Generic placeholder image

Current Proteomics


ISSN (Print): 1570-1646
ISSN (Online): 1875-6247

Research Article

Upregulated Retinol Binding Protein and Transthyretin as Predictive Biomarkers of Gestational Diabetes Mellitus

Author(s): Sadaf Ilyas*, Nabila Roohi, Samina Ashraf and Sobia Alyas

Volume 17, Issue 3, 2020

Page: [180 - 190] Pages: 11

DOI: 10.2174/1570164617666190822125837

Price: $65


Background: Gestational Diabetes Mellitus (GDM) is one of the most common medical complications of pregnancy. The untreated GDM affects both the baby and mother during gestation as well as presents the risk of subsequent type 2 diabetes in mothers and babies.

Objective: To determine the effect of GDM on plasma proteomics as variable plasma proteins can be secreted by the cells at the pathological sites and can serve as a biomarker of the disease.

Methods: Blood samples were taken from 400 pregnant women at early second trimester and they were followed till early third trimester or until the development of GDM. All the pregnant females were sampled again in 3rd trimester. Overall 42 pregnant females developed GDM. These females were grouped as GDM I and GDM II, before and after the development of gestational diabetes, respectively. An equivalent number of pregnant women who did not develop GDM served as control I and control II in early second and third trimester, respectively. Blood samples from all the groups were subjected to 2D gel electrophoresis.

Results: Nineteen protein spots were differently expressed between GDM and control groups, two spots were further confirmed by LC-MS/MS as Retinol binding protein A4 and Transthyretin. These two proteins were found to be up regulated in GDM group in early second trimester as well as early 3rd trimester.

Conclusion: Transthyretin and Retinol binding protein 4 can be used as predictive plasma biomarkers of GDM that might help in the identification of at-risk pregnancies, hence, providing the best opportunity for early treatment in order to prevent the onset or progression of the disease.

Keywords: Gestational Diabetes Mellitus (GDM), second trimester, Retinol-Binding Protein (RBP4), Transthyretin (TTR), type 2 diabetes, 2D gel electrophoresis.

Graphical Abstract
Landon, M.B.; Spong, C.Y.; Thom, E.; Carpenter, M.W.; Ramin, S.M.; Casey, B.; Wapner, R.J.; Varner, M.W.; Rouse, D.J.; Thorp, J.M.J.; Sciscione, A.; Catalano, P.; Harper, M.; Saade, G.; Lain, K.Y.; Sorokin, Y.; Peaceman, A.M.; Tolosa, J.E.; Anderson, G.B. Eunice Kennedy Shriver National Institute of child health and human development maternal-fetal medicine units network. A multicenter, randomized trial of treatment for mild gestational diabetes. N. Engl. J. Med., 2009, 361(14), 1339-1348.
[] [PMID: 19797280]
Coustan, D.R. Gestational diabetes mellitus. Clin. Chem., 2013, 59(9), 1310-1321.
[] [PMID: 23536513]
Ben-Haroush, A.; Yogev, Y.; Hod, M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet. Med., 2004, 21(2), 103-113.
[] [PMID: 14984444]
Ruchat, S.M.; Mottola, M.F. The important role of physical activity in the prevention and management of gestational diabetes mellitus. Diabetes Metab. Res. Rev., 2013, 29(5), 334-346.
[] [PMID: 23436340]
Wahabi, H.A.; Alzeidan, R.A.; Esmaeil, S.A. Pre-pregnancy care for women with pre-gestational diabetes mellitus: a systematic review and meta-analysis. BMC Public Health, 2012, 12(1), 792.
[] [PMID: 22978747]
Alyas, S.; Roohi, N.; Ashraf, S.; Ilyas, S.; Ilyas, A. Early pregnancy biochemical markers of placentation for screening of Gestational Diabetes Mellitus (GDM). Diabetes Metab. Syndr., 2019, 13(4), 2353-2356.
Buchanan, T.A.; Xiang, A.H.; Page, K.A. Gestational diabetes mellitus: risks and management during and after pregnancy. Nat. Rev. Endocrinol., 2012, 8(11), 639-649.
[] [PMID: 22751341]
Lee, A.J.; Hiscock, R.J.; Wein, P.; Walker, S.P.; Permezel, M. Gestational diabetes mellitus: clinical predictors and long-term risk of developing type 2 diabetes: a retrospective cohort study using survival analysis. Diabetes Care, 2007, 30(4), 878-883.
[] [PMID: 17392549]
Dabelea, D.; Hanson, R.L.; Lindsay, R.S.; Pettitt, D.J.; Imperatore, G.; Gabir, M.M.; Roumain, J.; Bennett, P.H.; Knowler, W.C. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes, 2000, 49(12), 2208-2211.
[] [PMID: 11118027]
Catalano, P.M.; Kirwan, J.P.; Haugel-de Mouzon, S.; King, J. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. J. Nutr., 2003, 133(5)(Suppl. 2), 1674S-1683S.
[] [PMID: 12730484]
Athukorala, C.; Crowther, C.A.; Willson, K. Austrailian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) trial group. Women with gestational diabetes mellitus in the ACHOIS trial: risk factors for shoulder dystocia. Aust. N. Z. J. Obstet. Gynaecol., 2007, 47(1), 37-41.
[] [PMID: 17261098]
American College of Obstetricians and Gynecologists. Gestational diabetes; Washington (DC): The College, 2011.
Kim, S.Y.; England, J.L.; Sharma, J.A.; Njoroge, T. Gestational diabetes mellitus and risk of childhood overweight and obesity in offspring: a systematic review. Exp. Diabetes Res., 2011, 2011541308
[] [PMID: 21960991]
Oostdam, N.; van Poppel, M.N.; Wouters, M.G.; van Mechelen, W. Interventions for preventing gestational diabetes mellitus: a systematic review and meta-analysis. J. Womens Health (Larchmt.), 2011, 20(10), 1551-1563.
[] [PMID: 21838525]
Elvidge, T.; Matthews, I.P.; Gregory, C.; Hoogendoorn, B. Feasibility of using biomarkers in blood serum as markers of effect following exposure of the lungs to particulate matter air pollution. J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev., 2013, 31(1), 1-44.
[] [PMID: 23534393]
Mirabelli, P.; Incoronato, M. Usefulness of traditional serum biomarkers for management of breast cancer patients. BioMed Res. Int., 2013, 2013685641
[] [PMID: 24350285]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72(1-2), 248-254.
[] [PMID: 942051]
Anderson, L.; Anderson, N.G. High resolution two-dimensional electrophoresis of human plasma proteins. Proc. Natl. Acad. Sci. USA, 1977, 74(12), 5421-5425.
[] [PMID: 271964]
Neuhoff, V.; Arold, N.; Taube, D.; Ehrhardt, W. Improved staining of proteins in polyacrylamide gels including isoelectric focusing gels with clear background at nanogram sensitivity using coomassie brilliant blue G-250 and R-250. Electrophoresis, 1988, 9(6), 255-262.
[] [PMID: 2466658]
Bringans, S.; Kendrick, T.S.; Lui, J.; Lipscombe, R. A comparative study of the accuracy of several de novo sequencing software packages for datasets derived by matrix-assisted laser desorption/ionisation and electrospray. Rapid Commun. Mass Spectrom., 2008, 22(21), 3450-3454.
[] [PMID: 18837480]
Zabetian-Targhi, F.; Mahmoudi, M.J.; Rezaei, N.; Mahmoudi, M. Retinol binding protein 4 in relation to diet, inflammation, immunity, and cardiovascular diseases. Adv. Nutr., 2015, 6(6), 748-762.
[] [PMID: 26567199]
Lu, H.Y.; Li, X.F.; Mu, P.W.; Jiang, W.; Zeng, L.Y. [Depotspecific expression of retinol-binding protein 4 in human adipose tissue and their relationship with obesity and insulin resistance]. Zhonghua Yi Xue Za Zhi, 2010, 90(48), 3395-3398.
[PMID: 21223811]
Friebe, D.; Neef, M.; Erbs, S.; Dittrich, K.; Kratzsch, J.; Kovacs, P.; Blüher, M.; Kiess, W.; Körner, A. Retinol Binding Protein 4 (RBP4) is primarily associated with adipose tissue mass in children. Int. J. Pediatr. Obes., 2011, 6(2-2), e345-e352.
[] [PMID: 20950077]
Du, M.; Wang, B.; Liang, Z.; Dong, M.; Chen, D. The Relationship between retinol-binding protein 4 concentrations and gestational diabetes mellitus in Chinese women. Gynecol. Obstet. Invest., 2015, 81(2), 174-180.
[] [PMID: 25998178]
Su, Y.X.; Hong, J.; Yan, Q.; Xu, C.; Gu, W.Q.; Zhang, Y.F.; Shen, C.F.; Chi, Z.N.; Dai, M.; Xu, M.; Zhang, Y.W.; Liu, Q.R.; Li, X.Y.; Ning, G.; Wang, W.Q. Increased serum retinol-binding protein-4 levels in pregnant women with and without gestational diabetes mellitus. Diabetes Metab., 2010, 36(6 Pt 1), 470-475.
[] [PMID: 21109476]
Inoue, S.; Takamoto, N.; Akahori, Y.; Masumoto, A.; Nakatsukasa, H.; Msuyama, H.; Hiramatsu, Y. Elevated level of serum retinol-binding protein 4 in pregnancy-induced hypertension. J. Obstet. Gynaecol. Res., 2009, 35(2), 293-300.
[] [PMID: 19708176]
Pullakhandam, R.; Palika, R.; Ghosh, S.; Reddy, G.B. Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: the significance of transthyretin. IUBMB Life, 2012, 64(12), 975-982.
[] [PMID: 23129325]
Wang, M.N.; Han, Y.B.; Li, Q.; Guo, L.; Yang, Y.M.; Wang, W.; Zhang, J.C. Higher serum retinol binding protein 4 may be a predictor of weak metabolic control in Chinese patients with type 2 diabetes mellitus. J. Int. Med. Res., 2012, 40(4), 1317-1324.
[] [PMID: 22971483]
Sun, Q.; Kiernan, U.A.; Shi, L.; Phillips, D.A.; Kahn, B.B.; Hu, F.B.; Manson, J.E.; Albert, C.M.; Rexrode, K.M. Plasma Retinol-Binding Protein 4 (RBP4) levels and risk of coronary heart disease: a prospective analysis among women in the nurses’ health study. Circulation, 2013, 127(19), 1938-1947.
[] [PMID: 23584360]
Fruscalzo, A.; Londero, A.P.; Driul, L.; Henze, A.; Tonutti, L.; Ceraudo, M.; Zanotti, G.; Berni, R.; Schweigert, F.J.; Raila, J. First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus. Clin. Chem. Lab. Med., 2015, 53(10), 1643-1651.
[] [PMID: 25781688]
Janke, J.; Engeli, S.; Boschmann, M.; Adams, F.; Böhnke, J.; Luft, F.C.; Sharma, A.M.; Jordan, J. Retinol-binding protein 4 in human obesity. Diabetes, 2006, 55(10), 2805-2810.
[] [PMID: 17003346]
Choi, S.H.; Kwak, S.H.; Youn, B-S.; Lim, S.; Park, Y.J.; Lee, H.; Lee, N.; Cho, Y.M.; Lee, H.K.; Kim, Y-B.; Park, K.S.; Jang, H.C. High plasma retinol binding protein-4 and low plasma adiponectin concentrations are associated with severity of glucose intolerance in women with previous gestational diabetes mellitus. J. Clin. Endocrinol. Metab., 2008, 93(8), 3142-3148.
[] [PMID: 18492757]
Maghbooli, Z.; Hossein-Nezhad, A.; Mirzaei, K.; Karimi, F.; Besharati, A.; Omidfar, K.; Larijani, B. Association between retinol-binding protein 4 concentrations and gestational diabetes mellitus and risk of developing metabolic syndrome after pregnancy. Reprod. Sci., 2010, 17(2), 196-201.
[] [PMID: 19897788]
Mody, N.; Timothy, E.; Graham, T.E.; Tsuji, Y.; Yang, Q.; Kahn, B.B. Decreased clearance of serum retinol-binding protein and elevated levels of transthyretin in insulin-resistant ob/ob mice. Am. Physiol. Soc., 2008, 29(4), E785-E793.
Yang, Q.; Graham, T.E.; Mody, N.; Preitner, F.; Peroni, O.D.; Zabolotny, J.M.; Kotani, K.; Quadro, L.; Kahn, B.B. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature, 2005, 436(7049), 356-362.
[] [PMID: 16034410]
Reinehr, T.; Stoffel-Wagner, B.; Roth, C.L. Retinol-binding protein 4 and its relation to insulin resistance in obese children before and after weight loss. J. Clin. Endocrinol. Metab., 2008, 93(6), 2287-2293.
[] [PMID: 18397979]
Norseen, J.; Hosooka, T.; Hammarstedt, A.; Yore, M.M.; Kant, S.; Aryal, P.; Kiernan, U.A.; Phillips, D.A.; Maruyama, H.; Kraus, B.J.; Usheva, A.; Davis, R.J.; Smith, U.; Kahn, B.B. Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. Mol. Cell. Biol., 2012, 32(10), 2010-2019.
[] [PMID: 22431523]
Ingelsson, E.; Lind, L. Circulating retinol-binding protein 4 and subclinical cardiovascular disease in the elderly. Diabetes Care, 2009, 32(4), 733-735.
[] [PMID: 19114616]
Cabré, A.; Lázaro, I.; Girona, J.; Manzanares, J.; Marimón, F.; Plana, N.; Heras, M.; Masana, L. Retinol-binding protein 4 as a plasma biomarker of renal dysfunction and cardiovascular disease in type 2 diabetes. J. Intern. Med., 2007, 262(4), 496-503.
[] [PMID: 17875187]
Ingelsson, E.; Sundström, J.; Melhus, H.; Michaëlsson, K.; Berne, C.; Vasan, R.S.; Risérus, U.; Blomhoff, R.; Lind, L.; Arnlöv, J. Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly. Atherosclerosis, 2009, 206(1), 239-244.
[] [PMID: 19339013]
Bobbert, T.; Raila, J.; Schwarz, F.; Mai, K.; Henze, A.; Pfeiffer, A.F.; Schweigert, F.J.; Spranger, J. Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness. Atherosclerosis, 2010, 213(2), 549-551.
[] [PMID: 20832065]
Du, C.; Kong, F. A prospective study of maternal plasma concentrations of retinol-binding protein 4 and risk of gestational diabetes mellitus. Ann. Nutr. Metab., 2019, 74(1), 1-8.
[] [PMID: 30428456]
Westermark, G.T.; Westermark, P. Transthyretin and amyloid in the islets of Langerhans in type-2 diabetes. Exp. Diabetes Res., 2008, 2008429274
[] [PMID: 18825272]
Xiong, T.; Zhong, C.; Zhou, X.; Chen, R.; Xiao, M.; Wu, Y.; Hu, X.; Wang, W.; Li, X.; Liu, C.; Xiong, G.; Yang, X.; Hao, L.; Yang, N. Maternal Circulating transthyretin level is longitudinally associated with increased risk of gestational diabetes mellitus: it is not just an indicator of nutritional status. Diabetes Care, 2017, 40(5), e53-e54.
[] [PMID: 28246122]
Zhu, L.; Chen, Y.; Liu, C.; Deng, H.; Zhang, N.; Wang, S.; Zhang, Z. Transthyretin as a novel candidate biomarker for preeclampsia. Exp. Ther. Med., 2014, 7(5), 1332-1336.
[] [PMID: 24940434]
Myron Johnson, A.; Merlini, G.; Sheldon, J.; Ichihara, K. Scientific division Committee on Plasma Proteins (C-PP), International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Clinical indications for plasma protein assays: transthyretin (prealbumin) in inflammation and malnutrition. Clin. Chem. Lab. Med., 2007, 45(3), 419-426.
[] [PMID: 17378745]
Refai, E.; Dekki, N.; Yang, S.N.; Imreh, G.; Cabrera, O.; Yu, L.; Yang, G.; Norgren, S.; Rössner, S.M.; Inverardi, L.; Ricordi, C.; Olivecrona, G.; Andersson, M.; Jörnvall, H.; Berggren, P.O.; Juntti-Berggren, L. Transthyretin constitutes a functional component in pancreatic beta-cell stimulus-secretion coupling. Proc. Natl. Acad. Sci. USA, 2005, 102(47), 17020-17025.
[] [PMID: 16286652]
Yoshida, A.; Matsutani, Y.; Fukuchi, Y.; Saito, K.; Naito, M. Analysis of the factors contributing to serum retinol binding protein and transthyretin levels in Japanese adults. J. Atheroscler. Thromb., 2006, 13(4), 209-215.
[] [PMID: 16908954]
Schweigert, F.J.; Sehouli, J. Transthyretin, a biomarker for nutritional status and ovarian cancer. Cancer Res., 2005, 65(3), 1114.
[PMID: 15705915]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy