Effect of the GSTM1 gene deletion on glycemic variability, sympatho-vagal balance and arterial stiffness in patients with metabolic syndrome, but without diabetes

Published:February 13, 2018DOI:



      An increased rate of cerebrovascular complications in patients with metabolic syndrome (MetS) has been reported. Previous studies demonstrated an association between glycemic variability (GV) and cerebrovascular reactivity (CRV) in MetS, thus suggesting a putative role of GV on cerebrovascular events. Although the pathophysiological mechanism linking GV to damage is still to be elucidated, evidence suggests oxidative stress plays a crucial role. Since functional variants in glutathione S-transferases (GST) genes modulate the cellular detoxification processes, the aim of this study was to elucidate the involvement of GSTs in MetS and investigating the correlation with GV, arterial stiffness, and sympatho-vagal (SV) balance.


      A hundred metabolic syndrome patients without diabetes underwent GST gene polymorphism analysis and a sub-sample 36 patients were randomly selected to investigate the correlation between GST gene polymorphisms and GV, and sympatho-vagal (SV) balance and arterial stiffness.


      GSTM1 showed a significant association with several GV, arterial stiffness, and SV balance indexes. In particular, the GSTM1 deletion positively correlates with lower values of these indexes when compared to the presence of the gene.


      Therefore, we suggested a global influence of GSTM1 deletion on the GV, arterial stiffness, and SV balance pathways in MetS patients, probably also interacting with AMP-activated protein kinase (AMPK) regulation.
      Our novel findings indicate GSTM1 could be a risk locus in MetS development and shed light novel scenarios on the role of glucose fluctuations in neurological impairments.


      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 to Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Tune J.D.
        • Goodwill A.G.
        • Sassoon D.J.
        • Mather K.J.
        Cardiovascular consequences of metabolic syndrome.
        Transl Res. 2017; 183: 57-70
        • Air E.L.
        • Kissela B.M.
        Diabetes, the metabolic syndrome, and ischemic stroke: epidemiology and possible mechanisms.
        Diabetes Care. 2007; 30: 3131-3140
        • Yaffe K.
        • Kanaya A.
        • Lindquist K.
        • Simonsick E.M.
        • Harris T.
        • Shorr R.I.
        • et al.
        The metabolic syndrome, inflammation, and risk of cognitive decline.
        JAMA. 2004; 292: 2237-2242
        • Pugazhenthi S.
        Metabolic syndrome and the cellular phase of Alzheimer's disease.
        Prog Mol Biol Transl Sci. 2017; 146: 243-258
        • Rojas-Gutierrez E.
        • Munoz-Arenas G.
        • Trevino S.
        • Espinosa B.
        • Chavez R.
        • Rojas K.
        • et al.
        Alzheimer's disease and metabolic syndrome: a link from oxidative stress and inflammation to neurodegeneration.
        Synapse. 2017;
        • Dekker J.M.
        • Crow R.S.
        • Folsom A.R.
        • Hannan P.J.
        • Liao D.
        • Swenne C.A.
        • et al.
        Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC Study. Atherosclerosis risk in communities.
        Circulation. 2000; 102: 1239-1244
        • Vinik A.I.
        • Erbas T.
        • Casellini C.M.
        Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease.
        J Diabetes Investig. 2013; 4: 4-18
        • Licht C.M.
        • de Geus E.J.
        • Penninx B.W.
        Dysregulation of the autonomic nervous system predicts the development of the metabolic syndrome.
        J Clin Endocrinol Metab. 2013; 98: 2484-2493
        • Picconi F.
        • Di Flaviani A.
        • Malandrucco I.
        • Giordani I.
        • Frontoni S.
        Impact of glycemic variability on cardiovascular outcomes beyond glycated hemoglobin. Evidence and clinical perspectives.
        Nutr Metab Cardiovasc Dis. 2012; 22: 691-696
        • Hirsch I.B.
        Glycemic variability and diabetes complications: does it matter? Of course it does!.
        Diabetes Care. 2015; 38: 1610-1614
        • Di Flaviani A.
        • Picconi F.
        • Di Stefano P.
        • Giordani I.
        • Malandrucco I.
        • Maggio P.
        • et al.
        Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients.
        Diabetes Care. 2011; 34: 1605-1609
        • Frontoni S.
        • Di Bartolo P.
        • Avogaro A.
        • Bosi E.
        • Paolisso G.
        • Ceriello A.
        Glucose variability: an emerging target for the treatment of diabetes mellitus.
        Diabetes Res Clin Pract. 2013; 102: 86-95
        • Giordani I.
        • Di Flaviani A.
        • Picconi F.
        • Malandrucco I.
        • Ylli D.
        • Palazzo P.
        • et al.
        Acute hyperglycemia reduces cerebrovascular reactivity: the role of glycemic variability.
        J Clin Endocrinol Metab. 2014; 99: 2854-2860
        • Buscemi S.
        • Re A.
        • Batsis J.A.
        • Arnone M.
        • Mattina A.
        • Cerasola G.
        • et al.
        Glycaemic variability using continuous glucose monitoring and endothelial function in the metabolic syndrome and in Type 2 diabetes.
        Diabet Med. 2010; 27: 872-878
        • Monnier L.
        • Mas E.
        • Ginet C.
        • Michel F.
        • Villon L.
        • Cristol J.P.
        • et al.
        Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.
        JAMA. 2006; 295: 1681-1687
        • Luque-Contreras D.
        • Carvajal K.
        • Toral-Rios D.
        • Franco-Bocanegra D.
        • Campos-Pena V.
        Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer's disease?.
        Oxid Med Cell Longev. 2014; 2014: 497802
        • Nebert D.W.
        • Vasiliou V.
        Analysis of the glutathione S-transferase (GST) gene family.
        Hum Genomics. 2004; 1: 460-464
        • McIlwain C.C.
        • Townsend D.M.
        • Tew K.D.
        Glutathione S-transferase polymorphisms: cancer incidence and therapy.
        Oncogene. 2006; 25: 1639-1648
        • Iorio A.
        • Polimanti R.
        • Piacentini S.
        • Liumbruno G.M.
        • Manfellotto D.
        • Fuciarelli M.
        Deletion polymorphism of GSTT1 gene as protective marker for allergic rhinitis.
        Clin Respir J. 2015; 9: 481-486
        • Piacentini S.
        • Polimanti R.
        • Iorio A.
        • Cortesi M.
        • Papa F.
        • Rongioletti M.
        • et al.
        GSTA1∗-69C/T and GSTO2∗N142D as asthma- and allergy-related risk factors in Italian adult patients.
        Clin Exp Pharmacol Physiol. 2014; 41: 180-184
        • Polimanti R.
        • Piacentini S.
        • Lazzarin N.
        • Re M.A.
        • Manfellotto D.
        • Fuciarelli M.
        Glutathione S-transferase variants as risk factor for essential hypertension in Italian patients.
        Mol Cell Biochem. 2011; 357: 227-233
        • Piacentini S.
        • Polimanti R.
        • Squitti R.
        • Mariani S.
        • Migliore S.
        • Vernieri F.
        • et al.
        GSTO1∗E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: association hypothesis for an uncommon genetic variant.
        Neurosci Lett. 2012; 506: 203-207
        • Piacentini S.
        • Monaci P.M.
        • Polimanti R.
        • Manfellotto D.
        • Fuciarelli M.
        GSTO2∗N142D gene polymorphism associated with hypothyroidism in Italian patients.
        Mol Biol Rep. 2013; 40: 1967-1971
        • Rao D.K.
        • Shaik N.A.
        • Imran A.
        • Murthy D.K.
        • Ganti E.
        • Chinta C.
        • et al.
        Variations in the GST activity are associated with single and combinations of GST genotypes in both male and female diabetic patients.
        Mol Biol Rep. 2014; 41: 841-848
        • Afrand M.
        • Bashardoost N.
        • Sheikhha M.H.
        • Afkhami-Ardekani M.
        Association between Glutathione S-Transferase GSTM1-T1 and P1 Polymorphisms with Metabolic Syndrome in Zoroastrians in Yazd, Iran.
        Iran J Public Health. 2015; 44: 673-682
        • Rafiee L.
        • Shokouh P.
        • Roohafza H.
        • Mansourian M.
        • Javanmard S.H.
        Association of glutathione S-transferases M1 and T1 gene polymorphisms with the risk of metabolic syndrome in an Iranian population.
        Adv Biomed Res. 2016; 5: 63
        • Baez-Duarte B.G.
        • Zamora-Ginez I.
        • De Jesus K.L.
        • Torres-Rasgado E.
        • Gonzalez-Mejia M.E.
        • Porchia L.
        • et al.
        Association of the metabolic syndrome with antioxidant defense and outstanding superoxide dismutase activity in mexican subjects.
        Metab Syndr Relat Disord. 2016; 14: 154-160
        • Vavrova L.
        • Kodydkova J.
        • Zeman M.
        • Dusejovska M.
        • Macasek J.
        • Stankova B.
        • et al.
        Altered activities of antioxidant enzymes in patients with metabolic syndrome.
        Obes Facts. 2013; 6: 39-47
        • American Diabetes A.
        (2) Classification and diagnosis of diabetes.
        Diabetes Care. 2015; 38: S8-S16
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • Naylor B.A.
        • Treacher D.F.
        • Turner R.C.
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Iorio A.
        • Spinelli M.
        • Polimanti R.
        • Lorenzi F.
        • Valensise H.
        • Manfellotto D.
        • et al.
        GSTA1 gene variation associated with gestational hypertension and its involvement in pregnancy-related pathogenic conditions.
        Eur J Obstet Gynecol Reprod Biol. 2015; 194: 34-37
        • Iorio A.
        • Piacentini S.
        • Polimanti R.
        • De Angelis F.
        • Calderon R.
        • Fuciarelli M.
        Functional variability of glutathione S-transferases in Basque populations.
        Am J Hum Biol. 2014; 26: 361-366
        • Aversa A.
        • Francomano D.
        • Bruzziches R.
        • Pili M.
        • Natali M.
        • Spera G.
        • et al.
        The application of digital pulse amplitude tonometry to the diagnostic investigation of endothelial dysfunction in men with erectile dysfunction.
        Andrologia. 2011; 43: 9-15
        • Hahsler M.
        • Grun B.
        • Hornik K.
        Arules – a computational environment for mining association rules and frequent item sets.
        J Stat Softw. 2005; 14
        • Karaca S.
        • Erge S.
        • Cesuroglu T.
        • Polimanti R.
        Nutritional habits, lifestyle, and genetic predisposition in cardiovascular and metabolic traits in Turkish population.
        Nutrition. 2016; 32: 693-701
        • Miyatake S.
        • Manabe Y.
        • Inagaki A.
        • Furuichi Y.
        • Takagi M.
        • Taoka M.
        • et al.
        Macrophage migration inhibitory factor diminishes muscle glucose transport induced by insulin and AICAR in a muscle type-dependent manner.
        Biochem Biophys Res Commun. 2014; 444: 496-501
        • Rodriguez-Sosa M.
        • Cabellos-Avelar T.
        • Sanchez-Zamora Y.
        • Juarez-Avelar I.
        • Garcia-Reyes E.
        • Lira-Leon A.
        • et al.
        Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function.
        Cytokine. 2017;
        • Khodaeian M.
        • Enayati S.
        • Tabatabaei-Malazy O.
        • Amoli M.M.
        Association between genetic variants and diabetes mellitus in Iranian populations: a systematic review of observational studies.
        J Diabetes Res. 2015; 2015: 585917
        • Zhang J.
        • Liu H.
        • Yan H.
        • Huang G.
        • Wang B.
        Null genotypes of GSTM1 and GSTT1 contribute to increased risk of diabetes mellitus: a meta-analysis.
        Gene. 2013; 518: 405-411
        • Pinheiro D.S.
        • Rocha Filho C.R.
        • Mundim C.A.
        • Junior Pde M.
        • Ulhoa C.J.
        • Reis A.A.
        • et al.
        Evaluation of glutathione S-transferase GSTM1 and GSTT1 deletion polymorphisms on type-2 diabetes mellitus risk.
        PLoS ONE. 2013; 8: e76262
        • Amer M.A.
        • Ghattas M.H.
        • Abo-Elmatty D.M.
        • Abou-El-Ela S.H.
        Influence of glutathione S-transferase polymorphisms on type-2 diabetes mellitus risk.
        Genet Mol Res. 2011; 10: 3722-3730
        • Coughlan K.A.
        • Valentine R.J.
        • Ruderman N.B.
        • Saha A.K.
        AMPK activation: a therapeutic target for type 2 diabetes?.
        Diabetes Metab Syndr Obes. 2014; 7: 241-253
        • Klaus A.
        • Zorman S.
        • Berthier A.
        • Polge C.
        • Ramirez S.
        • Michelland S.
        • et al.
        Glutathione S-transferases interact with AMP-activated protein kinase: evidence for S-glutathionylation and activation in vitro.
        PLoS ONE. 2013; 8: e62497
        • Safar M.E.
        • Levy B.I.
        • Struijker-Boudier H.
        Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases.
        Circulation. 2003; 107: 2864-2869
        • Domanski M.
        • Mitchell G.
        • Pfeffer M.
        • Neaton JD.
        • Norman J.
        • et al.
        Pulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT).
        JAMA. 2002; 287: 2677-2683
        • Nakano S.
        • Konishi K.
        • Furuya K.
        • Uehara K.
        • Nishizawa M.
        • Nakagawa A.
        • et al.
        A prognostic role of mean 24-h pulse pressure level for cardiovascular events in type 2 diabetic subjects under 60 years of age.
        Diabetes Care. 2005; 28: 95-100
        • Jamerson K.A.
        • Julius S.
        • Gudbrandsson T.
        • Andersson O.
        • Brant D.O.
        Reflex sympathetic activation induces acute insulin resistance in the human forearm.
        Hypertension. 1993; 21: 618-623
        • Masuo K.
        • Mikami H.
        • Ogihara T.
        • Tuck M.L.
        Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population.
        Am J Hypertens. 1997; 10: 77-83
        • Fleischer J.
        • Lebech Cichosz S.
        • Hoeyem P.
        • Laugesen E.
        • Loegstrup Poulsen P.
        • Sandahl Christiansen J.
        • et al.
        Glycemic variability is associated with reduced cardiac autonomic modulation in women with type 2 diabetes.
        Diabetes Care. 2015; 38: 682-688