ORIGINAL ARTICLE
Diabetes mellitus and late-onset hypogonadism: the role of Glu298Asp endothelial nitric oxide synthase polymorphism N. delli Muti1, G. Tirabassi1, G. R. Lamonica2, A. Lenzi3 & G. Balercia1 1 Andrology Unit, Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, School of Medicine, Polytechnic University of Marche, Ancona, Italy; 2 Department of Economy, School of Economy, Polytechnic University of Marche, Ancona, Italy; 3 Andrology, Pathophysiology of Reproduction and Endocrine Diagnosis Unit, Policlinic Umberto I, University of Rome “La Sapienza”, Rome, Italy
Keywords Diabetes mellitus—hypogonadism—nitric oxide synthase—polymorphisms Correspondence Giancarlo Balercia, MD, Department of Clinical and Molecular Sciences, School of Medicine, Polytechnic University of Marche, Via Tronto 10/A, 60126 Ancona, Italy. Tel.: 071 5963738; Fax: +39 071/2206119; E-mail: [email protected] Accepted: July 15, 2014 doi: 10.1111/and.12339
Summary Nitric oxide has been associated with insulin resistance and type 2 diabetes mellitus (DM). An association has been suggested between a single nucleotide polymorphism (Glu298Asp variant) of the endothelial nitric oxide synthase (eNOS) gene and increased risk of DM. However, the role of this polymorphism in favouring DM has not been investigated in hypogonadism, in which low testosterone and obesity are believed to play the major role. We aimed to evaluate whether eNOS gene single nucleotide polymorphism (Glu298Asp variant) might give a relevant contribution also to the onset of hypogonadismassociated DM. 110 men affected by late-onset hypogonadism were retrospectively reviewed. Patients were clinically and biochemically evaluated. Detection of eNOS Glu298Asp polymorphism was performed. After splitting the sample according to the three genetic variants (i.e. eNOSGG, eNOSGT, eNOSTT), no difference was evident in age, body mass index (BMI) and total testosterone. Conversely, DM prevalence, glycaemia and glycated haemoglobin were significantly higher in eNOSTT than in eNOSGT and eNOSGG. Logistic regression analysis showed that, after adjustment for age, BMI and total testosterone, eNOSTT was positively and significantly associated with DM. Our study suggests that Glu298Asp single nucleotide polymorphism of the eNOS gene may be an independent risk factor for hypogonadism-associated type 2 DM.
Introduction Nitric oxide (NO) is synthesised by the gene of nitric oxide synthase (NOS) isoenzymes, which are the endothelial (eNOS), neuronal and inducible isoforms (Forstermann & Sessa, 2012). NO has been associated with the onset of insulin resistance and type 2 diabetes mellitus (DM) (Jia et al., 2013). In fact, it has been demonstrated that systemic inhibition of NO synthesis significantly deteriorates glucose tolerance by increasing insulin-clearance and by inhibiting insulin secretion (Jia et al., 2013); also, a moderate increase in NO production could play a positive role in regulating skeletal muscle glucose uptake (Jia et al., 2013). In this regard, an association has been suggested between the presence of a single nucleotide polymorphism (SNP) of the eNOS gene and increased risk of type 2 DM (Jia et al., 2013). This SNP consists of a guanine to © 2014 Blackwell Verlag GmbH Andrologia 2015, 47, 867–871
thymine mutation at nucleotide position 894 of the eNOS cDNA, which causes glutamic acid to be replaced by aspartic acid at codon 298 (Glu298Asp) during eNOS mRNA translation (delli Muti et al., 2014). However, the role of this polymorphism in favouring DM has not been investigated in hypogonadic patients. This aspect gains relevance because a well-known association between the typical low testosterone levels and type 2 DM has been often reported (Corona et al., 2011): this link seems to be due to a complex, bidirectional, physiopathological interrelationship between these two conditions (Corona et al., 2011; Tirabassi et al., 2013b). However, the specific role of the genetic background has not been sufficiently investigated. Given this premise, in this study, we examined a large series of patients affected by late-onset hypogonadism, to evaluate whether eNOS gene SNP (Glu298Asp) might play a relevant role also in the onset of hypogonadismassociated DM. 867
eNOS Glu298Asp in late-onset male hypogonadism
Methods Subjects Registration of patients who attended our andrology unit between 2010 and 2013 was retrospectively reviewed, and 110 hypogonadal Italian men were considered. The following inclusion criteria were adopted: (i) diagnosis of late-onset hypogonadism, based on unequivocally low levels of serum testosterone (total testosterone
Diabetes mellitus and late-onset hypogonadism: the role of Glu298Asp endothelial nitric oxide synthase polymorphism N. delli Muti1, G. Tirabassi1, G. R. Lamonica2, A. Lenzi3 & G. Balercia1 1 Andrology Unit, Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, School of Medicine, Polytechnic University of Marche, Ancona, Italy; 2 Department of Economy, School of Economy, Polytechnic University of Marche, Ancona, Italy; 3 Andrology, Pathophysiology of Reproduction and Endocrine Diagnosis Unit, Policlinic Umberto I, University of Rome “La Sapienza”, Rome, Italy
Keywords Diabetes mellitus—hypogonadism—nitric oxide synthase—polymorphisms Correspondence Giancarlo Balercia, MD, Department of Clinical and Molecular Sciences, School of Medicine, Polytechnic University of Marche, Via Tronto 10/A, 60126 Ancona, Italy. Tel.: 071 5963738; Fax: +39 071/2206119; E-mail: [email protected] Accepted: July 15, 2014 doi: 10.1111/and.12339
Summary Nitric oxide has been associated with insulin resistance and type 2 diabetes mellitus (DM). An association has been suggested between a single nucleotide polymorphism (Glu298Asp variant) of the endothelial nitric oxide synthase (eNOS) gene and increased risk of DM. However, the role of this polymorphism in favouring DM has not been investigated in hypogonadism, in which low testosterone and obesity are believed to play the major role. We aimed to evaluate whether eNOS gene single nucleotide polymorphism (Glu298Asp variant) might give a relevant contribution also to the onset of hypogonadismassociated DM. 110 men affected by late-onset hypogonadism were retrospectively reviewed. Patients were clinically and biochemically evaluated. Detection of eNOS Glu298Asp polymorphism was performed. After splitting the sample according to the three genetic variants (i.e. eNOSGG, eNOSGT, eNOSTT), no difference was evident in age, body mass index (BMI) and total testosterone. Conversely, DM prevalence, glycaemia and glycated haemoglobin were significantly higher in eNOSTT than in eNOSGT and eNOSGG. Logistic regression analysis showed that, after adjustment for age, BMI and total testosterone, eNOSTT was positively and significantly associated with DM. Our study suggests that Glu298Asp single nucleotide polymorphism of the eNOS gene may be an independent risk factor for hypogonadism-associated type 2 DM.
Introduction Nitric oxide (NO) is synthesised by the gene of nitric oxide synthase (NOS) isoenzymes, which are the endothelial (eNOS), neuronal and inducible isoforms (Forstermann & Sessa, 2012). NO has been associated with the onset of insulin resistance and type 2 diabetes mellitus (DM) (Jia et al., 2013). In fact, it has been demonstrated that systemic inhibition of NO synthesis significantly deteriorates glucose tolerance by increasing insulin-clearance and by inhibiting insulin secretion (Jia et al., 2013); also, a moderate increase in NO production could play a positive role in regulating skeletal muscle glucose uptake (Jia et al., 2013). In this regard, an association has been suggested between the presence of a single nucleotide polymorphism (SNP) of the eNOS gene and increased risk of type 2 DM (Jia et al., 2013). This SNP consists of a guanine to © 2014 Blackwell Verlag GmbH Andrologia 2015, 47, 867–871
thymine mutation at nucleotide position 894 of the eNOS cDNA, which causes glutamic acid to be replaced by aspartic acid at codon 298 (Glu298Asp) during eNOS mRNA translation (delli Muti et al., 2014). However, the role of this polymorphism in favouring DM has not been investigated in hypogonadic patients. This aspect gains relevance because a well-known association between the typical low testosterone levels and type 2 DM has been often reported (Corona et al., 2011): this link seems to be due to a complex, bidirectional, physiopathological interrelationship between these two conditions (Corona et al., 2011; Tirabassi et al., 2013b). However, the specific role of the genetic background has not been sufficiently investigated. Given this premise, in this study, we examined a large series of patients affected by late-onset hypogonadism, to evaluate whether eNOS gene SNP (Glu298Asp) might play a relevant role also in the onset of hypogonadismassociated DM. 867
eNOS Glu298Asp in late-onset male hypogonadism
Methods Subjects Registration of patients who attended our andrology unit between 2010 and 2013 was retrospectively reviewed, and 110 hypogonadal Italian men were considered. The following inclusion criteria were adopted: (i) diagnosis of late-onset hypogonadism, based on unequivocally low levels of serum testosterone (total testosterone
