Genetic susceptibility to pre diabetes mellitus and related association with obesity and physical fitness components in Mexican-Mestizos

  • Paula Costa-Urrutia
    Corresponding author at: Department of Cell and Developmental Biology Institute of Biomedical Sciences, Faculty of Medicine, University of São Paulo, Av. Prof. Lineu Prestes, 2415, São Paulo, Brazil.
    Department of Cell and Developmental Biology Institute of Biomedical Sciences, Faculty of Medicine, University of São Paulo, Av. Prof. Lineu Prestes, 2415, São Paulo, Brazil

    Sport City, SA de CV, Grupo Marti, Blvd Adolfo López Mateos 1181, San Pedro de los Pinos, ZC: 01180 Álvaro Obregón, Mexico City, Mexico
    Search for articles by this author
  • Carolina Abud
    Sport City, SA de CV, Grupo Marti, Blvd Adolfo López Mateos 1181, San Pedro de los Pinos, ZC: 01180 Álvaro Obregón, Mexico City, Mexico
    Search for articles by this author
  • Valentina Franco-Trecu
    Departamento de Ecología y Evolución, Facultad de Ciencias, Universidad de la República, Iguá 4225, ZC: 11400 Montevideo, Uruguay
    Search for articles by this author
  • Valentina Colistro
    Departamento de Genética, Facultad de Medicina, Universidad de la República, Av. Gral. Flores 2125, ZC: 11800 Montevideo, Uruguay
    Search for articles by this author
  • Martha Eunice Rodríguez-Arellano
    Laboratorio de Medicina Genómica del Hospital Regional Lic, Adolfo López Mateos, ISSSTE, Av. Universidad 1321, Florida, ZC: 01030 Álvaro Obregón, Mexico City, Mexico
    Search for articles by this author
  • Julio Granados
    División de Inmunogenética, Departamento de Trasplantes, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Tlalpan, ZC: 14080, Mexico City, Mexico
    Search for articles by this author
  • Marilia Seelaender
    Department of Cell and Developmental Biology Institute of Biomedical Sciences, Faculty of Medicine, University of São Paulo, Av. Prof. Lineu Prestes, 2415, São Paulo, Brazil
    Search for articles by this author


      • Pre diabetes mellitus (pre-DM) was associated to ASCL1 rs9997745 and PPARGC1A rs8192678 mutations.
      • The effect of ASCL1 rs9997745 on pre-DM was modulated by obesity.
      • PPARGC1A rs8192678 was associated to pre-DM risk in subjects with obesity.
      • For PPARGC1A rs8192678 the effect was attenuated by higher cardiorespiratory values.
      • Genetic assessment may help preventing pre-DM from progressing to type two diabetes.


      Pre diabetes mellitus (pre-DM) is considered an early-reversible condition that can progress to Type 2 diabetes mellitus (T2DM) which is the main cause of death for adult Mexican population. Gene variants influencing fasting glucose levels may constitute helpful tool for prevention purposes in pre-DM condition. Physically active Mexican-Mestizo adults (n = 565) were genotyped for 6 single nucleotide polymorphisms (SNPs) (ADIPOQ rs2241766, ACSL1 rs9997745, LIPC rs1800588, PPARA rs1800206, PPARG rs1801282 and PPARGC1A rs8192678) related to lipid and carbohydrate metabolism. Fasting glucose was measured and values classified as pre-DM (≥100 mg/dL) or normal fasting glucose. Logistic models were used to test associations between pre-DM condition and SNPs, and interaction with Body Mass Index (BMI) and physical fitness components. The A allele of ASCL1 rs9997745 conferred increased risk (OR = 3.39, p = 0.001) of pre-DM which is modulated by BMI. The A allele of the PPARGC1A rs8192678 showed significant SNP*BMI (OR = 1.10, p = 0.008) interaction effect for pre-DM risk, meaning that obese subjects showed higher pre-DM risk but normal weight subjects showed lower risk. The effect increased with age and was attenuated by higher cardiorespiratory values. We found that both ACSL1 rs9997745 and PPARGC1A rs8192678 are associated with pre-DM, and that BMI significantly modified their association.


      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 Primary Care Diabetes
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Tuso P.
        Prediabetes and lifestyle modification: time to prevent a preventable disease.
        Perm. J. 2014; 18: 88-93
        • Rull J.A.
        • Aguilar-Salinas C.A.
        • Rojas R.
        • Rios-Torres J.M.
        • Gómez-Pérez F.J.
        • Olaiz G.
        Epidemiology of type 2 diabetes in Mexico.
        Arch. Med. Res. 2005; 36: 188-196
        • Olaiz G.R.
        • Shamah J.
        • Rojas T.
        • Villalpando R.
        Encuesta nacional de salud y nutrición 2006.
        • Genuth S.
        • Alberti K.
        • Bennett P.
        • Buse J.
        • DeFronzo R.
        • Kahn R.
        • Kitzmiller J.
        • Knowler W.C.
        • Lebovitz H.
        • Lernmark A.
        Follow-up report on the diagnosis of diabetes mellitus.
        Diabetes Care. 2003; 26: 3160-3168
        • ACSM
        Acsm’s Guidelines for Exercise Testing and Prescription.
        Wolters Kluwer. Lippincott Williams & Wilkins, Philadelphia2013
        • Santos R.L.
        • Zillikens M.C.
        • Rivadeneira F.R.
        • Pols H.A.
        • Oostra B.A.
        • van Duijn C.M.
        • Aulchenko Y.S.
        Heritability of fasting glucose levels in a young genetically isolated population.
        Diabetologia. 2006; 49: 667-672
        • Dupuis J.
        • Langenberg C.
        • Prokopenko I.
        • Saxena R.
        • Soranzo N.
        • Jackson A.U.
        • Wheeler E.
        • Glazer N.L.
        • Bouatia-Naji N.
        • Gloyn A.L.
        New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
        Nat. Genet. 2010; 42: 105-116
        • Martínez-Gómez L.E.
        • Cruz M.
        • Martínez-Nava G.A.
        • Madrid-Marina V.
        • Parra E.
        • García-Mena J.
        • Espinoza-Rojo M.
        • Estrada-Velasco B.I.
        • Piza-Roman L.F.
        • Aguilera P.
        A replication study of the IRS1, CAPN10, TCF7L2, and PPARG gene polymorphisms associated with type 2 diabetes in two different populations of Mexico.
        Ann. Hum. Genet. 2011; 75: 612-620
        • Gamboa-Meléndez M.A.
        • Huerta-Chagoya A.
        • Moreno-Macías H.
        • Vázquez-Cárdenas P.
        • Ordóñez-Sánchez M.L.
        • Rodríguez-Guillén R.
        • Riba L.
        • Rodríguez-Torres M.
        • Guerra-García M.T.
        • Guillén-Pineda L.E.
        Contribution of common genetic variation to the risk of type 2 diabetes in the Mexican Mestizo population.
        Diabetes. 2012; 61: 3314-3321
        • Cruz M.
        • Valladares-Salgado A.
        • Garcia-Mena J.
        • Ross K.
        • Edwards M.
        • Angeles-Martinez J.
        • Ortega-Camarillo C.
        • Escobedo de la Pena J.
        • Burguete-Garcia A.
        • Wacher-Rodarte N.
        Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico city.
        Diabet. Metab. Res. Rev. 2010; 26: 261-–270
        • del Bosque-Plata L.
        • Aguilar-Salinas C.A.
        • Tusié-Luna M.a.T.
        • Ramı́rez-Jiménez S.
        • Rodrı́guez-Torres M.
        • Aurón-Gómez M.
        • Ramı́rez E.
        • Velasco-Pérez M.a.L.
        • Ramı́rez-Silva A.
        • Gómez-Pérez F.
        Association of the calpain-10 gene with type 2 diabetes mellitus in a Mexican population.
        Mol. Genet. Metab. 2004; 81: 122-126
        • Burguete-Garcia A.I.
        • Cruz-Lopez M.
        • Madrid-Marina V.
        • Lopez-Ridaura R.
        • Hernández-Ávila M.
        • Cortina B.
        • Gómez R.E.
        • Velasco-Mondragón E.
        Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: a candidate gene study.
        Metabolism. 2010; 59: 38-45
        • Villarreal-Molina M.T.
        • Flores-Dorantes M.T.
        • Arellano-Campos O.
        • Villalobos-Comparan M.
        • Rodríguez-Cruz M.
        • Miliar-García A.
        • Huertas-Vazquez A.
        • Menjivar M.
        • Romero-Hidalgo S.
        • Wacher N.H.
        Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population.
        Diabetes. 2008; 57: 509-513
        • Consortium S.T.D.
        Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.
        Nature. 2014; 506: 97-101
        • Parra E.
        • Below J.
        • Krithika S.
        • Valladares A.
        • Barta J.
        • Cox N.
        • Hanis C.
        • Wacher N.
        • Garcia-Mena J.
        • Hu P.
        Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas.
        Diabetologia. 2011; 54: 2038-2046
        • Vander Molen J.
        • Frisse L.
        • Fullerton S.
        • Qian Y.
        • Del Bosque-Plata L.
        • Hudson R.
        • Di Rienzo A.
        Population genetics of CAPN10 and GPR35: implications for the evolution of type 2 diabetes variants.
        Am. J. Hum. Genet. 2005; 76: 548-560
        • Posadas-Sánchez R.
        • Ocampo-Arcos W.A.
        • López-Uribe Á.R.
        • Posadas-Romero C.
        • Villarreal-Molina T.
        • León E.Á.
        • Pérez-Hernández N.
        • Rodríguez-Pérez J.M.
        • Cardoso-Saldaña G.
        • Medina-Urrutia A.
        Hepatic lipase (LIPC) C-514T gene polymorphism is associated with cardiometabolic parameters and cardiovascular risk factors but not with fatty liver in Mexican population.
        Exp. Mol. Pathol. 2015; 98: 93-98
        • Vázquez-Del Mercado M.
        • Guzmán-Ornelas M.-O.
        • Corona Meraz F.-I.
        • Ríos-Ibarra C.-P.
        • Reyes-Serratos E.-A.
        • Castro-Albarran J.
        • Ruíz-Quezada S.-L.
        • Navarro-Hernández R.-E.
        The 482Ser of PPARGA and 12Pro of PPARG2 alleles are associated with reduction of metabolic risk factors even obesity in a Mexican-Mestizo population.
        BioMed Res. Int. 2015;
        • Povel C.
        • Feskens E.
        • Imholz S.
        • Blaak E.
        • Boer J.
        • Dollé M.
        Glucose levels and genetic variants across transcriptional pathways: interaction effects with BMI.
        Int. J. Obes. 2010; 34: 840-845
        • Cauchi S.
        • Nead K.T.
        • Choquet H.
        • Horber F.
        • Potoczna N.
        • Balkau B.
        • Marre M.
        • Charpentier G.
        • Froguel P.
        • Meyre D.
        The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies.
        BMC Med. Genet. 2008; 9: 1
        • Lukacs K.
        • Hosszufalusi N.
        • Dinya E.
        • Bakacs M.
        • Madacsy L.
        • Panczel P.
        The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study.
        Diabetologia. 2012; 55: 689-693
        • Häkkinen K.
        Neuromuscular and hormonal adaptations during strength and power training. A review.
        J. Sports Med. Phys. Fit. 1989; 29: 9-–26
        • Costa-Urrutia P.
        • Abud C.
        • Franco-Trecu V.
        • Colistro V.
        • Rodríguez-Arellano M.E.
        • Vázquez-Pérez J.
        • Granados J.
        • Seelaender M.
        Genetic obesity risk and attenuation effect of physical fitness in Mexican-Mestizo population: a case-control study.
        Ann. Hum. Genet. 2017;
        • Cooper K.H.
        A means of assessing maximal oxygen intake: correlation between field and treadmill testing.
        JAMA. 1968; 203: 201-204
        • Chamberlain J.J.
        • Rhinehart A.S.
        • Shaefer C.F.
        • Neuman A.
        Diagnosis and management of diabetes: synopsis ofthe 2016 American Diabetes Association standards of medical care in diabetes synopsis of the 2016 ADA standards of medical care in diabetes.
        Ann. Intern. Med. 2016; 164: 542-–552
        • McGarry J.D.
        Banting lecture 2001.
        Diabetes. 2002; 51: 7-18
        • Dedoussis G.
        • Kaliora A.C.
        • Panagiotakos D.B.
        Genes, diet and type 2 diabetes mellitus: a review.
        Rev. Diabet. Stud. 2007; 4: 13-–24
        • Phillips C.M.
        • Goumidi L.
        • Bertrais S.
        • Field M.R.
        • Cupples L.A.
        • Ordovas J.M.
        • Defoort C.
        • Lovegrove J.A.
        • Drevon C.A.
        • Gibney M.J.
        Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome.
        J. Lipid Res. 2010; 51: 1793-1800
        • Manichaikul A.
        • Wang X.-Q.
        • Zhao W.
        • Wojczynski M.K.
        • Siebenthall K.
        • Stamatoyannopoulos J.A.
        • Saleheen D.
        • Borecki I.B.
        • Reilly M.P.
        • Rich S.S.
        Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes and subclinical atherosclerosis.
        J. Lipid Res. 2015;
        • Matsubara M.
        • Maruoka S.
        • Katayose S.
        Decreased plasma adiponectin concentrations in women with dyslipidemia.
        J. Clin. Endocrinol. Metab. 2002; 87: 2764-2769
        • Lindsay R.S.
        • Funahashi T.
        • Hanson R.L.
        • Matsuzawa Y.
        • Tanaka S.
        • Tataranni P.A.
        • Knowler W.C.
        • Krakoff J.
        Adiponectin and development of type 2 diabetes in the Pima Indian population.
        Lancet. 2002; 360: 57-58
        • Carr M.C.
        • Hokanson J.E.
        • Deeb S.S.
        • Purnell J.Q.
        • Mitchell E.S.
        • Brunzell J.D.
        A hepatic lipase gene promoter polymorphism attenuates the increase in hepatic lipase activity with increasing intra-abdominal fat in women.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2701-2707
        • Cohen J.C.
        • Vega G.L.
        • Grundy S.M.
        Hepatic lipase: new insights from genetic and metabolic studies.
        Curr. Opin. Lipidol. 1999; 10: 259-268
        • McCarty M.F.
        Up-regulation of PPARγ coactivator-1α as a strategy for preventing and reversing insulin resistance and obesity.
        Med. Hypotheses. 2005; 64: 399-407
        • Barroso I.
        • Luan J.
        • Sandhu M.
        • Franks P.
        • Crowley V.
        • Schafer A.
        • O’rahilly S.
        • Wareham N.
        Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes.
        Diabetologia. 2006; 49: 501-505
        • Altshuler D.
        • Hirschhorn J.N.
        • Klannemark M.
        • Lindgren C.M.
        • Vohl M.-C.
        • Nemesh J.
        • Lane C.R.
        • Schaffner S.F.
        • Bolk S.
        • Brewer C.
        The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.
        Nat. Genet. 2000; 26: 76-80
        • Silva-Zolezzi I.
        • Hidalgo-Miranda A.
        • Estrada-Gil J.
        • Fernandez-Lopez J.C.
        • Uribe-Figueroa L.
        • Contreras A.
        • Balam-Ortiz E.
        • del Bosque-Plata L.
        • Velazquez-Fernandez D.
        • Lara C.
        Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico.
        Proc. Natl. Acad. Sci. 2009; 106: 8611-8616
        • Spurgeon S.L.
        • Jones R.C.
        • Ramakrishnan R.
        High throughput gene expression measurement with real time PCR in a microfluidic dynamic array.
        PLoS One. 2008; 3e1662
        • Wang J.
        • Lin M.
        • Crenshaw A.
        • Hutchinson A.
        • Hicks B.
        • Yeager M.
        • Berndt S.
        • Huang W.-Y.
        • Hayes R.B.
        • Chanock S.J.
        High-throughput single nucleotide polymorphism genotyping using nanofluidic dynamic arrays.
        BMC Genom. 2009; 10: 561
        • Purcell S.
        • Neale B.
        • Todd-Brown K.
        • Thomas L.
        • Ferreira M.A.
        • Bender D.
        • Maller J.
        • Sklar P.
        • De Bakker P.I.
        • Daly M.J.
        PLINK: a tool set for whole-genome association and population-based linkage analyses.
        Am. J. Hum. Genet. 2007; 81: 559-575
        • McCullagh P.
        • Nelder J.A.
        Generalized Linear Models.
        CRC Press, 1989
        • Burnham K.P.
        • Anderson D.R.
        Multimodel inference understanding AIC and BIC in model selection.
        Sociol. Methods Res. 2004; 33: 261-304
        • R Core Team
        R: A Language and Environment for Statistical Computing.
        R Foundation for Statistical Computing, Vienna, Austria2013 (ISBN 3-900051-07-0)
        • Hordern M.D.
        • Dunstan D.W.
        • Prins J.B.
        • Baker M.K.
        • Singh M.A.F.
        • Coombes J.S.
        Exercise prescription for patients with type 2 diabetes and pre-diabetes: a position statement from Exercise and Sport Science Australia.
        J. Sci. Med. Sport. 2012; 15: 25-31
        • Thorisson G.A.
        • Smith A.V.
        • Krishnan L.
        • Stein L.D.
        The international HapMap project web site.
        Genome Res. 2005; 15: 1592-1593
        • Torroni A.
        • Schurr T.G.
        • Cabell M.F.
        • Brown M.D.
        • Neel J.V.
        • Larsen M.
        • Smith D.G.
        • Vullo C.M.
        • Wallace D.C.
        Asian affinities and continental radiation of the four founding Native American mtDNAs.
        Am. J. Hum. Genet. 1993; 53: 563-590
        • Lehman J.J.
        • Barger P.M.
        • Kovacs A.
        • Saffitz J.E.
        • Medeiros D.M.
        • Kelly D.P.
        Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis.
        J. Clin. Investig. 2000; 106: 847-856
        • Handschin C.
        • Spiegelman B.M.
        Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism.
        Endocr. Rev. 2006; 27: 728-–735
        • Gillberg L.
        • Jacobsen S.
        • Ribel-Madsen R.
        • Gjesing A.P.
        • Boesgaard T.W.
        • Ling C.
        • Pedersen O.
        • Hansen T.
        • Vaag A.
        Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes?.
        PloS one. 2013; 8e58384
        • Patti M.-E.
        Gene expression in humans with diabetes and prediabetes: what have we learned about diabetes pathophysiology?.
        Curr. Opin. Clin. Nutr. Metab. Care. 2004; 7: 383-390