Metformin and insulin treatment of gestational diabetes: effects on inflammatory markers and IGF-binding protein-1 - secondary analysis of a randomized controlled trial

Mikael S Huhtala, Kristiina Tertti, Juuso Juhila, Timo Sorsa, Tapani Rönnemaa, Mikael S Huhtala, Kristiina Tertti, Juuso Juhila, Timo Sorsa, Tapani Rönnemaa

Abstract

Background: Gestational diabetes mellitus (GDM) is characterized by disturbed glucose metabolism and activation of low-grade inflammation. We studied whether metformin treatment has favorable or unfavorable effects on inflammatory markers and insulin-like growth factor-binding protein 1 (IGFBP-1) in GDM patients compared with insulin, and whether these markers associate with major maternal or fetal clinical outcomes.

Methods: This is a secondary analysis of a previous randomized controlled trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum samples were collected at the time of diagnosis (baseline, mean 30 gestational weeks [gw]) and at 36 gw. Inflammatory markers serum high-sensitivity CRP (hsCRP), interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glycoprotein acetylation (GlycA) as well as three IGFBP-1 phosphoisoform concentrations were determined.

Results: In the metformin and insulin groups combined, hsCRP decreased (p = 0.01), whereas IL-6 (p = 0.002), GlycA (p < 0.0001) and all IGFBP-1 phosphoisoforms (p < 0.0001) increased from baseline to 36 gw. GlycA (p = 0.02) and non-phosphorylated IGFBP-1 (p = 0.008) increased more in patients treated with metformin than those treated with insulin. Inflammatory markers did not clearly associate with pregnancy outcomes but non-phosphorylated IGFBP-1 was inversely associated with gestational weight gain.

Conclusions: Metformin had beneficial effects on maternal serum IGFBP-1 concentrations compared to insulin, as increased IGFBP-1 related to lower total and late pregnancy maternal weight gain. GlycA increased more during metformin treatment compared to insulin. The significance of this observation needs to be more profoundly examined in further studies. There were no evident clinically relevant relations between inflammatory markers and pregnancy outcome measures.

Trial registration: The trial comparing metformin and insulin treatment was registered in ClinicalTrials.gov ( NCT01240785 ) November 3, 2010. Retrospectively registered.

Keywords: Gestational diabetes; IGFBP-1; Insulin-like growth factor-binding protein 1; Low-grade inflammation; Metformin.

Conflict of interest statement

T.S. and J.J. are inventors of a diagnostic patent for serum MMP-8 (FI 127 416 B / 31.5.2018). M.H., K.T. and T.R. do not have any conflicts of interest.

Figures

Fig. 1
Fig. 1
Heatmap representation of Spearman’s correlations between age, pre-pregnancy BMI and glucose metabolism with inflammatory markers and IGFBP-1 phosphoisoforms at baseline (n = 196–208) and at 36 gestational weeks (n = 181–198). BMI = body mass index, OGTT = oral glucose tolerance test, gw = gestational weeks, hsCRP = high sensitivity CRP, IL-6 = interleukin 6, MMP-8 = matrix metalloproteinase 8, GlycA = glycoprotein acetylation, non/low/high-pIGFBP-1 = non/low/high-phosphorylated insulin-like growth factor-binding protein 1. *p < 0.05, **p < 0.01, ***p < 0.001. This figure was created using ggplot2 in R

References

    1. HAPO Study Cooperative Research Group. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and Adverse Pregnancy Outcomes. N Engl J Med. 2008;358:1991–2002. doi: 10.1056/NEJMoa0707943.
    1. Langer O, Yogev Y, Most O, Xenakis EMJ. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol. 2005;192:989–997. doi: 10.1016/j.ajog.2004.11.039.
    1. Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, Lauenborg J, et al. Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes. J Clin Endocrinol Metab. 2009;94:2464–2470. doi: 10.1210/jc.2009-0305.
    1. Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med. 2004;21:103–113. doi: 10.1046/j.1464-5491.2003.00985.x.
    1. Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet Med. 2017;34:27–36. doi: 10.1111/dme.13150.
    1. Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res Care. 2018;6:e000456. doi: 10.1136/bmjdrc-2017-000456.
    1. Wang X, Bao W, Liu J, Ouyang Y-Y, Wang D, Rong S, et al. Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care. 2013;36:166–175. doi: 10.2337/dc12-0702.
    1. Challier JC, Basu S, Bintein T, Minium J, Hotmire K, Catalano PM, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta. 2008;29:274–281. doi: 10.1016/j.placenta.2007.12.010.
    1. Lowe LP, Metzger BE, Lowe WL, Dyer AR, McDade TW, McIntyre HD. Inflammatory mediators and glucose in pregnancy: results from a subset of the hyperglycemia and adverse pregnancy outcome (HAPO) study. J Clin Endocrinol Metab. 2010;95:5427–5434. doi: 10.1210/jc.2010-1662.
    1. Wolf M, Sandler L, Hsu K, Vossen-Smirnakis K, Ecker JL, Thadhani R. First-trimester C-reactive protein and subsequent gestational diabetes. Diabetes Care. 2003;26:819–824. doi: 10.2337/diacare.26.3.819.
    1. Morisset AS, Dubé MC, Côté JA, Robitaille J, Weisnagel SJ, Tchernof A. Circulating interleukin-6 concentrations during and after gestational diabetes mellitus. Acta Obstet Gynecol Scand. 2011;90:524–530. doi: 10.1111/j.1600-0412.2011.01094.x.
    1. White SL, Pasupathy D, Sattar N, Nelson SM, Lawlor DA, Briley AL, et al. Metabolic profiling of gestational diabetes in obese women during pregnancy. Diabetologia. 2017;60:1903–1912. doi: 10.1007/s00125-017-4380-6.
    1. Durnwald CP, Downes K, Leite R, Elovitz M, Parry S. Predicting persistent impaired glucose tolerance in patients with gestational diabetes: the role of high sensitivity CRP and adiponectin. Diabetes Metab Res Rev. 2018;34:e2958. doi: 10.1002/dmrr.2958.
    1. Kim SM, Romero R, Park JW, Oh KJ, Jun JK, Yoon BH. The relationship between the intensity of intra-amniotic inflammation and the presence and severity of acute histologic chorioamnionitis in preterm gestation. J Matern Neonatal Med. 2015;28:1500–1509. doi: 10.3109/14767058.2014.961009.
    1. Kruit H, Heikinheimo O, Sorsa T, Juhila J, Paavonen J, Rahkonen L. Cervical biomarkers as predictors of successful induction of labour by Foley catheter. J Obstet Gynaecol (Lahore) 2018;38:927–932. doi: 10.1080/01443615.2018.1434763.
    1. Akcalı A, Gümüş P, Özçaka Ö, Öztürk-Ceyhan B, Tervahartiala T, Husu H, et al. Proteolytic mediators in gestational diabetes mellitus and gingivitis. J Periodontol. 2017;88:289–297. doi: 10.1902/jop.2016.160158.
    1. Lappas M. Insulin-like growth factor-binding protein 1 and 7 concentrations are lower in obese pregnant women, women with gestational diabetes and their fetuses. J Perinatol. 2015;35:32–38. doi: 10.1038/jp.2014.144.
    1. Madeleneau D, Buffat C, Mondon F, Grimault H, Rigourd V, Tsatsaris V, et al. Transcriptomic analysis of human placenta in intrauterine growth restriction. Pediatr Res. 2015;77:799–807. doi: 10.1038/pr.2015.40.
    1. Loukovaara M, Leinonen P, Teramo K, Nurminen E, Andersson S, Rutanen E-M. Effect of maternal diabetes on phosphorylation of insulin-like growth factor binding protein-1 in cord serum. Diabet Med. 2005;22:434–439. doi: 10.1111/j.1464-5491.2005.01430.x.
    1. Desai N, Roman A, Rochelson B, Gupta M, Xue X, Chatterjee PK, et al. Maternal metformin treatment decreases fetal inflammation in a rat model of obesity and metabolic syndrome. Am J Obstet Gynecol. 2013;209:136. doi: 10.1016/j.ajog.2013.05.001.
    1. Goldberg RB, Temprosa MG, Mather KJ, Orchard TJ, Kitabchi AE, Watson KE. Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention program except in those who develop diabetes. Diabetes Care. 2014;37:2253–2260. doi: 10.2337/dc13-2471.
    1. Suikkari AM, Koivisto VA, Koistinen R, Seppälä M, Yki-Järvinen H. Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin. J Clin Endocrinol Metab. 1989;68:135–140. doi: 10.1210/jcem-68-1-135.
    1. Pawelczyk L, Spaczynski RZ, Banaszewska B, Duleba AJ. Metformin therapy increases insulin-like growth factor binding protein-1 in hyperinsulinemic women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2004;113:209–213. doi: 10.1016/j.ejogrb.2003.09.031.
    1. Tertti K, Ekblad U, Koskinen P, Vahlberg T, Rönnemaa T. Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Diabetes. Obes Metab. 2013;15:246–251. doi: 10.1111/dom.12017.
    1. Nuutila M, Hiilesmaa V, Kärkkäinen T, Ylikorkala O, Rutanen EM. Phosphorylated isoforms of insulin-like growth factor binding protein-1 in the cervix as a predictor of cervical ripeness. Obstet Gynecol. 1999;94:243–249. doi: 10.1097/00006250-199908000-00017.
    1. Soininen P, Kangas AJ, Wurtz P, Tukiainen T, Tynkkynen T, Laatikainen R, et al. High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism. Analyst. 2009;134:1781–1785. doi: 10.1039/b910205a.
    1. Pihkala J, Hakala T, Voutilainen P, Raivio K. Characteristic of recent fetal growth curves in Finland. Duodecim. 1989;105:1540–1546.
    1. Kormi I, Nieminen MT, Havulinna AS, Zeller T, Blankenberg S, Tervahartiala T, et al. Matrix metalloproteinase-8 and tissue inhibitor of matrix metalloproteinase-1 predict incident cardiovascular disease events and all-cause mortality in a population-based cohort. Eur J Prev Cardiol. 2017;24:1136–1144. doi: 10.1177/2047487317706585.
    1. Akinkuolie AO, Buring JE, Ridker PM, Mora S. A novel protein glycan biomarker and future cardiovascular disease events. J Am Heart Assoc. 2014;3:e001221. doi: 10.1161/JAHA.114.001221.
    1. Christian LM, Porter K. Longitudinal changes in serum proinflammatory markers across pregnancy and postpartum: effects of maternal body mass index. Cytokine. 2014;70:134–140. doi: 10.1016/j.cyto.2014.06.018.
    1. Barrett HL, Gatford KL, Houda CM, De Blasio MJ, McIntyre HD, Callaway LK, et al. Maternal and neonatal circulating markers of metabolic and cardiovascular risk in the metformin in gestational diabetes (MiG) trial: responses to maternal metformin versus insulin treatment. Diabetes Care. 2013;36:529–536. doi: 10.2337/dc12-1097.
    1. Kuzmicki M, Telejko B, Zonenberg A, Szamatowicz J, Kretowski A, Nikolajuk A, et al. Circulating pro- and anti-inflammatory cytokines in polish women with gestational diabetes. Horm Metab Res. 2008;40:556–560. doi: 10.1055/s-2008-1073166.
    1. Matthews VB, Allen TL, Risis S, Chan MHS, Henstridge DC, Watson N, et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia. 2010;53:2431–2441. doi: 10.1007/s00125-010-1865-y.
    1. Murtha AP, Sinclair T, Hauser ER, Swamy GK, Herbert WNP, Heine RP. Maternal serum cytokines in preterm premature rupture of membranes. Obstet Gynecol. 2007;109:121–127. doi: 10.1097/01.AOG.0000250474.35369.12.
    1. Eppinga RN, Kofink D, Dullaart RPF, Dalmeijer GW, Lipsic E, van Veldhuisen DJ, et al. Effect of metformin on metabolites and relation with myocardial infarct size and left ventricular ejection fraction after myocardial infarction. Circ Cardiovasc Genet. 2017;10:e001564. doi: 10.1161/CIRCGENETICS.116.001564.
    1. Larsson A, Palm M, Hansson LO, Basu S, Axelsson O. Reference values for α1-acid glycoprotein, α1-antitrypsin, albumin, haptoglobin, C-reactive protein, IgA, IgG and IgM during pregnancy. Acta Obstet Gynecol Scand. 2008;87:1084–1088. doi: 10.1080/00016340802428146.
    1. Wang Q, Würtz P, Auro K, Mäkinen V-P, Kangas AJ, Soininen P, et al. Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence. BMC Med. 2016;14:205. doi: 10.1186/s12916-016-0733-0.
    1. Ritchie SC, Würtz P, Nath AP, Abraham G, Havulinna AS, Fearnley LG, et al. The biomarker GlycA is associated with chronic inflammation and predicts long-term risk of severe infection. Cell Syst. 2015;1:293–301. doi: 10.1016/j.cels.2015.09.007.
    1. Akinkuolie AO, Pradhan AD, Buring JE, Ridker PM, Mora S. Novel protein glycan side-chain biomarker and risk of incident type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2015;35:1544–1550. doi: 10.1161/ATVBAHA.115.305635.
    1. Mokkala K, Pellonperä O, Röytiö H, Pussinen P, Rönnemaa T, Laitinen K. Increased intestinal permeability, measured by serum zonulin, is associated with metabolic risk markers in overweight pregnant women. Metabolism. 2017;69:43–50. doi: 10.1016/j.metabol.2016.12.015.
    1. Ashford K, Chavan NR, Wiggins AT, Sayre MM, McCubbin A, Critchfield AS, et al. Comparison of serum and cervical cytokine levels throughout pregnancy between preterm and term births. AJP Rep. 2018;8:e113–e120. doi: 10.1055/s-0038-1656534.
    1. Larsson A, Palm M, Basu S, Axelsson O. Insulin-like growth factor binding protein-1 (IGFBP-1) during normal pregnancy. Gynecol Endocrinol. 2013;29:129–132. doi: 10.3109/09513590.2012.730574.
    1. Jakubowicz DJ, Seppälä M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86:1126–1133.
    1. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358:2003–2015. doi: 10.1056/NEJMoa0707193.
    1. Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, et al. Metformin versus placebo in obese pregnant women without diabetes mellitus. N Engl J Med. 2016;374:434–443. doi: 10.1056/NEJMoa1509819.
    1. Åsvold BO, Eskild A, Jenum PA, Vatten LJ. Maternal concentrations of insulin-like growth factor I and insulin-like growth factor binding protein 1 during pregnancy and birth weight of offspring. Am J Epidemiol. 2011;174:129–135. doi: 10.1093/aje/kwr067.
    1. Balani J, Hyer S, Syngelaki A, Akolekar R, Nicolaides KH, Johnson A, et al. Association between insulin resistance and preeclampsia in obese non-diabetic women receiving metformin. Obstet Med. 2017;10:170–173. doi: 10.1177/1753495X17725465.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe