RESUMO
AIMS: Our aims were to investigate in several large samples, with a wide range of adiposity, whether: (1) the effect of BMI on insulin sensitivity is different between sexes; (2) also waist circumference plays a sex-specific role on insulin sensitivity; and (3) serum adiponectin and resistin are mediators of such sex-dimorphic effect. METHODS: Samples used were: Gargano study 1 (GS1), GS2 and Catania study (CS) comprising 3274 individuals. Adiponectin and resistin were measured by ELISA. Associations between variables were tested by linear models. RESULTS: In all samples, relationship between BMI and HOMAIR was steeper in males than in females (BMI-by-sex interaction p = 0.04-0.0007). No interaction was observed on serum adiponectin and resistin (p = 0.40-059), which are therefore unlikely to mediate the sex-dimorphic effect of BMI on insulin resistance. Relationship between waist circumference and HOMAIR was similar between sexes in GS1 and GS2 but not in CS (waist-by-sex interaction p = 0.01), comprising much heavier individuals. This suggests that a sex-dimorphic effect of abdominal adiposity on insulin resistance is observable only in the context of high BMI. CONCLUSIONS: Our findings represent a proof of concept that BMI and insulin sensitivity are associated in a sex-specific manner. This may explain why females are protected from diabetes and cardiovascular disease, compared to males of similar BMI.
Assuntos
Adiposidade , Resistência à Insulina , Sobrepeso/fisiopatologia , Gordura Abdominal , Adiponectina/sangue , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Resistina/sangue , Caracteres Sexuais , Circunferência da CinturaRESUMO
Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552(∗)] and c.280G>A [p.Asp94Asn]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. Both mutations cause APPL1 loss of function. The p.Leu552(∗) alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3ß phosphorylation that is observed after wild-type APPL1 transfection. These findings-linking APPL1 mutations to familial forms of diabetes-reaffirm the critical role of APPL1 in glucose homeostasis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Adulto , Idoso , Feminino , Células Hep G2 , Humanos , Immunoblotting , Insulina/metabolismo , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estados UnidosRESUMO
This study tried to replicate in a large sample of white patients with type 2 diabetes (T2D) from Italy a previously reported association of the IRS1 G972R polymorphism with failure to oral antidiabetes drugs (OAD). A total of 2,409 patients from four independent studies were investigated. Case subjects (n = 1,193) were patients in whom, because of uncontrolled diabetes (i.e., HbA1c >8%), insulin therapy had been added either on, or instead of, maximal or near-maximal doses of OAD, mostly metformin and sulfonylureas; control subjects (n = 1,216) were patients with HbA1c <8% in the absence of insulin therapy. The IRS1 G972R polymorphism was typed by TaqMan allele discrimination. In all samples, individuals carrying the IRS1 R972 risk variant tended to be more frequent among case than control subjects, though reaching statistical significance only in one case. As no IRS1 G972R-by-study sample interaction was observed, data from the four samples were analyzed together; a significant association was observed (allelic odds ratio [OR] 1.30, 95% CI 1.03-1.63). When our present data were meta-analyzed with those obtained in a previous study, an overall R972 allelic OR of 1.37 (1.12-1.69) was observed. This study confirms in a large and ethnically homogeneous sample that IRS1 G972R polymorphism is associated with failure to OAD among patients with T2D.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Proteínas Substratos do Receptor de Insulina/genética , Polimorfismo de Nucleotídeo Único , Idoso , Diabetes Mellitus Tipo 2/genética , Humanos , Itália , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Compostos de Sulfonilureia/uso terapêutico , População Branca/genéticaRESUMO
BACKGROUND: High serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes. METHODS: We tested the association of circulating resistin concentrations with coronary artery disease, major cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and all-cause mortality in 2,313 diabetic patients of European ancestry from two cross-sectional and two prospective studies. In addition, the expression of resistin gene (RETN) was measured in blood cells of 68 diabetic patients and correlated with their serum resistin levels. RESULTS: In a model comprising age, sex, smoking habits, BMI, HbA1c, and insulin, antihypertensive and antidyslipidemic therapies, serum resistin was associated with coronary artery disease in both cross-sectional studies: OR (95%CI) per SD increment = 1.35 (1.10-1.64) and 1.99 (1.55-2.55). Additionally, serum resistin predicted incident major cardiovascular events (HR per SD increment = 1.31; 1.10-1.56) and all-cause mortality (HR per SD increment = 1.16; 1.06-1.26). Adjusting also for fibrinogen levels affected the association with coronary artery disease and incident cardiovascular events, but not that with all cause-mortality. Finally, serum resistin was positively correlated with RETN mRNA expression (rho = 0.343). CONCLUSIONS: This is the first study showing that high serum resistin (a likely consequence, at least partly, of increased RETN expression) is a risk factor for cardiovascular disease and all-cause mortality in diabetic patients of European ancestry.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Resistina/sangue , Doenças Cardiovasculares/complicações , Estudos de Casos e Controles , Intervalos de Confiança , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resistina/genética , Análise de SobrevidaRESUMO
CONTEXT: Reduced insulin signaling in insulin secreting ß-cells causes defective insulin secretion and hyperglycemia in mice. OBJECTIVE: We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH). DESIGN: Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607). RESULTS: Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R(2) = 0.80, P < .001). CONCLUSIONS: Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces ß-cell function and impairs glucose homeostasis.
Assuntos
Glucose/metabolismo , Homeostase , Insulina/metabolismo , Transdução de Sinais , Adulto , Idoso , Proteínas de Ciclo Celular/genética , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Pirofosfatases/genética , Proteínas Repressoras/genéticaRESUMO
OBJECTIVE: To develop and validate a parsimonious model for predicting short-term all-cause mortality in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Two cohorts of patients with T2DM were investigated. The Gargano Mortality Study (GMS, n = 679 patients) was the training set and the Foggia Mortality Study (FMS, n = 936 patients) represented the validation sample. GMS and FMS cohorts were prospectively followed up for 7.40 ± 2.15 and 4.51 ± 1.69 years, respectively, and all-cause mortality was registered. A new forward variable selection within a multivariate Cox regression was implemented. Starting from the empty model, each step selected the predictor that, once included into the multivariate Cox model, yielded the maximum continuous net reclassification improvement (cNRI). The selection procedure stopped when no further statistically significant cNRI increase was detected. RESULTS: Nine variables (age, BMI, diastolic blood pressure, LDL cholesterol, triglycerides, HDL cholesterol, urine albumin-to-creatinine ratio, and antihypertensive and insulin therapy) were included in the final predictive model with a C statistic of 0.88 (95% CI 0.82-0.94) in the GMS and 0.82 (0.76-0.87) in the FMS. Finally, we used a recursive partition and amalgamation algorithm to identify patients at intermediate and high mortality risk (hazard ratio 7.0 and 24.4, respectively, as compared with those at low risk). A web-based risk calculator was also developed. CONCLUSIONS: We developed and validated a parsimonious all-cause mortality equation in T2DM, providing also a user-friendly web-based risk calculator. Our model may help prioritize the use of available resources for targeting aggressive preventive and treatment strategies in a subset of very high-risk individuals.
Assuntos
Diabetes Mellitus Tipo 2/mortalidade , Modelos Teóricos , Idoso , Causas de Morte , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVE: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. DESIGN AND SETTING: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). RESULTS: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009). CONCLUSIONS: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.
Assuntos
Doenças Cardiovasculares/genética , Endotélio Vascular/metabolismo , Resistência à Insulina/genética , Insulina/genética , Transdução de Sinais/genética , Células Cultivadas , Estudos Transversais , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: High serum resistin levels have been associated with kidney dysfunction. Most of these studies have been carried out in individuals with severe kidney impairment, diabetes, cardiovascular disease and related treatments. Thus, the observed association might have been influenced by these confounders. Our aim was to study the relationship between serum resistin, urinary albumin/creatinine ratio (ACR) and glomerular filtration rate (GFR) in a family-based sample, the Gargano Family Study (GFS) of 635 non diabetic, untreated Whites. METHODS: A linear mixed effects model and bivariate analyses were used to evaluate the phenotypic and genetic relations between serum resistin and both ACR and eGFR. All analyses were adjusted for sex, age, age squared, BMI, systolic blood pressure, smoking habits and physical exercise. RESULTS: After adjustments, resistin levels were slightly positively associated with ACR (ß±SEâ=â0.049±0.023, pâ=â0.035) and inversely related to eGFR (ß±SEâ=â-1.43±0.61, pâ=â0.018) levels. These associations remained significant when either eGFR or ACR were, reciprocally, added as covariates. A genetic correlation (ρgâ=â-0.31±0.12; adjusted pâ=â0.013) was observed between resistin and eGFR (but not ACR) levels. CONCLUSION: Serum resistin levels are independently associated with ACR and eGFR in untreated non-diabetic individuals. Serum resistin and eGFR share also some common genetic background. Our data strongly suggest that resistin plays a role in modulating kidney function.
Assuntos
Taxa de Filtração Glomerular/fisiologia , Rim/fisiologia , Resistina/sangue , Fatores Etários , Albuminúria/urina , Pressão Sanguínea , Índice de Massa Corporal , Creatinina/urina , Exercício Físico , Família , Humanos , Modelos Lineares , Fatores Sexuais , Fumar , População BrancaRESUMO
OBJECTIVE: Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). DESIGN AND SETTING: SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case-control studies [n=740 from the Gargano Hearth Study (GHS, Italy); n=818 from the Joslin Hearth Study (JHS, Boston); n=457 from the University of Catanzaro (CZ, Italy)]. RESULTS: SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93-1.21; p=0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12-1.81; p=0.004) and in the three samples analyzed together (1.21, 1.04-1.41; p=0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n=4, p=0.03) but not the G/A (n=5, p=0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site. CONCLUSIONS: Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais da Veia Umbilical Humana/enzimologia , Infarto do Miocárdio/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/genética , Idoso , Boston , Estudos de Casos e Controles , Biologia Computacional , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/genética , Complicações do Diabetes/enzimologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Insulina/metabolismo , Itália , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Insulin resistance has a role in diabetic nephropathy. The A12 variant of the PPARγ2 P121A polymorphism has been firmly associated with reduced risk of insulin resistance, while its role on the risk of albuminuria in patients with type 2 diabetes is uncertain. This study investigated whether the PPARγ2 P12A polymorphism modulates the risk of albuminuria in these patients. METHODS: We tested the association between the A12 variant and albuminuria in three new case-control studies in diabetic patients from Italy (n = 841, n = 623 and n = 714 patients, respectively) and then performed a meta-analysis of all studies available to date. The nine studies we meta-analysed (six previously published and three presented here) comprised a total of 2376 cases and 4188 controls. RESULTS: In none of the three new studies was a significant association observed with odds ratio (OR) [95% confidence intervals (95% CI)] being 1.115, 0.799 and 0.849 (P = 0.603, 0.358 and 0.518, respectively). At meta-analysis, the overall OR (95% CI) for association between A12 and albuminuria was 0.694 (0.528-0.912). A significant heterogeneity of the genetic effect was observed (P = 0.026), which was totally explained by the different method of urine collection and albuminuria definition utilized across the studies. In fact, most of the effect was observed in the four studies determining albumin excretion rate rather than in those using albumin concentration in a single spot (OR, 95% CI: 0.529, 0.397-0.706, P = 0.0000164 and 0.919, 0.733-1.153, P = 0.47, respectively). CONCLUSION: The present study shows that the PPARγ2 Ala12 variant is significantly associated with a reduced risk of albuminuria among patients with type 2 diabetes.
Assuntos
Albuminúria/genética , Diabetes Mellitus Tipo 2/genética , PPAR gama/genética , Polimorfismo Genético , Albuminúria/complicações , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , HumanosRESUMO
Type 2 diabetes mellitus (T2DM) is a complex disorder that has a heterogeneous genetic and environmental background. In this Review, we discuss the role of relatively infrequent polymorphisms of genes that regulate insulin signaling (including the K121Q polymorphism of ENPP1, the G972R polymorphism of IRS1 and the Q84R polymorphism of TRIB3) in T2DM and other conditions related to insulin resistance. The biological relevance of these three polymorphisms has been very thoroughly characterized both in vitro and in vivo and the available data indicate that they all affect insulin signaling and action as well as insulin secretion. They also affect insulin-mediated regulation of endothelial cell function. In addition, several reports indicate that the effects of all three polymorphisms on the risk of T2DM and cardiovascular diseases related to insulin resistance depend on the clinical features of the individual, including their body weight and age at disease onset. Thus, these polymorphisms might be used to demonstrate how difficult it is to ascertain the contribution of relatively infrequent genetic variants with heterogeneous effects on disease susceptibility. Unraveling the role of such variants might be facilitated by improving disease definition and focusing on specific subsets of patients.
Assuntos
Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Transdução de Sinais , Proteínas de Ciclo Celular/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Diester Fosfórico Hidrolases/genética , Proteínas Serina-Treonina Quinases/genética , Pirofosfatases/genética , Proteínas Repressoras/genética , Fatores de Risco , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Type 2 diabetes is becoming epidemic. The personal and social burden imposed by diabetes will increase in the close future as its prevalence is expected to double in the next 15-20 years. Type 2 diabetes is caused by the combination of resistance to insulin action and inadequate insulin secretion. Despite the role of profound changes in individual environmental exposure is incontrovertible, several findings clearly indicate that type 2 diabetes and insulin resistance are also heritable. Among the several inhibitors of insulin signalling, which have been recently proposed as determinants of insulin resistance, is TRIB3, a mammalian tribbles homolog which affects insulin signalling at the level of Akt-2, a key modulator of insulin action in target cells. We here report data on a prevalent Q84R TRIB3 missense single nucleotide polymorphism (rs2295490) we first described few years ago. Several lines of evidences indicate that this amino-acid change is, in fact, a gain of function mutation with the potential to affect insulin signalling and thus, to increase the risk of insulin resistance and related clinical outcomes.
Assuntos
Proteínas de Ciclo Celular/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Substituição de Aminoácidos , Arginina , Efeitos Psicossociais da Doença , Diabetes Mellitus Tipo 2/economia , Diabetes Mellitus Tipo 2/epidemiologia , Variação Genética , Glutamina , Humanos , Incidência , Insulina/fisiologia , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Transdução de SinaisRESUMO
CONTEXT: The prevalence of type 2 diabetes (T2D), particularly among young adults, has been rising steadily during the past 2 decades. T2D, especially in its early-onset subtype, is under genetic control. TRIB3 inhibits insulin-stimulated Akt phosphorylation and subsequent insulin action. A TRIB3 gain-of-function polymorphism, Q84R (rs2295490), impairs insulin signaling. OBJECTIVE: The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped or not according to age at diagnosis (early-onset, <45 yr, or >or= 45 yr); 2) insulin secretion and sensitivity in nondiabetic individuals; or 3) in vitro insulin secretion from isolated human islets. DESIGN: Four different case-control samples comprising a total of 5,469 whites were examined. Insulinogenic and insulin sensitivity indexes and their interplay (disposition index) were assessed in 645 nondiabetic individuals at oral glucose tolerance test, glucose (16.7 mmol/liter)-induced in vitro insulin secretion was assessed in islets isolated from 54 nondiabetic donors. RESULTS: In the whole sample, the R84 variant was nominally associated with T2D (odds ratio 1.17, 95% confidence interval 1.00-1.36, P = 0.04). When stratifying according to age of diabetes onset, R84 carriers had an increased risk of early-onset T2D (odds ratio 1.32, 95% confidence interval 1.10-1.58, P = 0.002). Among 645 nondiabetic subjects, R84 carriers had higher glucose levels (P = 0.005) and lower insulinogenic (P = 0.03) and disposition index (P = 0.02) during the oral glucose tolerance test. R84 islets were more likely to display relatively low glucose-stimulated insulin release (P = 0.04). CONCLUSIONS: The TRIB3 R84 variant is associated with early-onset T2D in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association.
Assuntos
Proteínas de Ciclo Celular/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Adulto , Idade de Início , Idoso , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Conflicting results have been reported regarding the effect of the peroxisome proliferator-activated receptor-gamma-2 (PPARgamma2) Pro12Ala polymorphism, (singly or in combination with the silent C1431T polymorphism) on BMI. Gender-based dimorphism has been evidenced for genes that affect BMI, but few and conflicting data are available regarding PPARgamma2. We sought to investigate whether the Pro12Ala interacts with gender in modulating BMI in 566 nondiabetic unrelated white subjects (men:women = 211:355, age 36.59 +/- 11.85; BMI 25.36 +/- 4.53). In the whole study population, BMI, fasting glucose and insulin levels, and lipid profile were similar in Ala12 carriers (i.e., XA) and Pro/Pro homozygous subjects. Among the men, but not among the women, X/Ala individuals showed higher BMI (25.9 +/- 3.6 vs. 28.2 +/- 4.9, P = 0.006) and risk of obesity (odds ratio = 2.85, 95% confidence interval = 1.07-7.62). A significant gene-gender interaction in modulating BMI was observed (P = 0.039). Among the men, but not among the women, those carrying Ala-T haplotype (i.e., containing both Ala12 and T1431 variants) showed the highest BMI (haplo-score = 3.72, P = 0.0014). Our data indicate that in whites from Italy the PPARgamma2 Pro12Ala polymorphism interacts with gender in modulating BMI, thereby replicating some, but not all, earlier data obtained in different populations. Whether the PPARgamma2-gender interaction is a general phenomenon across different populations, is still an open question, the answer to which requires additional, specifically designed, studies.
Assuntos
Peso Corporal/genética , PPAR gama/genética , Caracteres Sexuais , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Feminino , Haplótipos , Humanos , Insulina/sangue , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , População Branca/genéticaRESUMO
OBJECTIVE: To investigate whether insulin resistance (IR) and the metabolic syndrome (MS) are associated with kidney dysfunction in obese non-diabetic (OND) subjects. METHODS AND PROCEDURES: Three-hundred and eighty (113M/267F; age = 41 +/- 14 years) OND subjects (BMI > or = 30 kg/m(2); range = 43 +/- 8 kg/m(2)) were studied. Anthropometric measures, blood pressure, fasting glucose, insulin, lipid profile, and serum creatinine were evaluated. Glomerular filtration rate (GFR) was estimated (e-GFR) with the Modification of Diet in Renal Disease equation. Chronic kidney disease (CKD) was defined as e-GFR <60 ml/min/1.73 m(2). RESULTS: e-GFR was associated with gender (being lower in women) (P = 0.001) and age (P < 0.0001). CKD was present in 32 subjects (8.4%), who were older (P < 0.0001) and more frequently affected by hypertension (P = 0.04) as compared to subjects without CKD. MS was present in 212 (55.8%) subjects. They were older (P< 0.001), had lower e-GFR (P = 0.02) and were more frequently affected by CKD (odds ratio (OR), 95% confidence interval (CI) = 2.3, 1.1-5.1) than those without MS. However, differences in e-GFR values and in the risk of CKD were no longer statistically significant after adjusting for age (P = 0.99 for e-GFR and OR, 95% CI = 1.2, 0.5-2.8 for the risk of CKD, respectively). Homeostasis model assessment of IR (HOMA(IR)) index was neither higher in subject with CKD (P = 0.1) nor inversely correlated with e-GFR (r = 0.1, P = 0.1). DISCUSSION: In OND individuals the risk of CKD is independent of the MS and related abnormalities. This suggests that these individuals are not susceptible to a further deleterious role on kidney function on the top of that played by obesity itself.
Assuntos
Nefropatias Diabéticas/epidemiologia , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Gordura Abdominal , Adulto , Nefropatias Diabéticas/diagnóstico , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão Renal/diagnóstico , Hipertensão Renal/epidemiologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco , Distribuição por SexoAssuntos
Arginina/genética , Proteínas de Ciclo Celular/genética , Diabetes Mellitus Tipo 2/genética , Glutamina/genética , Falência Renal Crônica/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , População Branca/genética , Idoso , Substituição de Aminoácidos/genética , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Homologia de Sequência de AminoácidosRESUMO
Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism. AQP7 knockout mice develop obesity and hyperglycemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNPs) in the AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, A-953G in the AQP7 promoter was associated with type 2 diabetes in 977 (530 female/447 male) Caucasians: odds ratio for XG (i.e., AG+GG) versus AA individuals was 1.36 (95% CI 1.01-1.84), P = 0.04. This finding was entirely due to the association among females (1.8 [1.2-2.6], P = 0.004), which was no longer significant when adjusted for BMI. In fact, BMI was higher in XG than in AA females (30.8 +/- 6.6 vs. 28.9 +/- 5.2, P = 0.002). This association was confirmed in independent case-control study (n = 299 female subjects) for morbid obesity (1.66 [1.01-2.74], P = 0.04). Luciferase and mobility shift assays showed that, compared with -953A, the -953G promoter had reduced transcriptional activity (P = 0.001) and impaired ability to bind CCAAT/enhancer binding protein (C/EBP)beta transcription factor (P = 0.01). Finally, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (P = 0.036). These data strongly suggest that AQP7 downregulation is pathogenic for obesity and/or type 2 diabetes.
Assuntos
Adipócitos/fisiologia , Aquaporinas/genética , Diabetes Mellitus Tipo 2/genética , Variação Genética , Doenças Metabólicas/genética , Obesidade/genética , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Genótipo , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/genética , Regiões Promotoras Genéticas , Valores de ReferênciaRESUMO
This study investigated the role of the ENPP1/PC-1 gene K121Q polymorphism in predicting BMI (kg/m2) in non-diabetic individuals. Three independent samples (n = 631, n = 304, and n = 505) of adult whites were analyzed. Selection criteria were fasting plasma glucose level <126 mg/dL, absence of severe obesity (BMI > or =40 kg/m2), and lack of treatment known to modulate BMI. In Sample 1, BMI values were different in individuals carrying the K121/K121 (KK), K121/Q121 (KQ), and Q121/Q121 (QQ) genotypes (25.5 +/- 4.3, 25.3 +/- 4.1, and 22.8 +/- 2.5 kg/m2, respectively (adjusted p = 0.022); BMI values in Samples 2 and 3 also tended to be different, although the differences, after adjustment for age and sex, did not reach statistical significance. When data were pooled, BMI values were 25.8 +/- 4.4, 25.6 +/- 4.4, and 23.6 +/- 3.3 kg/m2 in KK, KQ, and QQ individuals (adjusted p = 0.029). According to a recessive model, QQ individuals had lower BMI values than KK and KQ individuals combined (23.6 +/- 3.3 kg/m2 vs. 25.7 +/- 4.4 kg/m2; adjusted p = 0.008). These data suggest that the QQ genotype of the ENPP1/PC-1 gene is associated with lower BMI. If similar results are confirmed in prospective studies, the K121Q polymorphism may help identify people at risk for obesity.
Assuntos
Obesidade/genética , Diester Fosfórico Hidrolases/genética , Polimorfismo Genético , Pirofosfatases/genética , População Branca/genética , Adulto , Índice de Massa Corporal , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Itália , Masculino , Obesidade Mórbida/genéticaRESUMO
Insulin resistance plays a major role in dyslipidemia, cardiovascular disease, and type 2 diabetes. TRB3, a mammalian tribbles homolog, whose chromosomal region 20p13-p12 has been linked to human type 2 diabetes, impairs insulin signaling through the inhibition of Akt phosphorylation and is overexpressed in murine models of insulin resistance. We here report that the prevalent TRB3 missense Q84R polymorphism is significantly (P < 0.05) associated with several insulin resistance-related abnormalities in two independent cohorts (n = 178 and n = 605) of nondiabetic individuals and with the presence of a cluster of insulin resistance-related cardiovascular risk factors in 716 type 2 diabetic patients (OR 3.1 [95% CI 1.2-8.2], P = 0.02). In 100 additional type 2 diabetic patients who suffered from myocardial ischemia, age at myocardial ischemia was progressively and significantly (P = 0.03) reduced from Q84Q to Q84R to R84R individuals. To test the functional role of TRB3 variants, either Q84 or R84 TRB3 full-length cDNAs were transfected in human HepG2 hepatoma cell lines. As compared with control HepG2 cells, insulin-induced Ser473-Akt phosphorylation was reduced by 22% in Q84- (P < 0.05 vs. control cells) and by 45% in R84-transfected cells (P < 0.05 vs. Q84 transfected and P < 0.01 vs. control cells). These data provide the first evidence that TRB3 gene plays a role in human insulin resistance and related clinical outcomes.