Metabolic profiling identifies potential biomarkers associated with progression from gestational diabetes mellitus to prediabetes postpartum

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 a 2-h 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-h post-load time points 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-h 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 that a combination of three clinical markers yielded an area under the curve (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-h 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 prediabetes development in women with a history of GDM during the early postpartum period. 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.

Keywords

metabolomics / gestational diabetes mellitus / follow-up / prediabetes / UHPLC-Q-TOF-MS/MS / impaired glucose tolerance

Fundings

This work was supported by Key Medical Research Projects of Jiangsu Commission of Health (Grant No. ZD2022023).

Acknowledgments

We are grateful to Prof. Junsong Wang for the UHPLC-Q-TOF-MS/MS technical assistance.

References

[1] Wang H, Li N, Chivese T, et al. IDF diabetes atlas: Estimation of global and regional gestational diabetes mellitus prevalence for 2021 by International Association of Diabetes in Pregnancy Study Group's Criteria[J]. Diabetes Res Clin Pract, 2022, 183(5): 109050. doi: 10.1016/j.diabres.2021.109050

[2] Kramer CK, Campbell S, Retnakaran R. Gestational diabetes and the risk of cardiovascular disease in women: A systematic review and meta-analysis[J]. Diabetologia, 2019, 62(6): 905-914. doi: 10.1007/s00125-019-4840-2

[3] Bellamy L, Casas JP, Hingorani AD, et al. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis[J]. Lancet, 2009, 373(9677): 1773-1779. doi: 10.1016/S0140-6736(09)60731-5

[4] Vounzoulaki E, Khunti K, Abner SC, et al. Progression to type 2 diabetes in women with a known history of gestational diabetes: Systematic review and meta-analysis[J]. BMJ, 2020, 369: m1361.

[5] American Diabetes Association Professional Practice Committee. 15. Management of diabetes in pregnancy: Standards of care in diabetes-2024[J]. Diabetes Care, 2024, 47(Suppl 1): S282-S294. doi: 10.2337/dc24-S015

[6] Aroda VR, Christophi CA, Edelstein SL, et al. The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: The Diabetes Prevention Program outcomes study 10-year follow-up[J]. J Clin Endocrinol Metab, 2015, 100(4): 1646-1653. doi: 10.1210/jc.2014-3761

[7] Carson MP, Frank MI, Keely E. Original research: Postpartum testing rates among women with a history of gestational diabetes-systematic review[J]. Prim Care Diabetes, 2013, 7(3): 177-186. doi: 10.1016/j.pcd.2013.04.007

[8] Nouhjah S, Shahbazian H, Amoori N, et al. Postpartum screening practices, progression to abnormal glucose tolerance and its related risk factors in Asian women with a known history of gestational diabetes: A systematic review and meta-analysis[J]. Diabetes Metab Syndr, 2017, 11(Suppl 2): S703-S712.

[9] Lai M, Liu Y, Ronnett GV, et al. Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: A metabolic profiling study[J]. PLoS Med, 2020, 17(5): e1003112. doi: 10.1371/journal.pmed.1003112

[10] Liu Y, Kuang A, Bain JR, et al. Maternal metabolites associated with gestational diabetes mellitus and a postpartum disorder of glucose metabolism[J]. J Clin Endocrinol Metab, 2021, 106(11): 3283-3294. doi: 10.1210/clinem/dgab513

[11] Wang G, Buckley JP, Bartell TR, et al. Gestational diabetes mellitus, postpartum lipidomic signatures, and subsequent risk of type 2 diabetes: A lipidome-wide association study[J]. Diabetes Care, 2023, 46(6): 1223-1230. doi: 10.2337/dc22-1841

[12] American Diabetes Association Professional Practice Committee. 2. Diagnosis and classification of diabetes: Standards of care in diabetes—2024[J]. Diabetes Care, 2024, 47(Suppl 1): S20-S42. doi: 10.2337/dc24-S002

[13] Duke A, Yap C, Bradbury R, et al. The discordance between HbA1c and glucose tolerance testing for the postpartum exclusion of diabetes following gestational diabetes[J]. Diabetes Res Clin Pract, 2015, 108(1): 72-77. doi: 10.1016/j.diabres.2015.01.006

[14] Göbl CS, Bozkurt L, Yarragudi R, et al. Is early postpartum HbA1c an appropriate risk predictor after pregnancy with gestational diabetes mellitus?[J]. Acta Diabetol, 2014, 51(5): 715-722. doi: 10.1007/s00592-014-0574-2

[15] Gar C, Rottenkolber M, Prehn C, et al. Serum and plasma amino acids as markers of prediabetes, insulin resistance, and incident diabetes[J]. Crit Rev Clin Lab Sci, 2018, 55(1): 21-32. doi: 10.1080/10408363.2017.1414143

[16] Huopio H, Hakkarainen H, Pääkkönen M, et al. Long-term changes in glucose metabolism after gestational diabetes: A double cohort study[J]. BMC Pregnancy Childbirth, 2014, 14: 296. doi: 10.1186/1471-2393-14-296

[17] Kasuga Y, Miyakoshi K, Tajima A, et al. Clinical and genetic characteristics of abnormal glucose tolerance in Japanese women in the first year after gestational diabetes mellitus[J]. J Diabetes Invest, 2019, 10(3): 817-826. doi: 10.1111/jdi.12935

[18] Muche AA, Olayemi OO, Gete YK. Predictors of postpartum glucose intolerance in women with gestational diabetes mellitus: A prospective cohort study in Ethiopia based on the updated diagnostic criteria[J]. BMJ Open, 2020, 10(8): e036882. doi: 10.1136/bmjopen-2020-036882

[19] Capula C, Chiefari E, Vero A, et al. Prevalence and predictors of postpartum glucose intolerance in Italian women with gestational diabetes mellitus[J]. Diabetes Res Clin Pract, 2014, 105(2): 223-230. doi: 10.1016/j.diabres.2014.05.008

[20] Moore LE, Voaklander B, Savu A, et al. Association between the antepartum oral glucose tolerance test and the risk of future diabetes mellitus among women with gestational diabetes: A systematic review and meta-analysis[J]. J Diabetes Complications, 2021, 35(4): 107804. doi: 10.1016/j.jdiacomp.2020.107804

[21] Huhtala MS, Rönnemaa T, Paavilainen E, et al. Prediction of pre-diabetes and type 2 diabetes nine years postpartum using serum metabolome in pregnant women with gestational diabetes requiring pharmacological treatment[J]. J Diabetes Complications, 2023, 37(7): 108513. doi: 10.1016/j.jdiacomp.2023.108513

[22] Khan SR, Mohan H, Liu Y, et al. The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes[J]. Diabetologia, 2019, 62(4): 687-703. doi: 10.1007/s00125-018-4800-2

[23] Lai M, Al Rijjal D, Röst HL, et al. Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop type 2 diabetes[J]. eLife, 2020, 9: e59153. doi: 10.7554/eLife.59153

[24] Zhang Z, Lai M, Piro AL, et al. Intensive lactation among women with recent gestational diabetes significantly alters the early postpartum circulating lipid profile: The SWIFT study[J]. BMC Med, 2021, 19(1): 241. doi: 10.1186/s12916-021-02095-1

[25] Gonzalez-Franquesa A, Burkart AM, Isganaitis E, et al. What have metabolomics approaches taught us about type 2 diabetes?[J]. Curr Diab Rep, 2016, 16(8): 74. doi: 10.1007/s11892-016-0763-1

[26] Guasch-Ferré M, Santos JL, Martínez-González MA, et al. Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes[J]. Am J Clin Nutr, 2020, 111(4): 835-844. doi: 10.1093/ajcn/nqaa016

[27] Yagin FH, Al-Hashem F, Ahmad I, et al. Pilot-study to explore metabolic signature of type 2 diabetes: A pipeline of tree-based machine learning and bioinformatics techniques for biomarkers discovery[J]. Nutrients, 2024, 16(10): 1537. doi: 10.3390/nu16101537

[28] Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: An update[J]. Endocr Connect, 2015, 4(1): R1-R15. doi: 10.1530/EC-14-0092

[29] Petersen KF, Dufour S, Befroy D, et al. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes[J]. N Engl J Med, 2004, 350(7): 664-671. doi: 10.1056/NEJMoa031314

[30] Kubacka J, Cembrowska P, Sypniewska G, et al. The association between branched-chain amino acids (BCAAs) and cardiometabolic risk factors in middle-aged Caucasian women stratified according to glycemic status[J]. Nutrients, 2021, 13(10): 3307. doi: 10.3390/nu13103307

[31] Liu Y, Kuang A, Talbot O, et al. Metabolomic and genetic associations with insulin resistance in pregnancy[J]. Diabetologia, 2020, 63(9): 1783-1795. doi: 10.1007/s00125-020-05198-1

[32] Liu L, Liu L, Wang J, et al. Differentiation of gestational diabetes mellitus by nuclear magnetic resonance-based metabolic plasma analysis[J]. J Biomed Res, 2021, 35(5): 351-360. doi: 10.7555/JBR.35.20200191

[33] Andersson-Hall U, Gustavsson C, Pedersen A, et al. Higher concentrations of BCAAs and 3-HIB are associated with insulin resistance in the transition from gestational diabetes to type 2 diabetes[J]. J Diabetes Res, 2018, 2018: 4207067. doi: 10.1155/2018/4207067

[34] Lynch CJ. Role of leucine in the regulation of mTOR by amino acids: Revelations from structure-activity studies[J]. J Nutr, 2001, 131(3): 861S-865S. doi: 10.1093/jn/131.3.861S

[35] Tang Z, Wang P, Dong C, et al. Oxidative stress signaling mediated pathogenesis of diabetic cardiomyopathy[J]. Oxid Med Cell Longev, 2022, 2022: 5913374.