)
- Paul Bobin
- Nantes Université, INRAE, UMR1280 PhAN, Nantes, France
| | - Delphine Mitanchez
- Department of Neonatology, Bretonneau Hospital, François Rabelais University, Tours, France
- INSERM UMRS_938, Centre de Recherche Saint Antoine, Paris, France
| | | | - Isabelle Grit
- Nantes Université, INRAE, UMR1280 PhAN, Nantes, France
| | - Thomas Moyon
- Nantes Université, INRAE, UMR1280 PhAN, Nantes, France
| | - Axel Raux
- Oniris, INRAE, LABERCA, Nantes, France
| | - Anne Vambergue
- Department of Diabetology, Hospital Huriez, CHRU de Lille, University of Lille, EGID-UMR 8199, Lille, France
| | - Norbert Winer
- Nantes Université, INRAE, UMR1280 PhAN, Nantes, France
- Department of Obstetrics and Gynecology, CHU, Nantes University Hospital, Nantes, France
| | | | | | | | | |
Collapse
|
|
2
|
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
|
|
3
|
Zhao M, Yao Z, Zhang Y, Ma L, Pang W, Ma S, Xu Y, Wei L. Predictive value of machine learning for the progression of gestational diabetes mellitus to type 2 diabetes: a systematic review and meta-analysis. BMC Med Inform Decis Mak 2025; 25:18. [PMID: 39806461 PMCID: PMC11727323 DOI: 10.1186/s12911-024-02848-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/31/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND This systematic review aims to explore the early predictive value of machine learning (ML) models for the progression of gestational diabetes mellitus (GDM) to type 2 diabetes mellitus (T2DM). METHODS A comprehensive and systematic search was conducted in Pubmed, Cochrane, Embase, and Web of Science up to July 02, 2024. The quality of the studies included was assessed. The risk of bias was assessed through the prediction model risk of bias assessment tool and a graph was drawn accordingly. The meta-analysis was performed using Stata15.0. RESULTS A total of 13 studies were included in the present review, involving 11,320 GDM patients and 22 ML models. The meta-analysis for ML models showed a pooled C-statistic of 0.82 (95% CI: 0.79 ~ 0.86), a pooled sensitivity of 0.76 (0.72 ~ 0.80), and a pooled specificity of 0.57 (0.50 ~ 0.65). CONCLUSION ML has favorable diagnostic accuracy for the progression of GDM to T2DM. This provides evidence for the development of predictive tools with broader applicability.
Collapse
Affiliation(s)
- Meng Zhao
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China
| | - Zhixin Yao
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China
| | - Yan Zhang
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China
| | - Lidan Ma
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China
| | - Wenquan Pang
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China
| | - Shuyin Ma
- Department of Emergency Pediatric, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China
| | - Yijun Xu
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China.
| | - Lili Wei
- Department of Nursing, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, 266003, China.
| |
Collapse
|
|
4
|
Khan SR, Ye WW, Van JAD, Singh I, Rabiee Y, Rodricks KL, Zhang X, Nicholson RJ, Razani B, Summers SA, Futerman AH, Gunderson EP, Wheeler MB. Reduced circulating sphingolipids and CERS2 activity are linked to T2D risk and impaired insulin secretion. SCIENCE ADVANCES 2025; 11:eadr1725. [PMID: 39792658 PMCID: PMC11790001 DOI: 10.1126/sciadv.adr1725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 12/09/2024] [Indexed: 01/12/2025]
Abstract
Gestational diabetes mellitus (GDM), a transient form of diabetes that resolves postpartum, is a major risk factor for type 2 diabetes (T2D) in women. While the progression from GDM to T2D is not fully understood, it involves both genetic and environmental components. By integrating clinical, metabolomic, and genome-wide association study (GWAS) data, we identified associations between decreased sphingolipid biosynthesis and future T2D, in part through the rs267738 allele of the CERS2 gene in Hispanic women shortly after a GDM pregnancy. To understand the impact of the CERS2 gene and risk allele on glucose regulation, we examined whole-body Cers2 knockout and rs267738 knock-in mice. Both models exhibited glucose intolerance and impaired insulin secretion in vivo. Islets isolated from these models also demonstrated reduced β cell function, as shown by decreased insulin secretion ex vivo. Overall, reduced circulating sphingolipids may indicate a high risk of GDM-to-T2D progression and reflect deficits in CERS2 activity that negatively affect glucose homeostasis and β cell function.
Collapse
Affiliation(s)
- Saifur R. Khan
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
- VA Medical Center, Pittsburgh, PA, USA
- Center for Immunometabolism, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wenyue W. Ye
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Julie A. D. Van
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Ishnoor Singh
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Yasmin Rabiee
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | | | - Xiangyu Zhang
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
- VA Medical Center, Pittsburgh, PA, USA
- Center for Immunometabolism, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rebekah J. Nicholson
- Departments of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Babak Razani
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
- VA Medical Center, Pittsburgh, PA, USA
- Center for Immunometabolism, University of Pittsburgh, Pittsburgh, PA, USA
| | - Scott A. Summers
- Departments of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Anthony H. Futerman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Erica P. Gunderson
- Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
| | - Michael B. Wheeler
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
5
|
Lakey JRT, Casazza K, Lernhardt W, Mathur EJ, Jenkins I. Machine Learning and Augmented Intelligence Enables Prognosis of Type 2 Diabetes Prior to Clinical Manifestation. Curr Diabetes Rev 2025; 21:e010224226610. [PMID: 38303524 DOI: 10.2174/0115733998276990240117113408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 12/07/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024]
Abstract
BACKGROUND The global incidence of type 2 diabetes (T2D) persists at epidemic proportions. Early diagnosis and/or preventive efforts are critical to attenuate the multi-systemic clinical manifestation and consequent healthcare burden. Despite enormous strides in the understanding of pathophysiology and on-going therapeutic development, effectiveness and access are persistent limitations. Among the greatest challenges, the extensive research efforts have not promulgated reliable predictive biomarkers for early detection and risk assessment. The emerging fields of multi-omics combined with machine learning (ML) and augmented intelligence (AI) have profoundly impacted the capacity for predictive, preventive, and personalized medicine. OBJECTIVE This paper explores the current challenges associated with the identification of predictive biomarkers for T2D and discusses potential actionable solutions for biomarker identification and validation. METHODS The articles included were collected from PubMed queries. The selected topics of inquiry represented a wide range of themes in diabetes biomarker prediction and prognosis. RESULTS The current criteria and cutoffs for T2D diagnosis are not optimal nor consider a myriad of contributing factors in terms of early detection. There is an opportunity to leverage AI and ML to significantly enhance the understanding of the underlying mechanisms of the disease and identify prognostic biomarkers. The innovative technologies being developed by GATC are expected to play a crucial role in this pursuit via algorithm training and validation, enabling comprehensive and in-depth analysis of complex biological systems. CONCLUSION GATC is an emerging leader guiding the establishment of a systems approach towards research and predictive, personalized medicine. The integration of these technologies with clinical data can contribute to a more comprehensive understanding of T2D, paving the way for precision medicine approaches and improved patient outcomes.
Collapse
Affiliation(s)
- Jonathan R T Lakey
- GATC Health, 2030 Main Street, Suite 660, Irvine, CA 92614, CA, USA
- Department of Surgery and Biomedical Engineering, University of California Irvine, Irvine, CA, USA
| | - Krista Casazza
- GATC Health, 2030 Main Street, Suite 660, Irvine, CA 92614, CA, USA
| | | | - Eric J Mathur
- GATC Health, 2030 Main Street, Suite 660, Irvine, CA 92614, CA, USA
| | - Ian Jenkins
- GATC Health, 2030 Main Street, Suite 660, Irvine, CA 92614, CA, USA
| |
Collapse
|
|
6
|
Liu L, Yang Q, Shen P, Wang J, Zheng Q, Zhang G, Jin B. Metabolic profiling identifies potential biomarkers associated with progression from gestational diabetes mellitus to prediabetes postpartum. J Biomed Res 2024; 38:1-13. [PMID: 39512103 DOI: 10.7555/jbr.38.20240267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024] Open
Abstract
The current study aims to identify potential metabolic biomarkers that predict the progression to prediabetes in women with a history of gestational diabetes mellitus (GDM). We constructed a prediabetes group ( n = 42) and a control group ( n = 40) based on a2-hour 75 g oral glucose tolerance test for women with a history of GDM from six weeks to six months postpartum, and collected their clinical data and biochemical test results. We performed the plasma metabolomics analysis of the subjects at the fasting and 2-hour post-load time points by using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). We found that the prediabetes group was older and had higher 2-hour post-load glucose levels during pregnancy than the control group. The metabolomic analysis identified 164 differential metabolites between the groups. Compared with the control group, 15 metabolites in the prediabetes group exhibited consistent change trends at both time points, including three increased and 12 decreased metabolites. By building a prediction model of the progression from GDM to prediabetes, we found a combination of three clinical markers yielded an area under thecurve (AUC) of 0.71 (95% confidence interval [CI], 0.60-0.82). We also assessed the discriminative power of the panel of 15 metabolites for distinguishing between postpartum prediabetes and normal glucose tolerance of the subjects at the fasting (AUC, 0.98; 95% CI, 0.94-1.00) and 2-hour post-load (AUC, 0.99; 95% CI, 0.97-1.00) time points. The metabolic pathway analysis indicated that energy metabolism and branched-chain amino acids played a role in the development of prediabetes in women with a history of GDM during early postpartum. In conclusion, this study identified potential metabolic biomarkers and pathways associated with the progression from GDM to prediabetes in the early postpartum period. A panel of 15 metabolites showed promising discriminative power for distinguishing between postpartum prediabetes and normal glucose tolerance. These findings provide insights into the underlying pathophysiology of this transition and suggest the feasibility of developing a metabolic profiling test for the early identification of women at high risk of prediabetes following GDM.
Collapse
Affiliation(s)
- Lenan Liu
- School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Qian Yang
- Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Panyuan Shen
- Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Junsong Wang
- Center of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China
| | - Qi Zheng
- Center of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China
| | - Guoying Zhang
- Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Bai Jin
- Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| |
Collapse
|
|
7
|
Yu J, Ren J, Ren Y, Wu Y, Zeng Y, Zhang Q, Xiao X. Using metabolomics and proteomics to identify the potential urine biomarkers for prediction and diagnosis of gestational diabetes. EBioMedicine 2024; 101:105008. [PMID: 38368766 PMCID: PMC10882130 DOI: 10.1016/j.ebiom.2024.105008] [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: 11/28/2023] [Revised: 01/22/2024] [Accepted: 01/30/2024] [Indexed: 02/20/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common metabolic complications during pregnancy, threatening both maternal and fetal health. Prediction and diagnosis of GDM is not unified. Finding effective biomarkers for GDM is particularly important for achieving early prediction, accurate diagnosis and timely intervention. Urine, due to its accessibility in large quantities, noninvasive collection and easy preparation, has become a good sample for biomarker identification. In recent years, a number of studies using metabolomics and proteomics approaches have identified differential expressed urine metabolites and proteins in GDM patients. In this review, we summarized these potential urine biomarkers for GDM prediction and diagnosis and elucidated their role in development of GDM.
Collapse
Affiliation(s)
- Jie Yu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Jing Ren
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yaolin Ren
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yifan Wu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yuan Zeng
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Qian Zhang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| |
Collapse
|
|
8
|
Rais N, Ved A, Ahmad R, Parveen A. Research-based Analytical Procedures to Evaluate Diabetic Biomarkers and Related Parameters: In Vitro and In Vivo Methods. Curr Diabetes Rev 2024; 20:e201023222417. [PMID: 37867271 DOI: 10.2174/0115733998252495231011182012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 08/24/2023] [Accepted: 09/08/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND The degenerative tendency of diabetes leads to micro- and macrovascular complications due to abnormal levels of biochemicals, particularly in patients with poor diabetic control. Diabetes is supposed to be treated by reducing blood glucose levels, scavenging free radicals, and maintaining other relevant parameters close to normal ranges. In preclinical studies, numerous in vivo trials on animals as well as in vitro tests are used to assess the antidiabetic and antioxidant effects of the test substances. Since a substance that performs poorly in vitro won't perform better in vivo, the outcomes of in vitro studies can be utilized as a direct indicator of in vivo activities. OBJECTIVE The objective of the present study is to provide research scholars with a comprehensive overview of laboratory methods and procedures for a few selected diabetic biomarkers and related parameters. METHOD The search was conducted on scientific database portals such as ScienceDirect, PubMed, Google Scholar, BASE, DOAJ, etc. Conclusion: The development of new biomarkers is greatly facilitated by modern technology such as cell culture research, lipidomics study, microRNA biomarkers, machine learning techniques, and improved electron microscopies. These biomarkers do, however, have some usage restrictions. There is a critical need to find more accurate and sensitive biomarkers. With a few modifications, these biomarkers can be used with or even replace conventional markers of diabetes.
Collapse
Affiliation(s)
- Nadeem Rais
- Department of Pharmacy, Bhagwant University, Ajmer, Rajasthan 305004, India
| | - Akash Ved
- Goel Institute of Pharmaceutical Sciences, Lucknow, Uttar Pradesh 226028, India
| | - Rizwan Ahmad
- Department of Pharmacy, Vivek College of Technical Education, Bijnor, Uttar Pradesh 246701, India
| | - Aashna Parveen
- Faculty of Applied Science, Bhagwant Global University, Kotdwar, Uttarakhand 246149, India
| |
Collapse
|
|
9
|
Khan SS, Petito LC, Huang X, Harrington K, McNeil RB, Bello NA, Merz CNB, Miller EC, Ravi R, Scifres C, Catov J, Pemberton V, Varagic J, Zee PC, Yee LM, Ray M, Kim JK, Lane-Cordova A, Lewey J, Theilen LH, Saade GR, Greenland P, Grobman WA. Body Mass Index, Adverse Pregnancy Outcomes, and Cardiovascular Disease Risk. Circ Res 2023; 133:725-735. [PMID: 37814889 PMCID: PMC10578703 DOI: 10.1161/circresaha.123.322762] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 09/08/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND Obesity is a well-established risk factor for both adverse pregnancy outcomes (APOs) and cardiovascular disease (CVD). However, it is not known whether APOs are mediators or markers of the obesity-CVD relationship. This study examined the association between body mass index, APOs, and postpartum CVD risk factors. METHODS The sample included adults from the nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be) Heart Health Study who were enrolled in their first trimester (6 weeks-13 weeks 6 days gestation) from 8 United States sites. Participants had a follow-up visit at 3.7 years postpartum. APOs, which included hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and gestational diabetes, were centrally adjudicated. Mediation analyses estimated the association between early pregnancy body mass index and postpartum CVD risk factors (hypertension, hyperlipidemia, and diabetes) and the proportion mediated by each APO adjusted for demographics and baseline health behaviors, psychosocial stressors, and CVD risk factor levels. RESULTS Among 4216 participants enrolled, mean±SD maternal age was 27±6 years. Early pregnancy prevalence of overweight was 25%, and obesity was 22%. Hypertensive disorders of pregnancy occurred in 15%, preterm birth in 8%, small-for-gestational-age birth in 11%, and gestational diabetes in 4%. Early pregnancy obesity, compared with normal body mass index, was associated with significantly higher incidence of postpartum hypertension (adjusted odds ratio, 1.14 [95% CI, 1.10-1.18]), hyperlipidemia (1.11 [95% CI, 1.08-1.14]), and diabetes (1.03 [95% CI, 1.01-1.04]) even after adjustment for baseline CVD risk factor levels. APOs were associated with higher incidence of postpartum hypertension (1.97 [95% CI, 1.61-2.40]) and hyperlipidemia (1.31 [95% CI, 1.03-1.67]). Hypertensive disorders of pregnancy mediated a small proportion of the association between obesity and incident hypertension (13% [11%-15%]) and did not mediate associations with incident hyperlipidemia or diabetes. There was no significant mediation by preterm birth or small-for-gestational-age birth. CONCLUSIONS There was heterogeneity across APO subtypes in their association with postpartum CVD risk factors and mediation of the association between early pregnancy obesity and postpartum CVD risk factors. However, only a small or nonsignificant proportion of the association between obesity and CVD risk factors was mediated by any of the APOs, suggesting APOs are a marker of prepregnancy CVD risk and not a predominant cause of postpartum CVD risk.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Rupa Ravi
- Columbia University Irving Medical Center
| | | | | | | | | | | | - Lynn M Yee
- Northwestern University Feinberg School of Medicine
| | - Mitali Ray
- University of Pittsburgh School of Medicine
| | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Ye S, Hu YP, Zhou Q, Zhang H, Xia ZZ, Zhao SZ, Wang Z, Wang SY, Wang XY, Zhang YK, Chen ZD, Mao GY, Zheng C. Lipidomics Profiling Reveals Serum Phospholipids Associated with Albuminuria in Early Type 2 Diabetic Kidney Disease. ACS OMEGA 2023; 8:36543-36552. [PMID: 37810655 PMCID: PMC10552467 DOI: 10.1021/acsomega.3c05504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/06/2023] [Indexed: 10/10/2023]
Abstract
Early screening and administration of DKD are beneficial for renal outcomes of type 2 diabetic patients. However, the current early diagnosis using the albuminuria/creatine ratio (ACR) contains limitations. This study aimed to compare serum lipidome variation between type 2 diabetes and early DKD patients with increased albuminuria through an untargeted lipidomics method to explore the potential lipid biomarkers for DKD identification. 92 type 2 diabetic patients were enrolled and divided into two groups: DM group (ACR < 3 mg/mmol, n = 49) and early DKD group (3 mg/mmol ≤ ACR < 30 mg/mmol, n = 43). Fasting serum was analyzed through an ultraperformance liquid mass spectrometry tandem chromatography system (LC-MS). Orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate and multivariate analysis were performed to filter differentially depressed lipids. Receiver operating characteristic (ROC) curves were used to estimate the diagnostic capability of potential lipid biomarkers. We found that serum phospholipids including phosphatidylserine (PS), sphingomyelin (SM), and phosphatidylcholine (PC) were significantly upregulated in the DKD group and were highly correlated with the ACR. In addition, a panel of two phospholipids including PS(27:0)-H and PS(30:2e)-H showed good performance to help clinical lipids in early DKD identification, which increased the area under the curve (AUC) from 0.568 to 0.954. The study exhibited the serum lipidome variation in early DKD patients, and the increased phospholipids might participate in the development of albuminuria. The panel of PS(27:0)-H and PS(30:2e)-H could be a potential biomarker for DKD diagnosis.
Collapse
Affiliation(s)
- Shu Ye
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Ye-peng Hu
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Qiao Zhou
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Hang Zhang
- Diabetes
Center and Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital
of Wenzhou Medical University, Wenzhou 325027, China
| | - Zhe-zheng Xia
- Center
on Evidence-Based Medicine & Clinical Epidemiological Research,
School of Public Health, Wenzhou Medical
University, Wenzhou 325035, China
| | - Shu-zhen Zhao
- Center
on Evidence-Based Medicine & Clinical Epidemiological Research,
School of Public Health, Wenzhou Medical
University, Wenzhou 325035, China
| | - Zhe Wang
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Sheng-yao Wang
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Xin-yi Wang
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Yi-kai Zhang
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Zhi-da Chen
- Department
of Nephrology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
| | - Guang-yun Mao
- Center
on Evidence-Based Medicine & Clinical Epidemiological Research,
School of Public Health, Wenzhou Medical
University, Wenzhou 325035, China
| | - Chao Zheng
- Department
of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China
- Diabetes
Center and Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital
of Wenzhou Medical University, Wenzhou 325027, China
| |
Collapse
|
|
11
|
Khan SR, Obersterescu A, Gunderson EP, Razani B, Wheeler MB, Cox BJ. metGWAS 1.0: an R workflow for network-driven over-representation analysis between independent metabolomic and meta-genome-wide association studies. Bioinformatics 2023; 39:btad523. [PMID: 37610350 PMCID: PMC10491949 DOI: 10.1093/bioinformatics/btad523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 07/15/2023] [Accepted: 08/22/2023] [Indexed: 08/24/2023] Open
Abstract
MOTIVATION The method of genome-wide association studies (GWAS) and metabolomics combined provide an quantitative approach to pinpoint metabolic pathways and genes linked to specific diseases; however, such analyses require both genomics and metabolomics datasets from the same individuals/samples. In most cases, this approach is not feasible due to high costs, lack of technical infrastructure, unavailability of samples, and other factors. Therefore, an unmet need exists for a bioinformatics tool that can identify gene loci-associated polymorphic variants for metabolite alterations seen in disease states using standalone metabolomics. RESULTS Here, we developed a bioinformatics tool, metGWAS 1.0, that integrates independent GWAS data from the GWAS database and standalone metabolomics data using a network-based systems biology approach to identify novel disease/trait-specific metabolite-gene associations. The tool was evaluated using standalone metabolomics datasets extracted from two metabolomics-GWAS case studies. It discovered both the observed and novel gene loci with known single nucleotide polymorphisms when compared to the original studies. AVAILABILITY AND IMPLEMENTATION The developed metGWAS 1.0 framework is implemented in an R pipeline and available at: https://github.com/saifurbd28/metGWAS-1.0.
Collapse
Affiliation(s)
- Saifur R Khan
- Department of Medicine (Cardiology), University of Pittsburgh, Pittsburgh, PA 15261, United States
- University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
- Pittsburgh VA Medical Center, Pittsburgh, PA 15240, United States
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Toronto General Research Institute (Advanced Diagnostics), Toronto, ON M5G 2C4, Canada
| | | | - Erica P Gunderson
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, United States
- Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA 91101, United States
| | - Babak Razani
- Department of Medicine (Cardiology), University of Pittsburgh, Pittsburgh, PA 15261, United States
- University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
- Pittsburgh VA Medical Center, Pittsburgh, PA 15240, United States
| | - Michael B Wheeler
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Toronto General Research Institute (Advanced Diagnostics), Toronto, ON M5G 2C4, Canada
| | - Brian J Cox
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Obstetrics and Gynaecology, University of Toronto, ON M5G 1E2, Canada
| |
Collapse
|
|
12
|
Belsti Y, Moran L, Handiso DW, Versace V, Goldstein R, Mousa A, Teede H, Enticott J. Models Predicting Postpartum Glucose Intolerance Among Women with a History of Gestational Diabetes Mellitus: a Systematic Review. Curr Diab Rep 2023; 23:231-243. [PMID: 37294513 PMCID: PMC10435618 DOI: 10.1007/s11892-023-01516-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/22/2023] [Indexed: 06/10/2023]
Abstract
PURPOSE OF REVIEW Despite the crucial role that prediction models play in guiding early risk stratification and timely intervention to prevent type 2 diabetes after gestational diabetes mellitus (GDM), their use is not widespread in clinical practice. The purpose of this review is to examine the methodological characteristics and quality of existing prognostic models predicting postpartum glucose intolerance following GDM. RECENT FINDINGS A systematic review was conducted on relevant risk prediction models, resulting in 15 eligible publications from research groups in various countries. Our review found that traditional statistical models were more common than machine learning models, and only two were assessed to have a low risk of bias. Seven were internally validated, but none were externally validated. Model discrimination and calibration were done in 13 and four studies, respectively. Various predictors were identified, including body mass index, fasting glucose concentration during pregnancy, maternal age, family history of diabetes, biochemical variables, oral glucose tolerance test, use of insulin in pregnancy, postnatal fasting glucose level, genetic risk factors, hemoglobin A1c, and weight. The existing prognostic models for glucose intolerance following GDM have various methodological shortcomings, with only a few models being assessed to have low risk of bias and validated internally. Future research should prioritize the development of robust, high-quality risk prediction models that follow appropriate guidelines, in order to advance this area and improve early risk stratification and intervention for glucose intolerance and type 2 diabetes among women who have had GDM.
Collapse
Affiliation(s)
- Yitayeh Belsti
- Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Lisa Moran
- Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Demelash Woldeyohannes Handiso
- Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Vincent Versace
- Deakin Rural Health, School of Medicine, Deakin University, Warrnambool, Australia
| | - Rebecca Goldstein
- Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Monash Health, Clayton, Melbourne, Australia
| | - Aya Mousa
- Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Helena Teede
- Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Monash Health, Clayton, Melbourne, Australia
| | - Joanne Enticott
- Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
| |
Collapse
|
|
13
|
Khan SR, Rost H, Cox B, Razani B, Alexeeff S, Wheeler MB, Gunderson EP. Heterogeneity in Early Postpartum Metabolic Profiles Among Women with GDM Who Progressed to Type 2 Diabetes During 10-Year Follow-Up: The SWIFT Study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.06.13.23291346. [PMID: 37398098 PMCID: PMC10312884 DOI: 10.1101/2023.06.13.23291346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
GDM is a strong risk factor for progression to T2D after pregnancy. Although both GDM and T2D exhibit heterogeneity, the link between the distinct heterogeneity of GDM and incident T2D has not been established. Herein, we evaluate early postpartum profiles of women with recent GDM who later developed incident T2D using a soft clustering method, followed by the integration of both clinical phenotypic variables and metabolomics to characterize these heterogeneous clusters/groups clinically and their molecular mechanisms. We identified three clusters based on two indices of glucose homeostasis at 6-9 weeks postpartum - HOMA-IR and HOMA-B among women who developed incident T2D during the 12-year follow-up. The clusters were classified as follows: pancreatic beta-cell dysfunction group (cluster-1), insulin resistant group (cluster-3), and a combination of both phenomena (cluster-2) comprising the majority of T2D. We also identified postnatal blood test parameters to distinguish the three clusters for clinical testing. Moreover, we compared these three clusters in their metabolomics profiles at the early stage of the disease to identify the mechanistic insights. A significantly higher concentration of a metabolite at the early stage of a T2D cluster than other clusters indicates its essentiality for the particular disease character. As such, the early-stage characters of T2D cluster-1 pathology include a higher concentration of sphingolipids, acyl-alkyl phosphatidylcholines, lysophosphatidylcholines, and glycine, indicating their essentiality for pancreatic beta-cell function. In contrast, the early-stage characteristics of T2D cluster-3 pathology include a higher concentration of diacyl phosphatidylcholines, acyl-carnitines, isoleucine, and glutamate, indicating their essentiality for insulin actions. Notably, all these biomolecules are found in the T2D cluster-2 with mediocre concentrations, indicating a true nature of a mixed group. In conclusion, we have deconstructed incident T2D heterogeneity and identified three clusters with their clinical testing procedures and molecular mechanisms. This information will aid in adopting proper interventions using a precision medicine approach.
Collapse
Affiliation(s)
- Saifur R Khan
- Department of Cardiology, University of Pittsburgh, PA, USA
- Vascular Medicine Institute, University of Pittsburgh, PA, USA
- Departments of Physiology and Medicine, University of Toronto, Ontario, Canada
| | - Hannes Rost
- Donnelly Centre, University of Toronto, Ontario, Canada
| | - Brian Cox
- Department of Obstetrics and Gynaecology, University of Toronto, Ontario, Canada
| | - Babak Razani
- Department of Cardiology, University of Pittsburgh, PA, USA
- Vascular Medicine Institute, University of Pittsburgh, PA, USA
| | - Stacey Alexeeff
- Kaiser Permanente Northern California, Division of Research, Oakland, CA
| | - Michael B Wheeler
- Departments of Physiology and Medicine, University of Toronto, Ontario, Canada
| | - Erica P Gunderson
- Kaiser Permanente Northern California, Division of Research, Oakland, CA
- Kaiser Permanente Bernard J. Tyson School of Medicine, Department of Health Systems Science, Pasadena, CA
| |
Collapse
|
|
14
|
Wang G, Buckley JP, Bartell TR, Hong X, Pearson C, Wang X. Gestational Diabetes Mellitus, Postpartum Lipidomic Signatures, and Subsequent Risk of Type 2 Diabetes: A Lipidome-Wide Association Study. Diabetes Care 2023; 46:1223-1230. [PMID: 37043831 PMCID: PMC10234741 DOI: 10.2337/dc22-1841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 03/16/2023] [Indexed: 04/14/2023]
Abstract
OBJECTIVE To identify a postpartum lipidomic signature associated with gestational diabetes mellitus (GDM) and investigate the role of the identified lipids in the progression to type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This prospective cohort study enrolled 1,409 women at 24-72 h after delivery of a singleton baby and followed them prospectively at the Boston Medical Center. The lipidome was profiled by liquid chromatography-tandem mass spectrometry. Diagnoses of GDM and incident T2D were extracted from medical records and verified using plasma glucose levels. RESULTS Mean (SD) age of study women at baseline was 28.5 (6.6) years. A total of 219 (16.4%) women developed incident diabetes over a median follow-up of 11.8 (interquartile range 8.2-14.8) years. We identified 33 postpartum lipid species associated with GDM, including 16 inverse associations (primarily cholesterol esters and phosphatidylcholine plasmalogens), and 17 positive associations (primarily diacyglycerols and triacyglycerols). Of these, four were associated with risk of incident T2D and mediated ∼12% of the progression from GDM to T2D. The identified lipid species modestly improved the predictive performance for incident T2D above classical risk factors when the entire follow-up period was considered. CONCLUSIONS GDM was associated with a wide range of lipid metabolic alterations at early postpartum, among which some lipid species were also associated with incident T2D and mediated the progression from GDM to T2D. The improvements attained by including lipid species in the prediction of T2D provides new insights regarding the early detection and prevention of progression to T2D.
Collapse
Affiliation(s)
- Guoying Wang
- Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Jessie P. Buckley
- Department of Environmental Health and Engineering, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Tami R. Bartell
- Patrick M. Magoon Institute for Healthy Communities, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
| | - Xiumei Hong
- Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Colleen Pearson
- Department of Pediatrics, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA
| | - Xiaobin Wang
- Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
| |
Collapse
|
|
15
|
Liu H, Ju A, Dong X, Luo Z, Tang J, Ma B, Fu Y, Luo Y. Young and undamaged recombinant albumin alleviates T2DM by improving hepatic glycolysis through EGFR and protecting islet β cells in mice. J Transl Med 2023; 21:89. [PMID: 36747238 PMCID: PMC9903539 DOI: 10.1186/s12967-023-03957-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Albumin is the most abundant protein in serum and serves as a transporter of free fatty acids (FFA) in blood vessels. In type 2 diabetes mellitus (T2DM) patients, the reduced serum albumin level is a risk factor for T2DM development and progression, although this conclusion is controversial. Moreover, there is no study on the effects and mechanisms of albumin administration to relieve T2DM. We examined whether the administration of young and undamaged recombinant albumin can alleviate T2DM in mice. METHODS The serum albumin levels and metabolic phenotypes including fasting blood glucose, glucose tolerance tests, and glucose-stimulated insulin secretion were studied in db/db mice or diet-induced obesity mice treated with saline or young, undamaged, and ultrapure rMSA. Apoptosis assays were performed at tissue and cell levels to determine the function of rMSA on islet β cell protection. Metabolic flux and glucose uptake assays were employed to investigate metabolic changes in saline-treated or rMSA-treated mouse hepatocytes and compared their sensitivity to insulin treatments. RESULTS In this study, treatment of T2DM mice with young, undamaged, and ultrapure recombinant mouse serum albumin (rMSA) increased their serum albumin levels, which resulted in a reversal of the disease including reduced fasting blood glucose levels, improved glucose tolerance, increased glucose-stimulated insulin secretion, and alleviated islet atrophy. At the cellular level, rMSA improved glucose uptake and glycolysis in hepatocytes. Mechanistically, rMSA reduced the binding between CAV1 and EGFR to increase EGFR activation leading to PI3K-AKT activation. Furthermore, rMSA extracellularly reduced the rate of fatty acid uptake by islet β-cells, which relieved the accumulation of intracellular ceramide, endoplasmic reticulum stress, and apoptosis. This study provided the first clear demonstration that injections of rMSA can alleviate T2DM in mice. CONCLUSION Our study demonstrates that increasing serum albumin levels can promote glucose homeostasis and protect islet β cells, which alleviates T2DM.
Collapse
Affiliation(s)
- Hongyi Liu
- grid.12527.330000 0001 0662 3178School of Life Sciences, Tsinghua University, Beijing, 100084 China ,grid.452723.50000 0004 7887 9190Tsinghua-Peking Joint Center for Life Sciences, Beijing, 100084 China ,The National Engineering Research Center for Protein Technology, Beijing, 100084 China ,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084 China
| | - Anji Ju
- grid.12527.330000 0001 0662 3178School of Life Sciences, Tsinghua University, Beijing, 100084 China ,The National Engineering Research Center for Protein Technology, Beijing, 100084 China ,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084 China
| | - Xuan Dong
- grid.12527.330000 0001 0662 3178School of Life Sciences, Tsinghua University, Beijing, 100084 China ,The National Engineering Research Center for Protein Technology, Beijing, 100084 China ,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084 China
| | - Zongrui Luo
- grid.12527.330000 0001 0662 3178School of Life Sciences, Tsinghua University, Beijing, 100084 China ,The National Engineering Research Center for Protein Technology, Beijing, 100084 China ,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084 China
| | - Jiaze Tang
- grid.12527.330000 0001 0662 3178School of Life Sciences, Tsinghua University, Beijing, 100084 China ,The National Engineering Research Center for Protein Technology, Beijing, 100084 China ,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084 China
| | - Boyuan Ma
- grid.12527.330000 0001 0662 3178School of Life Sciences, Tsinghua University, Beijing, 100084 China ,The National Engineering Research Center for Protein Technology, Beijing, 100084 China ,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084 China
| | - Yan Fu
- School of Life Sciences, Tsinghua University, Beijing, 100084, China. .,The National Engineering Research Center for Protein Technology, Beijing, 100084, China. .,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084, China. .,School of Life Sciences, Tsinghua University, Beijing, 100084, China.
| | - Yongzhang Luo
- School of Life Sciences, Tsinghua University, Beijing, 100084, China. .,Tsinghua-Peking Joint Center for Life Sciences, Beijing, 100084, China. .,The National Engineering Research Center for Protein Technology, Beijing, 100084, China. .,Beijing Key Laboratory for Protein Therapeutics, Beijing, 100084, China. .,School of Life Sciences, Tsinghua University, Beijing, 100084, China.
| |
Collapse
|
|
16
|
Abstract
PURPOSE OF REVIEW Epidemiological and mechanistic studies have reported relationships between blood lipids, mostly measured by traditional method in clinical settings, and gestational diabetes mellitus (GDM). Recent advances of high-throughput lipidomics techniques have made available more comprehensive lipid profiling in biological samples. This review aims to summarize evidence from prospective studies in assessing relations between blood lipids and GDM, and discuss potential underlying mechanisms. RECENT FINDINGS Mass spectrometry and nuclear magnetic resonance spectroscopy-based analytical platforms are extensively used in lipidomics research. Epidemiological studies have identified multiple novel lipidomic biomarkers that are associated with risk of GDM, such as certain types of fatty acids, glycerolipids, glycerophospholipids, sphingolipids, cholesterol, and lipoproteins. However, the findings are inconclusive mainly due to the heterogeneities in study populations, sample sizes, and analytical platforms. Mechanistic evidence indicates that abnormal lipid metabolism may be involved in the pathogenesis of GDM by impairing pancreatic β-cells and inducing insulin resistance through several etiologic pathways, such as inflammation and oxidative stress. SUMMARY Lipidomics is a powerful tool to study pathogenesis and biomarkers for GDM. Lipidomic biomarkers and pathways could help to identify women at high risk for GDM and could be potential targets for early prevention and intervention of GDM.
Collapse
Affiliation(s)
- Yi Wang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Xiong-Fei Pan
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University
- Shuangliu Institute of Women's and Children's Health, Shuangliu Maternal and Child Health Hospital, Chengdu, China
| | - An Pan
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| |
Collapse
|
|
17
|
Hasbullah FY, Yusof BNM, Ghani RA, Daud Z’AM, Appannah G, Abas F, Shafie NH, Khir HIM, Murphy HR. Dietary Patterns, Metabolomic Profile, and Nutritype Signatures Associated with Type 2 Diabetes in Women with Postgestational Diabetes Mellitus: MyNutritype Study Protocol. Metabolites 2022; 12:metabo12090843. [PMID: 36144247 PMCID: PMC9503098 DOI: 10.3390/metabo12090843] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/26/2022] [Accepted: 09/02/2022] [Indexed: 11/20/2022] Open
Abstract
Women with previous gestational diabetes mellitus (post-GDM) have an increased risk of cardiometabolic diseases including type 2 diabetes (T2D). Current diabetes screening is based on the oral glucose tolerance test without nutritional assessments, even though unhealthy dietary patterns were found to expedite disease progression in women post-GDM. While a healthful dietary pattern reduces T2D risk, limited data support a dietary pattern tailored to the Asian population, especially in the Malaysian context. Metabolomic profiles associated with dietary patterns in this population are also lacking. The proposed study aims to investigate both components of dietary patterns and metabolomic profile, known as nutritype signatures, and their association with T2D in women post-GDM. The comparative cross-sectional study will involve a minimum of 126 Malaysian women post-GDM aged 18–49 years. Dietary patterns will be analysed using principal component analysis. Plasma and urinary metabolites will be quantified using one-dimensional proton nuclear magnetic resonance (1H NMR) spectroscopy. The aim of the study is identifying the nutritype signatures associated with T2D. The findings will support the development of early prevention measures against T2D in women post-GDM.
Collapse
Affiliation(s)
- Farah Yasmin Hasbullah
- Department of Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Barakatun-Nisak Mohd Yusof
- Department of Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Research Centre of Excellence for Nutrition and Non-Communicable Diseases, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Institute for Social Science Studies, Putra Infoport, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Correspondence: ; Tel.: +60-3-97692606
| | - Rohana Abdul Ghani
- Department of Internal Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
| | - Zulfitri ’Azuan Mat Daud
- Department of Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Geeta Appannah
- Department of Nutrition, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Faridah Abas
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Nurul Husna Shafie
- Department of Nutrition, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Hannah Izzati Mohamed Khir
- Department of Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Helen R. Murphy
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
| |
Collapse
|
|
18
|
Petrenko V, Sinturel F, Loizides-Mangold U, Montoya JP, Chera S, Riezman H, Dibner C. Type 2 diabetes disrupts circadian orchestration of lipid metabolism and membrane fluidity in human pancreatic islets. PLoS Biol 2022; 20:e3001725. [PMID: 35921354 PMCID: PMC9348689 DOI: 10.1371/journal.pbio.3001725] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/24/2022] [Indexed: 11/18/2022] Open
Abstract
Recent evidence suggests that circadian clocks ensure temporal orchestration of lipid homeostasis and play a role in pathophysiology of metabolic diseases in humans, including type 2 diabetes (T2D). Nevertheless, circadian regulation of lipid metabolism in human pancreatic islets has not been explored. Employing lipidomic analyses, we conducted temporal profiling in human pancreatic islets derived from 10 nondiabetic (ND) and 6 T2D donors. Among 329 detected lipid species across 8 major lipid classes, 5% exhibited circadian rhythmicity in ND human islets synchronized in vitro. Two-time point-based lipidomic analyses in T2D human islets revealed global and temporal alterations in phospho- and sphingolipids. Key enzymes regulating turnover of sphingolipids were rhythmically expressed in ND islets and exhibited altered levels in ND islets bearing disrupted clocks and in T2D islets. Strikingly, cellular membrane fluidity, measured by a Nile Red derivative NR12S, was reduced in plasma membrane of T2D diabetic human islets, in ND donors’ islets with disrupted circadian clockwork, or treated with sphingolipid pathway modulators. Moreover, inhibiting the glycosphingolipid biosynthesis led to strong reduction of insulin secretion triggered by glucose or KCl, whereas inhibiting earlier steps of de novo ceramide synthesis resulted in milder inhibitory effect on insulin secretion by ND islets. Our data suggest that circadian clocks operative in human pancreatic islets are required for temporal orchestration of lipid homeostasis, and that perturbation of temporal regulation of the islet lipid metabolism upon T2D leads to altered insulin secretion and membrane fluidity. These phenotypes were recapitulated in ND islets bearing disrupted clocks.
Collapse
Affiliation(s)
- Volodymyr Petrenko
- Thoracic and Endocrine Surgery Division, Department of Surgery, University Hospital of Geneva, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland
| | - Flore Sinturel
- Thoracic and Endocrine Surgery Division, Department of Surgery, University Hospital of Geneva, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland
| | - Ursula Loizides-Mangold
- Thoracic and Endocrine Surgery Division, Department of Surgery, University Hospital of Geneva, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland
| | - Jonathan Paz Montoya
- Proteomics Core Facility, EPFL, Lausanne, Switzerland
- Institute of Bioengineering, School of Life Sciences, EPFL, Lausanne, Switzerland
| | - Simona Chera
- Thoracic and Endocrine Surgery Division, Department of Surgery, University Hospital of Geneva, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Howard Riezman
- Department of Biochemistry, Faculty of Science, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Charna Dibner
- Thoracic and Endocrine Surgery Division, Department of Surgery, University Hospital of Geneva, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland
- * E-mail:
| |
Collapse
|
|
19
|
Qiu G, Wang H, Yan Q, Ma H, Niu R, Lei Y, Xiao Y, Zhou L, Yang H, Xu C, Zhang X, He M, Tang H, Hu Z, Pan A, Shen H, Wu T. A Lipid Signature with Perturbed Triacylglycerol Co-Regulation, Identified from Targeted Lipidomics, Predicts Risk for Type 2 Diabetes and Mediates the Risk from Adiposity in Two Prospective Cohorts of Chinese Adults. Clin Chem 2022; 68:1094-1107. [PMID: 35708664 DOI: 10.1093/clinchem/hvac090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/18/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND The roles of individual and co-regulated lipid molecular species in the development of type 2 diabetes (T2D) and mediation from metabolic risk factors remain unknown. METHODS We conducted profiling of 166 plasma lipid species in 2 nested case-control studies within 2 independent cohorts of Chinese adults, the Dongfeng-Tongji and the Jiangsu non-communicable disease cohorts. After 4.61 (0.15) and 7.57 (1.13) years' follow-up, 1039 and 520 eligible participants developed T2D in these 2 cohorts, respectively, and controls were 1:1 matched to cases by age and sex. RESULTS We found 27 lipid species, including 10 novel ones, consistently associated with T2D risk in the 2 cohorts. Differential correlation network analysis revealed significant correlations of triacylglycerol (TAG) 50:3, containing at least one oleyl chain, with 6 TAGs, at least 3 of which contain the palmitoyl chain, all downregulated within cases relative to controls among the 27 lipids in both cohorts, while the networks also both identified the oleyl chain-containing TAG 50:3 as the central hub. We further found that 13 of the 27 lipids consistently mediated the association between adiposity indicators (body mass index, waist circumference, and waist-to-height ratio) and diabetes risk in both cohorts (all P < 0.05; proportion mediated: 20.00%, 17.70%, and 17.71%, and 32.50%, 28.73%, and 33.86%, respectively). CONCLUSIONS Our findings suggested notable perturbed co-regulation, inferred from differential correlation networks, between oleyl chain- and palmitoyl chain-containing TAGs before diabetes onset, with the oleyl chain-containing TAG 50:3 at the center, and provided novel etiological insight regarding lipid dysregulation in the progression from adiposity to overt T2D.
Collapse
Affiliation(s)
- Gaokun Qiu
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hao Wang
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qi Yan
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongxia Ma
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Rundong Niu
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yanshou Lei
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yang Xiao
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lue Zhou
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Handong Yang
- Department of Cardiovascular Disease, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan 442008, China
| | - Chengwei Xu
- Department of Cardiovascular Disease, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan 442008, China
| | - Xiaomin Zhang
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Meian He
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huiru Tang
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China.,CAS Key Laboratory of Magnetic Resonance in Biological Systems, University of Chinese Academy of Sciences, Wuhan 430071, China
| | - Zhibin Hu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - An Pan
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongbing Shen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Tangchun Wu
- Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| |
Collapse
|
|
20
|
Abstract
A recent paper published in PLoS Biology reported the application of lipidomics in predicting the incidence of diabetes and cardiovascular diseases in a population cohort. The study is clearly remarkable in demonstrating the role of lipidomics in prediction of diseases and translational research. We believe it comes to an era with quantitative lipidomics.
Collapse
Affiliation(s)
- Xianlin Han
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
| |
Collapse
|
|
21
|
Alqahtani A. Application of Artificial Intelligence in Discovery and Development of Anticancer and Antidiabetic Therapeutic Agents. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:6201067. [PMID: 35509623 PMCID: PMC9060979 DOI: 10.1155/2022/6201067] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/17/2022] [Accepted: 04/05/2022] [Indexed: 11/18/2022]
Abstract
Spectacular developments in molecular and cellular biology have led to important discoveries in cancer research. Despite cancer is one of the major causes of morbidity and mortality globally, diabetes is one of the most leading sources of group of disorders. Artificial intelligence (AI) has been considered the fourth industrial revolution machine. The most major hurdles in drug discovery and development are the time and expenditures required to sustain the drug research pipeline. Large amounts of data can be explored and generated by AI, which can then be converted into useful knowledge. Because of this, the world's largest drug companies have already begun to use AI in their drug development research. In the present era, AI has a huge amount of potential for the rapid discovery and development of new anticancer drugs. Clinical studies, electronic medical records, high-resolution medical imaging, and genomic assessments are just a few of the tools that could aid drug development. Large data sets are available to researchers in the pharmaceutical and medical fields, which can be analyzed by advanced AI systems. This review looked at how computational biology and AI technologies may be utilized in cancer precision drug development by combining knowledge of cancer medicines, drug resistance, and structural biology. This review also highlighted a realistic assessment of the potential for AI in understanding and managing diabetes.
Collapse
Affiliation(s)
- Amal Alqahtani
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, 31541, Saudi Arabia
- Department of Basic Sciences, Deanship of Preparatory Year and Supporting Studies, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 34212, Saudi Arabia
| |
Collapse
|
|
22
|
Kawamura MY, Mau MK, Soon R, Yamasato K. A Scoping Review on Gestational Diabetes in Hawai'i: A "Window of Opportunity" to Address Intergenerational Risk for Type 2 Diabetes Mellitus. HAWAI'I JOURNAL OF HEALTH & SOCIAL WELFARE 2022; 81:58-70. [PMID: 35261986 PMCID: PMC8899083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The health of women over the entire span of their reproductive years is crucial - beginning in adolescence and extending through the postpartum period. This paper provides a scoping review of the relevant literature on risk factors for gestational diabetes mellitus (GDM) and progression from GDM to type 2 diabetes mellitus (T2DM), particularly among women of Native Hawaiian and Pacific Islander (NHPI) and Asian racial/ethnic backgrounds in Hawai'i, using the PubMed database (July 2010 to July 2020). NHPI and Asian populations have a greater likelihood of developing GDM compared to their White counterparts. Risk factors such as advanced maternal age, high maternal body mass index, and lack of education about GDM have varying levels of impact on GDM diagnosis between ethnic populations. Mothers who have a history of GDM are also at higher risk of developing T2DM. Common risk factors include greater increase in postpartum body mass index and use of diabetes medications during pregnancy. However, few studies investigate the progression from GDM to T2DM in Hawai'i's Asian and NHPI populations, and no studies present upstream preconception care programs to prevent an initial GDM diagnosis among Hawai'i's women. Thus, updated reports are necessary for optimal early interventions to prevent the onset of GDM and break the intergenerational cycle of increased susceptibility to T2DM and GDM in both mother and child. Further attention to the development of culturally sensitive interventions may reduce disparities in GDM and improve the health for all affected by this condition.
Collapse
Affiliation(s)
- Megan Y. Kawamura
- Department of Native Hawaiian Health Summer 2020 Research Intern, John A. Burns School of Medicine, University of Hawai‘i at Manoa, Honolulu, HI
| | - Marjorie K. Mau
- Department of Native Hawaiian Health, John A. Burns School of Medicine, University of Hawai‘i at Manoa, Honolulu, HI
| | - Reni Soon
- Department of Obstetrics, Gynecology and Women’s Health, John A. Burns School of Medicine, University of Hawai‘i at Manoa, Honolulu, HI
| | - Kelly Yamasato
- Department of Obstetrics, Gynecology and Women’s Health, John A. Burns School of Medicine, University of Hawai‘i at Manoa, Honolulu, HI
| |
Collapse
|
|
23
|
Ilari L, Piersanti A, Göbl C, Burattini L, Kautzky-Willer A, Tura A, Morettini M. Unraveling the Factors Determining Development of Type 2 Diabetes in Women With a History of Gestational Diabetes Mellitus Through Machine-Learning Techniques. Front Physiol 2022; 13:789219. [PMID: 35250610 PMCID: PMC8892139 DOI: 10.3389/fphys.2022.789219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a type of diabetes that usually resolves at the end of the pregnancy but exposes to a higher risk of developing type 2 diabetes mellitus (T2DM). This study aimed to unravel the factors, among those that quantify specific metabolic processes, which determine progression to T2DM by using machine-learning techniques. Classification of women who did progress to T2DM (labeled as PROG, n = 19) vs. those who did not (labeled as NON-PROG, n = 59) progress to T2DM has been performed by using Orange software through a data analysis procedure on a generated data set including anthropometric data and a total of 34 features, extracted through mathematical modeling/methods procedures. Feature selection has been performed through decision tree algorithm and then Naïve Bayes and penalized (L2) logistic regression were used to evaluate the ability of the selected features to solve the classification problem. Performance has been evaluated in terms of area under the operating receiver characteristics (AUC), classification accuracy (CA), precision, sensitivity, specificity, and F1. Feature selection provided six features, and based on them, classification was performed as follows: AUC of 0.795, 0.831, and 0.884; CA of 0.827, 0.813, and 0.840; precision of 0.830, 0.854, and 0.834; sensitivity of 0.827, 0.813, and 0.840; specificity of 0.700, 0.821, and 0.662; and F1 of 0.828, 0.824, and 0.836 for tree algorithm, Naïve Bayes, and penalized logistic regression, respectively. Fasting glucose, age, and body mass index together with features describing insulin action and secretion may predict the development of T2DM in women with a history of GDM.
Collapse
Affiliation(s)
- Ludovica Ilari
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Agnese Piersanti
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Christian Göbl
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Laura Burattini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Alexandra Kautzky-Willer
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andrea Tura
- Metabolic Unit, CNR Institute of Neuroscience, Padua, Italy
| | - Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
- *Correspondence: Micaela Morettini,
| |
Collapse
|
|
24
|
Han X, Gross RW. The foundations and development of lipidomics. J Lipid Res 2022; 63:100164. [PMID: 34953866 PMCID: PMC8953652 DOI: 10.1016/j.jlr.2021.100164] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/15/2022] Open
Abstract
For over a century, the importance of lipid metabolism in biology was recognized but difficult to mechanistically understand due to the lack of sensitive and robust technologies for identification and quantification of lipid molecular species. The enabling technological breakthroughs emerged in the 1980s with the development of soft ionization methods (Electrospray Ionization and Matrix Assisted Laser Desorption/Ionization) that could identify and quantify intact individual lipid molecular species. These soft ionization technologies laid the foundations for what was to be later named the field of lipidomics. Further innovative advances in multistage fragmentation, dramatic improvements in resolution and mass accuracy, and multiplexed sample analysis fueled the early growth of lipidomics through the early 1990s. The field exponentially grew through the use of a variety of strategic approaches, which included direct infusion, chromatographic separation, and charge-switch derivatization, which facilitated access to the low abundance species of the lipidome. In this Thematic Review, we provide a broad perspective of the foundations, enabling advances, and predicted future directions of growth of the lipidomics field.
Collapse
Affiliation(s)
- Xianlin Han
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Departments of Medicine - Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
| | - Richard W Gross
- Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Chemistry, Washington University, St. Louis, MO, USA
| |
Collapse
|
|
25
|
Juchnicka I, Kuźmicki M, Zabielski P, Krętowski A, Błachnio-Zabielska A, Szamatowicz J. Serum C18:1-Cer as a Potential Biomarker for Early Detection of Gestational Diabetes. J Clin Med 2022; 11:384. [PMID: 35054078 PMCID: PMC8781005 DOI: 10.3390/jcm11020384] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/29/2021] [Accepted: 01/10/2022] [Indexed: 01/27/2023] Open
Abstract
We hypothesized that sphingolipids may be early biomarkers of gestational diabetes mellitus (GDM). Here, 520 women with normal fasting plasma glucose levels were recruited in the first trimester and tested with a 75 g oral glucose tolerance test in the 24th-28th week of pregnancy. Serum sphingolipids concentrations were measured in the first and the second trimester by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC/MS/MS) in 53 patients who were diagnosed with GDM, as well as 82 pregnant women with normal glucose tolerance (NGT) and 32 non-pregnant women. In the first trimester, pregnant women showed higher concentrations of C16:0, C18:1, C22:0, C24:1, and C24:0-Cer and lower levels of sphinganine (SPA) and sphingosine-1-phosphate (S1P) compared to non-pregnant women. During pregnancy, we observed significant changes in C16:0, C18:0, C18:1, and C24:1-Cer levels in the GDM group and C18:1 and C24:0-Cer in NGT. The GDM (pre-conversion) and NGT groups in the first trimester differed solely in the levels of C18:1-Cer (AUC = 0.702 p = 0.008), also considering glycemia. Thus, C18:1-Cer revealed its potential as a GDM biomarker. Sphingolipids are known to be a modulator of insulin resistance, and our results indicate that ceramide measurements in early pregnancy may help with GDM screening.
Collapse
Affiliation(s)
- Ilona Juchnicka
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, 15-276 Bialystok, Poland; (I.J.); (J.S.)
| | - Mariusz Kuźmicki
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, 15-276 Bialystok, Poland; (I.J.); (J.S.)
| | - Piotr Zabielski
- Department of Medical Biology, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Adam Krętowski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland;
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Agnieszka Błachnio-Zabielska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Jacek Szamatowicz
- Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, 15-276 Bialystok, Poland; (I.J.); (J.S.)
| |
Collapse
|
|
26
|
Zhang Z, Piro AL, Dai FF, Wheeler MB. Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice. Front Endocrinol (Lausanne) 2022; 13:852149. [PMID: 35600586 PMCID: PMC9116578 DOI: 10.3389/fendo.2022.852149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Pregnancy is a dynamic state involving multiple metabolic adaptions in various tissues including the endocrine pancreas. However, a detailed characterization of the maternal islet metabolome in relation to islet function and the ambient circulating metabolome during pregnancy has not been established. METHODS A timed-pregnancy mouse model was studied, and age-matched non-pregnant mice were used as controls. Targeted metabolomics was applied to fasting plasma and purified islets during each trimester of pregnancy. Glucose homeostasis and islet function was assessed. Bioinformatic analyses were performed to reveal the metabolic adaptive changes in plasma and islets, and to identify key metabolic pathways associated with pregnancy. RESULTS Fasting glucose and insulin were found to be significantly lower in pregnant mice compared to non-pregnant controls, throughout the gestational period. Additionally, pregnant mice had superior glucose excursions and greater insulin response to an oral glucose tolerance test. Interestingly, both alpha and beta cell proliferation were significantly enhanced in early to mid-pregnancy, leading to significantly increased islet size seen in mid to late gestation. When comparing the plasma metabolome of pregnant and non-pregnant mice, phospholipid and fatty acid metabolism pathways were found to be upregulated throughout pregnancy, whereas amino acid metabolism initially decreased in early through mid pregnancy, but then increased in late pregnancy. Conversely, in islets, amino acid metabolism was consistently enriched throughout pregnancy, with glycerophospholid and fatty acid metabolism was only upregulated in late pregnancy. Specific amino acids (glutamate, valine) and lipids (acyl-alkyl-PC, diacyl-PC, and sphingomyelin) were found to be significantly differentially expressed in islets of the pregnant mice compared to controls, which was possibly linked to enhanced insulin secretion and islet proliferation. CONCLUSION Beta cell proliferation and function are elevated during pregnancy, and this is coupled to the enrichment of islet metabolites and metabolic pathways primarily associated with amino acid and glycerophospholipid metabolism. This study provides insight into metabolic adaptive changes in glucose homeostasis and islet function seen during pregnancy, which will provide a molecular rationale to further explore the regulation of maternal metabolism to avoid the onset of pregnancy disorders, including gestational diabetes.
Collapse
Affiliation(s)
- Ziyi Zhang
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Anthony L. Piro
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Feihan F. Dai
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- *Correspondence: Feihan F. Dai, ; Michael B. Wheeler,
| | - Michael B. Wheeler
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Metabolism Research Group, Division of Advanced Diagnostics, Toronto General Hospital Research Institute, Toronto, ON, Canada
- *Correspondence: Feihan F. Dai, ; Michael B. Wheeler,
| |
Collapse
|
|
27
|
Wang Y, Huang Y, Wu P, Ye Y, Sun F, Yang X, Lu Q, Yuan J, Liu Y, Zeng H, Song X, Yan S, Qi X, Yang CX, Lv C, Wu JHY, Liu G, Pan XF, Chen D, Pan A. Plasma lipidomics in early pregnancy and risk of gestational diabetes mellitus: a prospective nested case-control study in Chinese women. Am J Clin Nutr 2021; 114:1763-1773. [PMID: 34477820 DOI: 10.1093/ajcn/nqab242] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 06/28/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Lipid metabolism plays an important role in the pathogenesis of diabetes. There is little evidence regarding the prospective association of the maternal lipidome with gestational diabetes mellitus (GDM), especially in Chinese populations. OBJECTIVES We aimed to identify novel lipid species associated with GDM risk in Chinese women, and assess the incremental predictive capacity of the lipids for GDM. METHODS We conducted a nested case-control study using the Tongji-Shuangliu Birth Cohort with 336 GDM cases and 672 controls, 1:2 matched on age and week of gestation. Maternal blood samples were collected at 6-15 wk, and lipidomes were profiled by targeted ultra-HPLC-tandem MS. GDM was diagnosed by oral-glucose-tolerance test at 24-28 wk. The least absolute shrinkage and selection operator is a regression analysis method that was used to select novel biomarkers. Multivariable conditional logistic regression was used to estimate the associations. RESULTS Of 366 detected lipids, 10 were selected and found to be significantly associated with GDM independently of confounders: there were positive associations with phosphatidylinositol 40:6, alkylphosphatidylcholine 36:1, phosphatidylethanolamine plasmalogen 38:6, diacylglyceride 18:0/18:1, and alkylphosphatidylethanolamine 40:5 (adjusted ORs per 1 log-SD increment range: 1.34-2.86), whereas there were inverse associations with sphingomyelin 34:1, dihexosyl ceramide 24:0, mono hexosyl ceramide 18:0, dihexosyl ceramide 24:1, and phosphatidylcholine 40:7 (adjusted ORs range: 0.48-0.68). Addition of these novel lipids to the classical GDM prediction model resulted in a significant improvement in the C-statistic (discriminatory power of the model) to 0.801 (95% CI: 0.772, 0.829). For every 1-point increase in the lipid risk score of the 10 lipids, the OR of GDM was 1.66 (95% CI: 1.50, 1.85). Mediation analysis suggested the associations between specific lipid species and GDM were partially explained by glycemic and insulin-related indicators. CONCLUSIONS Specific plasma lipid biomarkers in early pregnancy were associated with GDM in Chinese women, and significantly improved the prediction for GDM.
Collapse
Affiliation(s)
- Yi Wang
- Department of Epidemiology & Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yichao Huang
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, Guangdong, China
| | - Ping Wu
- Department of Epidemiology & Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yi Ye
- Department of Epidemiology & Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fengjiang Sun
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, Guangdong, China
| | - Xue Yang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qi Lu
- Department of Epidemiology & Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiaying Yuan
- Department of Science and Education, Shuangliu Maternal and Child Health Hospital, Chengdu, Sichuan, China
| | - Yan Liu
- Department of Obstetrics and Gynecology, Shuangliu Maternal and Child Health Hospital, Chengdu, Sichuan, China
| | - Huayan Zeng
- Nutrition Department, Shuangliu Maternal and Child Health Hospital, Chengdu, Sichuan, China
| | - Xingyue Song
- Department of Emergency, Hainan Clinical Research Center for Acute and Critical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.,Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China
| | - Shijiao Yan
- Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China.,School of Public Health, Hainan Medical University, Haikou, Hainan, China
| | - Xiaorong Qi
- Department of Gynecology and Obstetrics, West China Second Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Chun-Xia Yang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chuanzhu Lv
- Department of Emergency, Hainan Clinical Research Center for Acute and Critical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.,Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan, China.,Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Jason H Y Wu
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Gang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiong-Fei Pan
- Department of Epidemiology & Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.,Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Da Chen
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, Guangdong, China
| | - An Pan
- Department of Epidemiology & Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
28
|
Gautier T, Ziegler LB, Gerber MS, Campos-Náñez E, Patek SD. Artificial intelligence and diabetes technology: A review. Metabolism 2021; 124:154872. [PMID: 34480920 DOI: 10.1016/j.metabol.2021.154872] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/27/2021] [Accepted: 08/28/2021] [Indexed: 12/15/2022]
Abstract
Artificial intelligence (AI) is widely discussed in the popular literature and is portrayed as impacting many aspects of human life, both in and out of the workplace. The potential for revolutionizing healthcare is significant because of the availability of increasingly powerful computational platforms and methods, along with increasingly informative sources of patient data, both in and out of clinical settings. This review aims to provide a realistic assessment of the potential for AI in understanding and managing diabetes, accounting for the state of the art in the methodology and medical devices that collect data, process data, and act accordingly. Acknowledging that many conflicting definitions of AI have been put forth, this article attempts to characterize the main elements of the field as they relate to diabetes, identifying the main perspectives and methods that can (i) affect basic understanding of the disease, (ii) affect understanding of risk factors (genetic, clinical, and behavioral) of diabetes development, (iii) improve diagnosis, (iv) improve understanding of the arc of disease (progression and personal/societal impact), and finally (v) improve treatment.
Collapse
Affiliation(s)
- Thibault Gautier
- Dexcom/TypeZero, 946 Grady Avenue, Suite 203, Charlottesville, VA 22903, United States of America.
| | - Leah B Ziegler
- Dexcom/TypeZero, 946 Grady Avenue, Suite 203, Charlottesville, VA 22903, United States of America
| | - Matthew S Gerber
- Dexcom/TypeZero, 946 Grady Avenue, Suite 203, Charlottesville, VA 22903, United States of America
| | - Enrique Campos-Náñez
- Dexcom/TypeZero, 946 Grady Avenue, Suite 203, Charlottesville, VA 22903, United States of America
| | - Stephen D Patek
- Dexcom/TypeZero, 946 Grady Avenue, Suite 203, Charlottesville, VA 22903, United States of America
| |
Collapse
|
|
29
|
Liu Y, Kuang A, Bain JR, Muehlbauer MJ, Ilkayeva OR, Lowe LP, Metzger BE, Newgard CB, Scholtens DM, Lowe WL. Maternal Metabolites Associated With Gestational Diabetes Mellitus and a Postpartum Disorder of Glucose Metabolism. J Clin Endocrinol Metab 2021; 106:3283-3294. [PMID: 34255031 PMCID: PMC8677596 DOI: 10.1210/clinem/dgab513] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Indexed: 12/15/2022]
Abstract
CONTEXT Gestational diabetes is associated with a long-term risk of developing a disorder of glucose metabolism. However, neither the metabolic changes characteristic of gestational diabetes in a large, multi-ancestry cohort nor the ability of metabolic changes during pregnancy, beyond glucose levels, to identify women at high risk for progression to a disorder of glucose metabolism has been examined. OBJECTIVE This work aims to identify circulating metabolites present at approximately 28 weeks' gestation associated with gestational diabetes mellitus (GDM) and development of a disorder of glucose metabolism 10 to 14 years later. METHODS Conventional clinical and targeted metabolomics analyses were performed on fasting and 1-hour serum samples following a 75-g glucose load at approximately 28 weeks' gestation from 2290 women who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Postpartum metabolic traits included fasting and 2-hour plasma glucose following a 75-g glucose load, insulin resistance estimated by the homeostasis model assessment of insulin resistance, and disorders of glucose metabolism (prediabetes and type 2 diabetes) during the HAPO Follow-Up Study. RESULTS Per-metabolite analyses identified numerous metabolites, ranging from amino acids and carbohydrates to fatty acids and lipids, before and 1-hour after a glucose load that were associated with GDM as well as development of a disorder of glucose metabolism and metabolic traits 10 to 14 years post partum. A core group of fasting and 1-hour metabolites mediated, in part, the relationship between GDM and postpartum disorders of glucose metabolism, with the fasting and 1-hour metabolites accounting for 15.7% (7.1%-30.8%) and 35.4% (14.3%-101.0%) of the total effect size, respectively. For prediction of a postpartum disorder of glucose metabolism, the addition of circulating fasting or 1-hour metabolites at approximately 28 weeks' gestation showed little improvement in prediction performance compared to clinical factors alone. CONCLUSION The results demonstrate an association of multiple metabolites with GDM and postpartum metabolic traits and begin to define the underlying pathophysiology of the transition from GDM to a postpartum disorder of glucose metabolism.
Collapse
Affiliation(s)
- Yu Liu
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P. R. China
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
| | - Alan Kuang
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
| | - James R Bain
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina 27705, USA
- Duke Molecular Physiology Institute, Durham, North Carolina 27701, USA
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27707, USA
| | - Michael J Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina 27705, USA
- Duke Molecular Physiology Institute, Durham, North Carolina 27701, USA
| | - Olga R Ilkayeva
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina 27705, USA
- Duke Molecular Physiology Institute, Durham, North Carolina 27701, USA
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27707, USA
| | - Lynn P Lowe
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
| | - Boyd E Metzger
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P. R. China
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina 27705, USA
- Duke Molecular Physiology Institute, Durham, North Carolina 27701, USA
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27707, USA
| | - Denise M Scholtens
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
| | - William L Lowe
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
- Correspondence: William L. Lowe Jr, MD, Department of Medicine, Northwestern University Feinberg School of Medicine, Rubloff 12, 420 E Superior St, Chicago, IL 60611, USA.
| |
Collapse
|
|
30
|
Liu Y, Wang Z, Zhao L. Identification of diagnostic cytosine-phosphate-guanine biomarkers in patients with gestational diabetes mellitus via epigenome-wide association study and machine learning. Gynecol Endocrinol 2021; 37:857-862. [PMID: 34254540 DOI: 10.1080/09513590.2021.1937101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE To explore gestational diabetes mellitus (GDM) diagnostic markers and establish the predictive model of GDM. METHODS We downloaded the DNA methylation data of GSE70453 and GSE102177 from the Gene Expression Omnibus database. Epigenome-wide association study (EWAS) was performed to analyze the relationship between cytosine-phosphate-guanine (CpG) methylation and GDM. And then the logistic regression models were constructed, with the β-values of CpG sites as predictor variable and the GDM occurrence as binary outcome variable. Data from GSE70453 served as training sets and data from GSE102177 served as verification sets. RESULTS The EWAS and overlap analysis identified nine-shared significant CpGs in the two DNA methylation data sets. Remarkably, these nine CpGs were differently methylated in GDM samples compared to their matched normal specimens, among which five fully methylated CpGs were finally selected. Importantly, we established a binary logistic regression model based on the above five CpGs, in which cg11169102, cg21179618 and cg21620107 were critical. Hence, we further built a logistic regression model by using the three CpGs and found that the area under the curve was 0.8209. The validation of the model by using the verification sets indicated the area under the curve was 0.8519. CONCLUSIONS We identified potential CpG biomarkers for the diagnosis of gestational diabetes mellitus patients through using EWAS and Logistic regression models in combination.
Collapse
Affiliation(s)
- Yan Liu
- Department of Obstetrics, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Zhenglu Wang
- Biobank, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Lin Zhao
- Department of Obstetrics, Tianjin First Central Hospital, Nankai University, Tianjin, China
| |
Collapse
|
|
31
|
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: 11] [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: 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
|
|
32
|
Metabolic signatures in the conversion from gestational diabetes mellitus to postpartum abnormal glucose metabolism: a pilot study in Asian women. Sci Rep 2021; 11:16435. [PMID: 34385555 PMCID: PMC8361021 DOI: 10.1038/s41598-021-95903-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/27/2021] [Indexed: 01/07/2023] Open
Abstract
We aimed to identify serum metabolites related to abnormal glucose metabolism (AGM) among women with gestational diabetes mellitus (GDM). The study recruited 50 women diagnosed with GDM during mid-late pregnancy and 50 non-GDM matchees in a Singapore birth cohort. At the 5-year post-partum follow-up, we applied an untargeted approach to investigate the profiles of serum metabolites among all participants. We first employed OPLS-DA and logistic regression to discriminate women with and without follow-up AGM, and then applied area under the curve (AUC) to assess the incremental indicative value of metabolic signatures on AGM. We identified 23 candidate metabolites that were associated with postpartum AGM among all participants. We then narrowed down to five metabolites [p-cresol sulfate, linoleic acid, glycocholic acid, lysoPC(16:1) and lysoPC(20:3)] specifically associating with both GDM and postpartum AGM. The combined metabolites in addition to traditional risks showed a higher indicative value in AUC (0.92–0.94 vs. 0.74 of traditional risks and 0.77 of baseline diagnostic biomarkers) and R2 (0.67–0.70 vs. 0.25 of traditional risks and 0.32 of baseline diagnostic biomarkers) in terms of AGM indication, compared with the traditional risks model and traditional risks and diagnostic biomarkers combined model. These metabolic signatures significantly increased the AUC value of AGM indication in addition to traditional risks, and might shed light on the pathophysiology underlying the transition from GDM to AGM.
Collapse
|
|
33
|
Pinho-Gomes AC, Morelli G, Jones A, Woodward M. Association of lactation with maternal risk of type 2 diabetes: A systematic review and meta-analysis of observational studies. Diabetes Obes Metab 2021; 23:1902-1916. [PMID: 33908692 DOI: 10.1111/dom.14417] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022]
Abstract
AIM To investigate the association between lactation and maternal risk of type 2 diabetes, including a potential graded association according to lactation duration. METHODS A systematic review and meta-analysis of observational studies that investigated the reported association between lactation (irrespective of duration, intensity or mode) and maternal risk of type 2 diabetes was conducted. RESULTS A total of 22 studies (17 cohort studies and five cross-sectional studies) were included in this systematic review, and 16 contributed to the meta-analysis. Studies that investigated the association of lactation with risk of type 2 diabetes in the first months after birth in women with gestational diabetes reported conflicting results. Studies with a longer follow-up showed a graded protective association for lactation and the risk of type 2 diabetes, with a potentially larger risk reduction in women with gestational diabetes than in those without gestational diabetes. Overall, ever versus never lactation was associated with a 27% lower risk of type 2 diabetes (RR 0.73, 95% CI [0.65, 0.83]). Each additional month of lactation was associated with a 1% lower risk of type 2 diabetes (RR 0.99, 95% CI [0.98, 0.99]). However, the overall quality of the studies was modest. CONCLUSIONS Lactation is associated with a significantly reduced risk of maternal type 2 diabetes over the life course, particularly in women with gestational diabetes. The protective effect seems to increase with longer duration of lactation. Further research is warranted to understand whether this association is modified by exposure to other risk factors.
Collapse
Affiliation(s)
- Ana-Catarina Pinho-Gomes
- King's College London, London, UK
- The George Institute for Global Health, Imperial College London, London, UK
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Georgia Morelli
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Alexandra Jones
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Mark Woodward
- The George Institute for Global Health, Imperial College London, London, UK
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
- Welch Center for Epidemiology, Prevention and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA
| |
Collapse
|
|
34
|
Joglekar MV, Wong WKM, Ema FK, Georgiou HM, Shub A, Hardikar AA, Lappas M. Postpartum circulating microRNA enhances prediction of future type 2 diabetes in women with previous gestational diabetes. Diabetologia 2021; 64:1516-1526. [PMID: 33755745 DOI: 10.1007/s00125-021-05429-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 01/14/2021] [Indexed: 12/18/2022]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes mellitus is a major cause of morbidity and death worldwide. Women with gestational diabetes mellitus (GDM) have greater than a sevenfold higher risk of developing type 2 diabetes in later life. Accurate methods for postpartum type 2 diabetes risk stratification are lacking. Circulating microRNAs (miRNAs) are well recognised as biomarkers/mediators of metabolic disease. We aimed to determine whether postpartum circulating miRNAs can predict the development of type 2 diabetes in women with previous GDM. METHODS In an observational study, plasma samples were collected at 12 weeks postpartum from 103 women following GDM pregnancy. Utilising a discovery approach, we measured 754 miRNAs in plasma from type 2 diabetes non-progressors (n = 11) and type 2 diabetes progressors (n = 10) using TaqMan-based real-time PCR on an OpenArray platform. Machine learning algorithms involving penalised logistic regression followed by bootstrapping were implemented. RESULTS Fifteen miRNAs were selected based on their importance in discriminating type 2 diabetes progressors from non-progressors in our discovery cohort. The levels of miRNA miR-369-3p remained significantly different (p < 0.05) between progressors and non-progressors in the validation sample set (n = 82; 71 non-progressors, 11 progressors) after adjusting for age and correcting for multiple comparisons. In a clinical model of prediction of type 2 diabetes that included six traditional risk factors (age, BMI, pregnancy fasting glucose, postpartum fasting glucose, cholesterol and triacylglycerols), the addition of the circulating miR-369-3p measured at 12 weeks postpartum improved the prediction of future type 2 diabetes from traditional AUC 0.83 (95% CI 0.68, 0.97) to an AUC 0.92 (95% CI 0.84, 1.00). CONCLUSIONS This is the first demonstration of miRNA-based type 2 diabetes prediction in women with previous GDM. Improved prediction will facilitate early lifestyle/drug intervention for type 2 diabetes prevention.
Collapse
Affiliation(s)
- Mugdha V Joglekar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
- Diabetes and Islet Biology Group, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
| | - Wilson K M Wong
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
- Diabetes and Islet Biology Group, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
| | - Fahmida K Ema
- Diabetes and Islet Biology Group, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
| | - Harry M Georgiou
- Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, VIC, Australia
| | - Alexis Shub
- Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, VIC, Australia
| | - Anandwardhan A Hardikar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia.
- Diabetes and Islet Biology Group, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.
- Department of Science and Environment, Roskilde University, Roskilde, Denmark.
| | - Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, VIC, Australia.
- Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, VIC, Australia.
| |
Collapse
|
|
35
|
Saberi-Karimian M, Khorasanchi Z, Ghazizadeh H, Tayefi M, Saffar S, Ferns GA, Ghayour-Mobarhan M. Potential value and impact of data mining and machine learning in clinical diagnostics. Crit Rev Clin Lab Sci 2021; 58:275-296. [PMID: 33739235 DOI: 10.1080/10408363.2020.1857681] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 07/28/2020] [Accepted: 11/26/2020] [Indexed: 12/14/2022]
Abstract
Data mining involves the use of mathematical sciences, statistics, artificial intelligence, and machine learning to determine the relationships between variables from a large sample of data. It has previously been shown that data mining can improve the prediction and diagnostic precision of type 2 diabetes mellitus. A few studies have applied machine learning to assess hypertension and metabolic syndrome-related biomarkers, as well as refine the assessment of cardiovascular disease risk. Machine learning methods have also been applied to assess new biomarkers and survival outcomes in patients with renal diseases to predict the development of chronic kidney disease, disease progression, and renal graft survival. In the latter, random forest methods were found to be the best for the prediction of chronic kidney disease. Some studies have investigated the prognosis of nonalcoholic fatty liver disease and acute liver failure, as well as therapy response prediction in patients with viral disorders, using decision tree models. Machine learning techniques, such as Sparse High-Order Interaction Model with Rejection Option, have been used for diagnosing Alzheimer's disease. Data mining techniques have also been applied to identify the risk factors for serious mental illness, such as depression and dementia, and help to diagnose and predict the quality of life of such patients. In relation to child health, some studies have determined the best algorithms for predicting obesity and malnutrition. Machine learning has determined the important risk factors for preterm birth and low birth weight. Published studies of patients with cancer and bacterial diseases are limited and should perhaps be addressed more comprehensively in future studies. Herein, we provide an in-depth review of studies in which biochemical biomarker data were analyzed using machine learning methods to assess the risk of several common diseases, in order to summarize the potential applications of data mining methods in clinical diagnosis. Data mining techniques have now been increasingly applied to clinical diagnostics, and they have the potential to support this field.
Collapse
Affiliation(s)
- Maryam Saberi-Karimian
- International UNESCO Center for Health Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Khorasanchi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamideh Ghazizadeh
- International UNESCO Center for Health Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Tayefi
- Norwegian Center for e-health Research, University Hospital of North Norway, Tromsø, Norway
| | - Sara Saffar
- International UNESCO Center for Health Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Falmer, UK
| | - Majid Ghayour-Mobarhan
- International UNESCO Center for Health Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
36
|
Identification of Diagnostic CpG Signatures in Patients with Gestational Diabetes Mellitus via Epigenome-Wide Association Study Integrated with Machine Learning. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1984690. [PMID: 34104645 PMCID: PMC8162250 DOI: 10.1155/2021/1984690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 04/01/2021] [Accepted: 05/06/2021] [Indexed: 12/13/2022]
Abstract
Background Gestational diabetes mellitus (GDM) is the most prevalent metabolic disease during pregnancy, but the diagnosis is controversial and lagging partly due to the lack of useful biomarkers. CpG methylation is involved in the development of GDM. However, the specific CpG methylation sites serving as diagnostic biomarkers of GDM remain unclear. Here, we aimed to explore CpG signatures and establish the predicting model for the GDM diagnosis. Methods DNA methylation data of GSE88929 and GSE102177 were obtained from the GEO database, followed by the epigenome-wide association study (EWAS). GO and KEGG pathway analyses were performed by using the clusterProfiler package of R. The PPI network was constructed in the STRING database and Cytoscape software. The SVM model was established, in which the β-values of selected CpG sites were the predictor variable and the occurrence of GDM was the outcome variable. Results We identified 62 significant CpG methylation sites in the GDM samples compared with the control samples. GO and KEGG analyses based on the 62 CpG sites demonstrated that several essential cellular processes and signaling pathways were enriched in the system. A total of 12 hub genes related to the identified CpG sites were found in the PPI network. The SVM model based on the selected CpGs within the promoter region, including cg00922748, cg05216211, cg05376185, cg06617468, cg17097119, and cg22385669, was established, and the AUC values of the training set and testing set in the model were 0.8138 and 0.7576. The AUC value of the independent validation set of GSE102177 was 0.6667. Conclusion We identified potential diagnostic CpG signatures by EWAS integrated with the SVM model. The SVM model based on the identified 6 CpG sites reliably predicted the GDM occurrence, contributing to the diagnosis of GDM. Our finding provides new insights into the cross-application of EWAS and machine learning in GDM investigation.
Collapse
|
|
37
|
Bengtson AM, Ramos SZ, Savitz DA, Werner EF. Risk Factors for Progression From Gestational Diabetes to Postpartum Type 2 Diabetes: A Review. Clin Obstet Gynecol 2021; 64:234-243. [PMID: 33306495 PMCID: PMC7855576 DOI: 10.1097/grf.0000000000000585] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Gestational diabetes mellitus (GDM) complicates 6% to 8% of pregnancies and up to 50% of women with GDM progress to type 2 diabetes mellitus (DM) within 5 years postpartum. Clinicians have little guidance on which women are most at risk for DM progression or when evidence-based prevention strategies should be implemented in a woman's lifecycle. To help address this gap, the authors review identifiable determinants of progression from GDM to DM across the perinatal period, considering prepregnancy, pregnancy, and postpartum periods. The authors categorize evidence by pathways of risk including genetic, metabolic, and behavioral factors that influence progression to DM among women with GDM.
Collapse
Affiliation(s)
- Angela M Bengtson
- Department of Epidemiology, Brown University School of Public Health
| | - Sebastian Z Ramos
- Department of Obstetrics and Gynecology, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - David A Savitz
- Department of Epidemiology, Brown University School of Public Health
- Department of Obstetrics and Gynecology, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Erika F Werner
- Department of Epidemiology, Brown University School of Public Health
- Department of Obstetrics and Gynecology, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| |
Collapse
|
|
38
|
Rahman ML, Feng YCA, Fiehn O, Albert PS, Tsai MY, Zhu Y, Wang X, Tekola-Ayele F, Liang L, Zhang C. Plasma lipidomics profile in pregnancy and gestational diabetes risk: a prospective study in a multiracial/ethnic cohort. BMJ Open Diabetes Res Care 2021; 9:9/1/e001551. [PMID: 33674279 PMCID: PMC7939004 DOI: 10.1136/bmjdrc-2020-001551] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 11/17/2020] [Accepted: 11/29/2020] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Disruption of lipid metabolism is implicated in gestational diabetes (GDM). However, prospective studies on lipidomics and GDM risk in race/ethnically diverse populations are sparse. Here, we aimed to (1) identify lipid networks in early pregnancy to mid-pregnancy that are associated with subsequent GDM risk and (2) examine the associations of lipid networks with glycemic biomarkers to understand the underlying mechanisms. RESEARCH DESIGN AND METHODS This study included 107 GDM cases confirmed using the Carpenter and Coustan criteria and 214 non-GDM matched controls from the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, untargeted lipidomics data of 420 metabolites (328 annotated and 92 unannotated), and information on glycemic biomarkers in maternal plasma at visit 0 (10-14 weeks) and visit 1 (15-26 weeks). We constructed lipid networks using weighted correlation network analysis technique. We examined prospective associations of lipid networks and individual lipids with GDM risk using linear mixed effect models. Furthermore, we calculated Pearson's partial correlation for GDM-related lipid networks and individual lipids with plasma glucose, insulin, C-peptide and glycated hemoglobin at both study visits. RESULTS Lipid networks primarily characterized by elevated plasma diglycerides and short, saturated/low unsaturated triglycerides and lower plasma cholesteryl esters, sphingomyelins and phosphatidylcholines were associated with higher risk of developing GDM (false discovery rate (FDR) <0.05). Among individual lipids, 58 metabolites at visit 0 and 96 metabolites at visit 1 (40 metabolites at both time points) significantly differed between women who developed GDM and who did not (FDR <0.05). Furthermore, GDM-related lipid networks and individual lipids showed consistent correlations with maternal glycemic markers particularly in early pregnancy at visit 0. CONCLUSIONS Plasma lipid metabolites in early pregnancy both individually and interactively in distinct networks were associated with subsequent GDM risk in race/ethnically diverse US women. Future research is warranted to assess lipid metabolites as etiologic markers of GDM.
Collapse
Affiliation(s)
- Mohammad L Rahman
- Department of Population Medicine and Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, Massachusetts, USA
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
| | - Yen-Chen A Feng
- Massachusetts General Hospital Center for Genomic Medicine, Boston, Massachusetts, USA
- Program in Medical and Population Genetics, Broad Institute Harvard, Cambridge, Massachusetts, USA
| | - Oliver Fiehn
- West Coast Metabolomics Center, University of California Davis, Davis, California, USA
| | - Paul S Albert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Michael Y Tsai
- Laboratory Medicine and Pathology, University of Minnesota System, Minneapolis, Minnesota, USA
| | - Yeyi Zhu
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
| | - Xiaobin Wang
- Department of Population, Family, and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Fasil Tekola-Ayele
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
| | - Liming Liang
- Department of Biostatistics, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
| | - Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
| |
Collapse
|
|
39
|
Khan SR, Al Rijjal D, Piro A, Wheeler MB. Integration of AI and traditional medicine in drug discovery. Drug Discov Today 2021; 26:982-992. [PMID: 33476566 DOI: 10.1016/j.drudis.2021.01.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/01/2020] [Accepted: 01/11/2021] [Indexed: 11/24/2022]
Abstract
AI integration in plant-based traditional medicine could be used to overcome drug discovery challenges.
Collapse
Affiliation(s)
- Saifur R Khan
- Endocrine and Diabetes Platform, Department of Physiology, University of Toronto, Medical Sciences Building, Room 3352, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Advanced Diagnostics, Metabolism, Toronto General Hospital Research Institute, Toronto, ON, Canada.
| | - Dana Al Rijjal
- Endocrine and Diabetes Platform, Department of Physiology, University of Toronto, Medical Sciences Building, Room 3352, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Advanced Diagnostics, Metabolism, Toronto General Hospital Research Institute, Toronto, ON, Canada
| | - Anthony Piro
- Endocrine and Diabetes Platform, Department of Physiology, University of Toronto, Medical Sciences Building, Room 3352, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Advanced Diagnostics, Metabolism, Toronto General Hospital Research Institute, Toronto, ON, Canada
| | - Michael B Wheeler
- Endocrine and Diabetes Platform, Department of Physiology, University of Toronto, Medical Sciences Building, Room 3352, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Advanced Diagnostics, Metabolism, Toronto General Hospital Research Institute, Toronto, ON, Canada
| |
Collapse
|
|
40
|
Khan SR, Manialawy Y, Obersterescu A, Cox BJ, Gunderson EP, Wheeler MB. Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction. iScience 2020; 23:101566. [PMID: 33103069 PMCID: PMC7578680 DOI: 10.1016/j.isci.2020.101566] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/20/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-control design was applied to a prospective cohort with GDM history. Women who were non-diabetic 6-9 weeks postpartum (baseline) were monitored for the development of T2D. Metabolomics were performed on baseline plasma to identify metabolic pathways associated with T2D risk. Notably, diminished sphingolipid metabolism was highly associated with future T2D. Defects in sphingolipid metabolism were further implicated by integrating metabolomics and genome-wide association data, which identified two significantly enriched T2D-linked genes, CERS2 and CERS4. Follow-up experiments in mice and cells demonstrated that inhibiting sphingolipid metabolism impaired pancreatic β cell function. These data suggest early postpartum alterations in sphingolipid biosynthesis contribute to β cell dysfunction and T2D risk.
Collapse
Affiliation(s)
- Saifur R. Khan
- Department of Physiology, University of Toronto, ON, Canada
- Advanced Diagnostics, Metabolism, Toronto General Research Institute, ON, Canada
| | - Yousef Manialawy
- Department of Physiology, University of Toronto, ON, Canada
- Advanced Diagnostics, Metabolism, Toronto General Research Institute, ON, Canada
| | | | - Brian J. Cox
- Department of Physiology, University of Toronto, ON, Canada
- Department of Obstetrics and Gynaecology, University of Toronto, ON, Canada
| | - Erica P. Gunderson
- Kaiser Permanente Northern California, Division of Research, Oakland, CA, USA
| | - Michael B. Wheeler
- Department of Physiology, University of Toronto, ON, Canada
- Advanced Diagnostics, Metabolism, Toronto General Research Institute, ON, Canada
| |
Collapse
|
|
41
|
Lai M, Al Rijjal D, Röst HL, Dai FF, Gunderson EP, Wheeler MB. Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop type 2 diabetes. eLife 2020; 9:59153. [PMID: 32748787 PMCID: PMC7417169 DOI: 10.7554/elife.59153] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/18/2020] [Indexed: 12/15/2022] Open
Abstract
Approximately, 35% of women with Gestational Diabetes (GDM) progress to Type 2 Diabetes (T2D) within 10 years. However, links between GDM and T2D are not well understood. We used a well-characterised GDM prospective cohort of 1035 women following up to 8 years postpartum. Lipidomics profiling covering >1000 lipids was performed on fasting plasma samples from participants 6–9 week postpartum (171 incident T2D vs. 179 controls). We discovered 311 lipids positively and 70 lipids negatively associated with T2D risk. The upregulation of glycerolipid metabolism involving triacylglycerol and diacylglycerol biosynthesis suggested activated lipid storage before diabetes onset. In contrast, decreased sphingomyelines, hexosylceramide and lactosylceramide indicated impaired sphingolipid metabolism. Additionally, a lipid signature was identified to effectively predict future diabetes risk. These findings demonstrate an underlying dyslipidemia during the early postpartum in those GDM women who progress to T2D and suggest endogenous lipogenesis may be a driving force for future diabetes onset.
Collapse
Affiliation(s)
- Mi Lai
- Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada
| | - Dana Al Rijjal
- Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada
| | - Hannes L Röst
- Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Ontario, Canada
| | - Feihan F Dai
- Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada
| | - Erica P Gunderson
- Kaiser Permanente Northern California, Division of Research, Oakland, United States
| | - Michael B Wheeler
- Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada.,Advanced Diagnostics, Metabolism, Toronto General Research Institute, Ontario, Canada
| |
Collapse
|
|
42
|
Altered Metabolome of Lipids and Amino Acids Species: A Source of Early Signature Biomarkers of T2DM. J Clin Med 2020; 9:jcm9072257. [PMID: 32708684 PMCID: PMC7409008 DOI: 10.3390/jcm9072257] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/12/2020] [Accepted: 07/14/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus, a disease of modern civilization, is considered the major mainstay of mortalities around the globe. A great number of biochemical changes have been proposed to occur at metabolic levels between perturbed glucose, amino acid, and lipid metabolism to finally diagnoe diabetes mellitus. This window period, which varies from person to person, provides us with a unique opportunity for early detection, delaying, deferral and even prevention of diabetes. The early detection of hyperglycemia and dyslipidemia is based upon the detection and identification of biomarkers originating from perturbed glucose, amino acid, and lipid metabolism. The emerging “OMICS” technologies, such as metabolomics coupled with statistical and bioinformatics tools, proved to be quite useful to study changes in physiological and biochemical processes at the metabolic level prior to an eventual diagnosis of DM. Approximately 300–400 such metabolites have been reported in the literature and are considered as predicting or risk factor-reporting metabolic biomarkers for this metabolic disorder. Most of these metabolites belong to major classes of lipids, amino acids and glucose. Therefore, this review represents a snapshot of these perturbed plasma/serum/urinary metabolic biomarkers showing a significant correlation with the future onset of diabetes and providing a foundation for novel early diagnosis and monitoring the progress of metabolic syndrome at early symptomatic stages. As most metabolites also find their origin from gut microflora, metabolism and composition of gut microflora also vary between healthy and diabetic persons, so we also summarize the early changes in the gut microbiome which can be used for the early diagnosis of diabetes.
Collapse
|
|
43
|
Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: A metabolic profiling study. PLoS Med 2020; 17:e1003112. [PMID: 32433647 PMCID: PMC7239388 DOI: 10.1371/journal.pmed.1003112] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/20/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) during midlife and an elevated risk of developing hypertension and cardiovascular disease. Glucose tolerance reclassification after delivery is recommended, but fewer than 40% of women with GDM are tested. Thus, improved risk stratification methods are needed, as is a deeper understanding of the pathology underlying the transition from GDM to T2D. We hypothesize that metabolites during the early postpartum period accurately distinguish risk of progression from GDM to T2D and that metabolite changes signify underlying pathophysiology for future disease development. METHODS AND FINDINGS The study utilized fasting plasma samples collected from a well-characterized prospective research study of 1,035 women diagnosed with GDM. The cohort included racially/ethnically diverse pregnant women (aged 20-45 years-33% primiparous, 37% biparous, 30% multiparous) who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. Participants attended in-person research visits including 2-hour 75-g oral glucose tolerance tests (OGTTs) at study baseline (6-9 weeks postpartum) and annually thereafter for 2 years, and we retrieved diabetes diagnoses from electronic medical records for 8 years. In a nested case-control study design, we collected fasting plasma samples among women without diabetes at baseline (n = 1,010) to measure metabolites among those who later progressed to incident T2D or did not develop T2D (non-T2D). We studied 173 incident T2D cases and 485 controls (pair-matched on BMI, age, and race/ethnicity) to discover metabolites associated with new onset of T2D. Up to 2 years post-baseline, we analyzed samples from 98 T2D cases with 239 controls to reveal T2D-associated metabolic changes. The longitudinal analysis tracked metabolic changes within individuals from baseline to 2 years of follow-up as the trajectory of T2D progression. By building prediction models, we discovered a distinct metabolic signature in the early postpartum period that predicted future T2D with a median discriminating power area under the receiver operating characteristic curve of 0.883 (95% CI 0.820-0.945, p < 0.001). At baseline, the most striking finding was an overall increase in amino acids (AAs) as well as diacyl-glycerophospholipids and a decrease in sphingolipids and acyl-alkyl-glycerophospholipids among women with incident T2D. Pathway analysis revealed up-regulated AA metabolism, arginine/proline metabolism, and branched-chain AA (BCAA) metabolism at baseline. At follow-up after the onset of T2D, up-regulation of AAs and down-regulation of sphingolipids and acyl-alkyl-glycerophospholipids were sustained or strengthened. Notably, longitudinal analyses revealed only 10 metabolites associated with progression to T2D, implicating AA and phospholipid metabolism. A study limitation is that all of the analyses were performed with the same cohort. It would be ideal to validate our findings in an independent longitudinal cohort of women with GDM who had glucose tolerance tested during the early postpartum period. CONCLUSIONS In this study, we discovered a metabolic signature predicting the transition from GDM to T2D in the early postpartum period that was superior to clinical parameters (fasting plasma glucose, 2-hour plasma glucose). The findings suggest that metabolic dysregulation, particularly AA dysmetabolism, is present years prior to diabetes onset, and is revealed during the early postpartum period, preceding progression to T2D, among women with GDM. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01967030.
Collapse
|
|
44
|
Unbiased data analytic strategies to improve biomarker discovery in precision medicine. Drug Discov Today 2019; 24:1735-1748. [PMID: 31158511 DOI: 10.1016/j.drudis.2019.05.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/23/2019] [Accepted: 05/28/2019] [Indexed: 12/25/2022]
Abstract
Omics technologies promised improved biomarker discovery for precision medicine. The foremost problem of discovered biomarkers is irreproducibility between patient cohorts. From a data analytics perspective, the main reason for these failures is bias in statistical approaches and overfitting resulting from batch effects and confounding factors. The keys to reproducible biomarker discovery are: proper study design, unbiased data preprocessing and quality control analyses, and a knowledgeable application of statistics and machine learning algorithms. In this review, we discuss study design and analysis considerations and suggest standards from an expert point-of-view to promote unbiased decision-making in biomarker discovery in precision medicine.
Collapse
|