Advertisement

Relationship Between Plasma Growth Differentiation Factor 15 Levels and Complications of Type 2 Diabetes Mellitus: A Cross-sectional Study

Published:September 13, 2022DOI:https://doi.org/10.1016/j.jcjd.2022.09.116

      Abstract

      Objective

      Our aim in this study was to identify the associations between growth differentiation factor 15 (GDF15) and type 2 diabetes mellitus (T2DM) complications in a community-based population in China.

      Methods

      Based on a cross-sectional study registered in the National Basic Public Health Service for disease management of Changshu in China, a total of 1,689 T2DM patients were enrolled and tested further for plasma GDF15 levels. Macrovascular (cardiovascular disease and diabetic foot) and microvascular (diabetic kidney disease [DKD], diabetic retinopathy and neuropathy) complications were evaluated. Logistic regression models were conducted to identify the associations of GDF15 with the risk of diabetic complications, and linear regression models were used to assess relationships between GDF15 and other clinical features.

      Results

      Overall, 459 of the 1,689 T2DM patients (27.18%) had complications. GDF15 levels were significantly higher in patients with any type of complication compared with their counterparts. With each standard deviation increase of base 10 logarithms of GDF15 (lg-GDF15), the risk of overall complications increased by 1.17-fold (95% confidence interval [CI], 1.03 to 1.32). In contrast to macrovascular complications, associations of GDF15 with microvascular complications appeared to be stronger (adjusted odds ratio [OR], 1.24; 95% CI, 1.08 to 1.43), especially for DKD (adjusted OR, 1.51; 95% CI, 1.19 to 1.93). Subgroup analyses showed that the strength of association between GDF15 and complications varied by distinct age and T2DM duration subgroups. Patients with 2 or more types of complications had higher levels of GDF15 than those with fewer types of complications. Also, linear relationships were identified between GDF15 and several liver and kidney function indices.

      Conclusion

      Higher GDF15 levels were associated with T2DM complications, especially DKD. GDF15 may serve as a biomarker for monitoring the deterioration of T2DM.

      Résumé

      Objectifs

      L’objectif de notre étude était de cerner les associations entre le facteur de différenciation de croissance 15 (GDF15, de l’anglais growth differentiation factor 15) 15 et les complications liées au diabète sucré de type 2 (DST2) d’une population chinoise.

      Méthodes

      Selon une étude transversale sur la prise en charge de la maladie du National Basic Public Health Service de Changshu, en Chine, les 1689 patients atteints du DST2 inscrits ont subi des analyses de laboratoire pour déterminer les concentrations plasmatiques du GDF15. Nous avons évalué les complications macrovasculaires (maladie cardiovasculaire et pied diabétique) et microvasculaires (néphropathie diabétique [ND], rétinopathie et neuropathie diabétiques). Nous avons effectué une régression logistique pour cerner les associations entre le GDF15 et le risque de complications liées au diabète, et utilisé une régression linéaire pour évaluer les relations entre le GDF15 et les autres caractéristiques cliniques.

      Résultats

      Dans l’ensemble, 459 des 1689 patients atteints du DST2 (27,18 %) avaient des complications. Les concentrations du GDF15 étaient significativement plus élevées chez les patients de tout type de complications que leurs homologues. À chaque augmentation de l’écart type des logarithmes de base 10 du GDF15 (lg-GDF15), le risque de complications globales augmentait de 1,17 fois (intervalle de confiance [IC] à 95 %, de 1,03 à 1,32). Contrairement aux complications macrovasculaires, les associations du GDF15 aux complications microvasculaires semblaient être plus fortes (rapport de cotes ajusté [RC], 1,24; IC à 95 %, de 1,08 à 1,43), particulièrement pour la ND (RC ajusté, 1,51; IC à 95 %, de 1,19 à 1,93). Les analyses en sous-groupes montraient que la force de l’association entre le GDF15 et les complications variaient en fonction des sous-groupes d’âge distincts et de durée du DST2. Les patients qui avaient 2 types ou plus de complications avaient des concentrations plus élevées de GDF15 que ceux qui avaient un moins grand nombre de types de complications. De plus, nous avons observé des relations linéaires entre le GDF15 et plusieurs paramètres des bilans hépatique et rénal.

      Conclusion

      Les concentrations plus élevées de GDF15 étaient associées aux complications liées au DST2, particulièrement la ND.

      Keywords

      Mots clés

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Diabetes
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • World Health Organization. 2022
        https://www.who.int/health-topics/diabetes#tab=tab_1
        Date: 2022
        Date accessed: August 1, 2022
        • International Diabetes Federation
        Diabetes Atlas. 9th ed. 2019.
        https://www.diabetesatlas.org
        Date: 2019
        Date accessed: January 1, 2021
        • Ronaldson A.
        • Arias de la Torre J.
        • Prina M.
        • et al.
        Associations between physical multimorbidity patterns and common mental health disorders in middle-aged adults: A prospective analysis using data from the UK Biobank.
        Lancet Reg Health Eur. 2021; 8100149
        • Chatterjee S.
        • Khunti K.
        • Davies M.J.
        Type 2 diabetes.
        Lancet. 2017; 389: 2239-2251
        • Gedebjerg A.
        • Almdal T.P.
        • Berencsi K.
        • et al.
        Prevalence of micro- and macrovascular diabetes complications at time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional baseline study of 6958 patients in the Danish DD2 cohort.
        J Diabetes Complications. 2018; 32: 34-40
        • Kosiborod M.
        • Gomes M.B.
        • Nicolucci A.
        • et al.
        Vascular complications in patients with type 2 diabetes: Prevalence and associated factors in 38 countries (the DISCOVER study program).
        Cardiovasc Diabetol. 2018; 17: 150
        • Win Tin S.T.
        • Kenilorea G.
        • Gadabu E.
        • Tasserei J.
        • Colagiuri R.
        The prevalence of diabetes complications and associated risk factors in Pacific Islands countries.
        Diabetes Res Clin Pract. 2014; 103: 114-118
        • Tancredi M.
        • Rosengren A.
        • Svensson A.M.
        • et al.
        Excess mortality among persons with type 2 diabetes.
        N Engl J Med. 2015; 373: 1720-1732
        • Gerstein H.C.
        • Werstuck G.H.
        Dysglycaemia, vasculopenia, and the chronic consequences of diabetes.
        Lancet Diabetes Endocrinol. 2013; 1: 71-78
        • Bootcov M.R.
        • Bauskin A.R.
        • Valenzuela S.M.
        • et al.
        MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily.
        Proc Natl Acad Sci USA. 1997; 94: 11514-11519
        • Hsiao E.C.
        • Koniaris L.G.
        • Zimmers-Koniaris T.
        • et al.
        Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury.
        Mol Cell Biol. 2000; 20: 3742-3751
        • Kempf T.
        • Wollert K.C.
        Growth-differentiation factor-15 in heart failure.
        Heart Fail Clin. 2009; 5: 537-547
        • Luan H.H.
        • Wang A.
        • Hilliard B.K.
        • et al.
        GDF15 Is an inflammation-induced central mediator of tissue tolerance.
        Cell. 2019; 178: 1231-1244.e11
        • Schlittenhardt D.
        • Schober A.
        • Strelau J.
        • et al.
        Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions.
        Cell Tissue Res. 2004; 318: 325-333
        • Brown D.A.
        • Moore J.
        • Johnen H.
        • et al.
        Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: A potential marker of erosive joint destruction.
        Arthritis Rheum. 2007; 56: 753-764
        • Koopmann J.
        • Buckhaults P.
        • Brown D.A.
        • et al.
        Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.
        Clin Cancer Res. 2004; 10: 2386-2392
        • Lind L.
        • Wallentin L.
        • Kempf T.
        • et al.
        Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: Results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.
        Eur Heart J. 2009; 30: 2346-2353
        • Tsai V.W.W.
        • Husaini Y.
        • Sainsbury A.
        • Brown D.A.
        • Breit S.N.
        The MIC-1/GDF15-GFRAL pathway in energy homeostasis: Implications for obesity, cachexia, and other associated diseases.
        Cell Metab. 2018; 28: 353-368
        • Mullican S.E.
        • Lin-Schmidt X.
        • Chin C.-N.
        • et al.
        GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.
        Nature Med. 2017; 23: 1150-1157
        • Coll A.P.
        • Chen M.
        • Taskar P.
        • et al.
        GDF15 mediates the effects of metformin on body weight and energy balance.
        Nature. 2020; 578: 444-448
        • Johnen H.
        • Lin S.
        • Kuffner T.
        • et al.
        Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1.
        Nat Med. 2007; 13: 1333-1340
        • Lu J.
        • Zhang Y.
        • Dong X.
        • et al.
        Association between MIC-1 and type 2 diabetes: A combined analysis.
        Dis Markers. 2019; 20197284691
        • Kempf T.
        • Guba-Quint A.
        • Torgerson J.
        • et al.
        Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: Results from the XENDOS trial.
        Eur J Endocrinol. 2012; 167: 671
        • Ding Q.
        • Mracek T.
        • Gonzalez-Muniesa P.
        • et al.
        Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes.
        Endocrinology. 2009; 150: 1688-1696
        • Aguilar-Recarte D.
        • Barroso E.
        • Gumà A.
        • et al.
        GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK.
        Cell Rep. 2021; 36109501
        • Pavo N.
        • Wurm R.
        • Neuhold S.
        • et al.
        GDF-15 is associated with cancer incidence in patients with type 2 diabetes.
        Clin Chem. 2016; 62: 1612-1620
        • Carlsson A.C.
        • Nowak C.
        • Lind L.
        • et al.
        Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: A proteomics approach.
        Ups J Med Sci. 2020; 125: 37-43
        • Shin M.Y.
        • Kim J.M.
        • Kang Y.E.
        • et al.
        Association between growth differentiation factor 15 (GDF15) and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus.
        J Korean Med Sci. 2016; 31: 1413-1418
        • Frimodt-Møller M.
        • von Scholten B.J.
        • Reinhard H.
        • et al.
        Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes–an observational follow-up study.
        PLoS One. 2018; 13e0196634
        • Mazagova M.
        • Buikema H.
        • van Buiten A.
        • et al.
        Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes.
        Am J Physiol Renal Physiol. 2013; 305: F1249-F1264
      1. Standards of medical care in diabetes---2013.
        Diabetes Care. 2013; 36: S11-S66
        • Wiklund F.E.
        • Bennet A.M.
        • Magnusson P.K.
        • et al.
        Macrophage inhibitory cytokine-1 (MIC-1/GDF15): A new marker of all-cause mortality.
        Aging Cell. 2010; 9: 1057-1064
        • Jha J.C.
        • Ho F.
        • Dan C.
        • Jandeleit-Dahm K.
        A causal link between oxidative stress and inflammation in cardiovascular and renal complications of diabetes.
        Clin Sci (Lond). 2018; 132: 1811-1836
        • Liu H.
        • Lyu Y.N.
        • Li D.
        • Cui Y.
        • Dai W.
        • Li Y.
        Association of circulating growth differentiation factor-15, Krüppel-like factor 4 and growth arrest-specific 6 with coronary artery disease.
        Clin Chim Acta. 2019; 495: 630-636
        • Li E.
        • Chen P.
        • Lu J.
        • et al.
        Serum growth differentiation factor 15 is closely associated with metabolic abnormalities in Chinese pregnant women.
        J Diabetes Investig. 2021; 12: 1501-1507
        • Chung J.O.
        • Chung M.Y.
        • Park S.Y.
        • Cho D.H.
        • Chung D.J.
        Relationship between plasma growth differentiation factor-15 level and estimated glomerular filtration rate in type 2 diabetes patients with and without albuminuria.
        J Diabetes Complications. 2021; 107849
        • Nair V.
        • Robinson-Cohen C.
        • Smith M.R.
        • et al.
        Growth differentiation factor-15 and risk of CKD progression.
        J Am Soc Nephrol. 2017; 28: 2233-2240
        • Hellemons M.E.
        • Mazagova M.
        • Gansevoort R.T.
        • et al.
        Growth-differentiation factor 15 predicts worsening of albuminuria in patients with type 2 diabetes.
        Diabetes Care. 2012; 35: 2340-2346
        • Li J.
        • Yang L.
        • Qin W.
        • Zhang G.
        • Yuan J.
        • Wang F.
        Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus.
        PLoS One. 2013; 8e65549
        • Ho F.M.
        • Lin W.W.
        • Chen B.C.
        • et al.
        High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-κB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway.
        Cell Signal. 2006; 18: 391-399
        • Bao X.
        • Borne Y.
        • Muhammad I.F.
        • et al.
        Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: The Malmo Diet and Cancer–Cardiovascular Cohort.
        Diabetologia. 2019; 62: 78-86
        • Fujita Y.
        • Taniguchi Y.
        • Shinkai S.
        • Tanaka M.
        • Ito M.
        • et al.
        Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders.
        Geriatr Gerontol Int. 2016; 16: 17-29
        • Simm A.
        • Nass N.
        • Bartling B.
        • Hofmann B.
        • Silber R.E.
        • Navarrete Santos A.
        Potential biomarkers of ageing.
        Biol Chem. 2008; 389: 257-265
        • Daniels L.B.
        • Clopton P.
        • Laughlin G.A.
        • Maisel A.S.
        • Barrett-Connor E.J.C.
        Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: The Rancho Bernardo Study.
        Circulation. 2011; 123: 2101-2110
        • Ho J.E.
        • Mahajan A.
        • Chen M.H.
        • et al.
        Clinical and genetic correlates of growth differentiation factor 15 in the community.
        Clin Chem. 2012; 58: 1582-1591
        • Tsai V.
        • Zhang H.
        • Manandhar R.
        • et al.
        Treatment with the TGF-b superfamily cytokine MIC-1/GDF15 reduces the adiposity and corrects the metabolic dysfunction of mice with diet-induced obesity.
        Int J Obes (Lond). 2018; 42: 561-571
        • Zhang M.
        • Sun W.
        • Qian J.
        • Tang Y.
        Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in liver.
        Redox Biol. 2018; 16: 87-96

      References

        • Wilkinson C.P.
        • Ferris 3rd, F.L.
        • Klein R.E.
        • et al.
        Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales.
        Ophthalmology. 2003; 110: 1677-1682
        • Tuttle K.R.
        • Bakris G.L.
        • Bilous R.L.
        • et al.
        Diabetic kidney disease: A report from an ADA Consensus Conference.
        Diabetes Care. 2014; 37: 2864-2883
      1. Guidelines for Prevention and Care of Type 2 Diabetes in China [in Chinese].
        J Chin J Diabetes. 2012; 20: 81-117
      2. Guideline for diagnosis and treatment of patients with ST-elevation myocardial infarction [in Chinese].
        Zhonghua Xin Xue Guan Bing Za Zhi. 2010; 38: 675-690
      3. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes [in Chinese].
        Zhonghua Xin Xue Guan Bing Za Zhi. 2012; 40: 353-367
        • Rao M.
        China Guideline for Cerebrovascular Disease Prevention and Treatment.
        People’s Medical Publishing House, Beijing2007 (pg. 145)
      4. Guidelines for the diagnosis and treatment of chronic heart failure [in Chinese].
        Zhonghua Xin Xue Guan Bing Za Zhi. 2007; 35: 1076-1095
      5. Guidelines for the diagnosis and treatment of acute heart failure [in Chinese].
        Zhonghua Shen Jing Ke Za Zhi. 2010; : 146-153