RESUMO
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Assuntos
Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Receptores ErbB/genética , Falência Renal Crônica , Proteínas Nucleares/genética , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Fibrose/genética , Fibrose/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Receptor ErbB-4 , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both, is observed in about 20% of individuals with premature coronary heart disease. We previously identified a locus linked to FCHL on 1q21-q23 in Finnish families with the disease. This region has also been linked to FCHL in families from other populations as well as to type 2 diabetes mellitus. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies combined hyperlipidemia in mice, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism.
Assuntos
Proteínas de Ligação a DNA/genética , Hiperlipidemia Familiar Combinada/genética , Fatores de Transcrição/genética , Animais , Proteínas de Transporte/genética , Cromossomos Humanos Par 1 , Genes Reporter , Humanos , Polimorfismo de Nucleotídeo Único , Tiorredoxinas/genética , Fatores Estimuladores UpstreamRESUMO
Diabetes is characterized by accelerated atherosclerosis with widely distributed vascular lesions. An important mechanism by which hyperglycaemia contributes to vascular injury is through the extensive intracellular and extracellular formation of AGEs (advanced glycation end products). AGEs represent a heterogeneous group of proteins, lipids and nucleic acids, irreversibly cross-linked with reducing sugars. AGEs are implicated in the atherosclerotic process, either directly or via receptor-mediated mechanisms, the most extensively studied receptor being RAGE (receptor for AGEs). The AGE-RAGE interaction alters cellular signalling, promotes gene expression and enhances the release of pro-inflammatory molecules. It elicits the generation of oxidative stress in numerous cell types. The importance of the AGE-RAGE interaction and downstream pathways leading to injurious effects as a result of chronic hyperglycaemia in the development, progression and instability of diabetic atherosclerotic lesions has been amply demonstrated in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. In the present review, our current understanding of their role as an important mediator of vascular injury through the various stages of atherosclerosis in diabetes will be reviewed and critically assessed.
Assuntos
Aterosclerose/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Receptores Imunológicos/fisiologia , Animais , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Produtos Finais de Glicação Avançada/fisiologia , Humanos , Ligantes , Camundongos , Ratos , Receptor para Produtos Finais de Glicação AvançadaRESUMO
AIMS: Insulin possesses both vasodilatory and sympathomimetic activities. The aim was to examine the relationship between changes in insulin exposure and arterial stiffness in type 2 diabetes (T2D). METHODS: Patients with T2D with (n = 22) or without (n = 24) albuminuria, and non-diabetic controls (n = 25) were randomized to a crossover study having a breakfast with or without pre-meal rapid-acting insulin. Pulse wave velocity (PWV) was measured at 30 min before and at 60-min intervals up to 240 min after the breakfast. RESULTS: At baseline, both postprandial aortic (p = 0.022) and brachial (p = 0.011) PWV were higher in individuals with T2D than in healthy controls irrespective of the presence of albuminuria. In patients with albuminuria, weight-adjusted insulin dose correlated inversely with the excursion of the aortic (r = - 0.412, p = 0.006) and brachial (r = - 0.372; p = 0.014) PWV. Similarly, circulating endogenous insulin concentrations correlated inversely with the aortic (r = - 0.347, p = 0.026) and brachial (r = - 0.622, p = <0.001) PWV. No correlations between insulin and PWV were observed in patients without albuminuria or in healthy controls. CONCLUSIONS: The inverse correlation between insulin and PWV in T2D with albuminuria may reflect a vasorelaxing effect of insulin. CLINICAL TRIAL REGISTRATION NUMBER: The study was registered (clinicaltrials.gov) with the identifier of NCT01159938.
Assuntos
Albuminúria/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Insulina/farmacologia , Rigidez Vascular/efeitos dos fármacos , Adulto , Aorta/fisiopatologia , Feminino , Humanos , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Análise de Onda de PulsoRESUMO
1. There is increasing evidence that advanced glycation end-products (AGEs) and their interaction with the receptor RAGE play a pivotal role in atherosclerosis, in particular in the setting of diabetes. 2. Previous studies have shown that inhibition of AGE accumulation and RAGE expression in diabetes by either reduction of the formation of AGEs or cross-link breakers was associated with reduced atherosclerosis and renal disease. Advanced glycation end-products bind to RAGE, thereby leading to activation of a range of inflammatory and fibrotic pathways causing tissue injury. Different splice variants of RAGE exist, including a soluble form that lacks the intracellular domain and fails to induce signal transduction. Therapeutic approaches using soluble RAGE as a decoy binding protein for circulating AGE have been effective in preventing externally induced arterial injury and atherosclerosis in the absence and presence of diabetes. 3. In order to delineate the role of RAGE in vascular disease in more detail, it was necessary to create RAGE(-/-) mice, as well as transgenic mice overexpressing RAGE in endothelial cells. It was shown that RAGE overexpression was associated with increased vascular injury, nephropathy and retinopathy. 4. In contrast, RAGE deletion was associated with partial vascular protection, such as reduced neointima formation after arterial denudation, as well as protection from diabetic nephropathy. The present review summarizes the evidence for RAGE being a pro-inflammatory and pro-fibrotic receptor. 5. Further studies are needed to delineate the effect of RAGE deletion and overexpression in diabetic macrovascular disease. Based on these findings, RAGE could be a potential therapeutic target in combating inflammatory vascular diseases, including diabetes-associated atherosclerosis.
Assuntos
Aterosclerose/complicações , Diabetes Mellitus/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Receptores Imunológicos/metabolismo , Animais , Humanos , Receptor para Produtos Finais de Glicação AvançadaRESUMO
OBJECTIVE: High-density lipoprotein (HDL) cholesterol correlates inversely with the risk of coronary heart disease (CHD). The precise antiatherogenic mechanisms of HDL subspecies are not thoroughly elucidated. We studied the relationship between carotid intima-media thickness (IMT) and HDL subspecies distribution in Finnish families with low HDL cholesterol and premature CHD. METHODS AND RESULTS: Altogether, 148 members of Finnish low-HDL families and 133 healthy control subjects participated in our study. HDL particle size was significantly smaller in affected family members (HDL < or =10th Finnish age-sex specific percentile) compared with unaffected family members and control subjects (9.1+/-0.04 nm versus 9.5+/-0.05 nm, P<0.0001, versus 9.8+/-0.03 nm, P<0.0001 [mean+/-SE]). Large HDL2b particles as well as prebeta-HDL concentration were significantly decreased among the affected family members. Mean IMT was significantly higher in the affected family members than in the control subjects (0.85+/-0.01 mm versus 0.79+/-0.01 mm; P<0.0001). Age, HDL2b, systolic blood pressure, and prebeta-HDL were significant independent determinants of mean IMT. CONCLUSIONS: The decreased levels of HDL2b and prebeta-HDL reflect the potentially efflux-deficient HDL subspecies profile in the affected low-HDL family members. Decreased HDL particle size caused by the decrease of plasma concentration of HDL2b and decreased prebeta-HDL levels correlate with increased IMT.
Assuntos
Artérias Carótidas/patologia , HDL-Colesterol/deficiência , Adulto , Fatores Etários , Índice de Massa Corporal , Artérias Carótidas/metabolismo , HDL-Colesterol/química , Doença das Coronárias/etiologia , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Análise de Regressão , Fatores de Risco , Fatores SexuaisRESUMO
AIMS: Although oxygen is commonly used to treat various medical conditions, it has recently been shown to worsen vascular function (arterial stiffness) in healthy volunteers and even more in patients in whom vascular function might already be impaired. The effects of oxygen on arterial function in patients with type 1 diabetes (T1D) are unknown, although such patients display disturbed vascular function already at rest. Therefore, we tested whether short-term oxygen administration may alter the arterial function in patients with T1D. METHODS: We estimated arterial stiffness by augmentation index (AIx) and the pulse wave velocity equivalent (SI-DVP) in 98 patients with T1D and 49 age- and sex-matched controls at baseline and during hyperoxia by obtaining continuous noninvasive finger pressure waveforms using a recently validated method. RESULTS: AIx and SI-DVP increased in patients (P < 0.05) but not in controls in response to hyperoxia. The increase in AIx (P = 0.05), systolic (P < 0.05), and diastolic (P < 0.05) blood pressure was higher in the patients than in the controls. CONCLUSIONS: Short-term oxygen administration deteriorates arterial function in patients with T1D compared to non-diabetic control subjects. Since disturbed arterial function plays a major role in the development of diabetic complications, these findings may be of clinical relevance.
Assuntos
Artérias/efeitos dos fármacos , Diabetes Mellitus Tipo 1/complicações , Oxigenoterapia/efeitos adversos , Oxigênio/efeitos adversos , Rigidez Vascular , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Oxigênio/administração & dosagem , Análise de Onda de PulsoRESUMO
CONTEXT: Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease. OBJECTIVE: The objective of the study was to determine whether postprandial hyperglycemia affects arterial function in T2D. DESIGN: A single-center, open-label study of three groups of men were studied: 1) T2D patients with albuminuria (n = 22), 2) T2D patients without albuminuria (n = 24), and 3) nondiabetic controls (n = 25). Patients were randomized to a two-period crossover study schedule, ingesting breakfast, with or without insulin lispro (to induce low or high postprandial glycemia). MAIN OUTCOME MEASURES: Arterial stiffness was assessed by calculating pulse wave velocity (PWV) and augmentation index using applanation tonometry, and endothelial dysfunction was assessed using peripheral arterial tonometry, 30 minutes before breakfast and up to 240 minutes after breakfast. RESULTS: At baseline, arterial stiffness was increased in patients. When adjusted for age and body mass index, in a combined group of patients with and without albuminuria, brachial PWV was higher during low (P = .032) and high (P = .038) postprandial glycemia vs controls. These differences were driven by the albuminuria group vs controls during low (P = .014) and high (P = .018) postprandial glycemia. No differences were observed in aortic PWV, augmentation index, or peripheral arterial tonometry ratio between patients and controls. Endothelin-1 and IL-6 were higher, and superoxide dismutase was lower, during postprandial hyperglycemia in T2D patients vs controls. CONCLUSIONS: In patients with T2D and albuminuria, brachial PWV was higher under postprandial hyperglycemic conditions, relative to controls. These data suggest that hyperglycemia induces an increase in stiffness of intermediate-sized arteries. We found no changes in other parts of the arterial bed.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Rigidez Vascular/fisiologia , Idoso , Velocidade do Fluxo Sanguíneo , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Humanos , Hiperglicemia/metabolismo , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Análise de Onda de Pulso , Artéria Radial/fisiopatologiaRESUMO
OBJECTIVE: Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D. RESEARCH DESIGN AND METHODS: Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD; dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9-11.8) years. RESULTS: Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L; P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L; P < 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L; P < 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L; P < 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP. CONCLUSIONS: Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D.
Assuntos
Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/mortalidade , Osteopontina/sangue , Adulto , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Causas de Morte , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
OBJECTIVE: Osteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Serum OPG was measured in 1,939 adults with T1D participating in the Finnish Diabetic Nephropathy (FinnDiane) Study. Patients with end-stage renal disease (dialysis or transplantation) at baseline were excluded from analysis. Data on cardiovascular (CV) events and mortality during follow-up were verified from hospital discharge registries (ICD codes) and the Finnish National Death Registry, respectively. The follow-up time was 10.4 ± 2.0 (mean ± SD) years. RESULTS: Only patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01-1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13-1.88]; P = 0.004) during follow-up. CONCLUSIONS: We showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.
Assuntos
Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 1/sangue , Osteoprotegerina/sangue , Adulto , Albuminúria/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Finlândia , Humanos , MasculinoRESUMO
OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of angiotensin (AT)II and promotes vasodilatation. Circulating ACE2 activity is increased in diabetes in experimental models. The role of ACE2 in human pathophysiology is unknown. We examined whether ACE2 activity is altered in patients with type 1 diabetes (T1D), with and without diabetic nephropathy. METHODS: Quantitative ACE2 activity in serum was measured by a fluorometric assay in 859 patients with T1D in the Finnish Diabetic Nephropathy (FinnDiane) study and in 204 healthy controls. Pulse-wave analysis with augmentation index (AIx) measurement was performed in 319 patients with T1D and 114 controls. RESULTS: ACE2 activity was increased in men with T1D and microalbuminuria (30.2â±â1.5ângE/ml) when compared to patients without albuminuria (27.0â±â0.5ângE/ml, Pâ<â0.05) or controls (25.6â±â0.8ângE/ml, Pâ<â0.05). ACE2 activity was increased in male and female patients who were on ACE inhibitor (ACEi) treatment, also independently of albuminuria. Male and female patients with coronary heart disease (CHD) had significantly increased ACE2 activity (35.5â±â2.5 vs. 27.0â±â0.5ângE/ml, Pâ<â0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (rsâ=â0.175, Pâ<â0.001), AIx (rsâ=â0.191, Pâ=â0.010) and diabetes duration (rsâ=â0.198, Pâ<â0.001), and negatively with estimated glomerular filtration rate (rsâ=â-0.109, Pâ=â0.016) among male T1D patients. CONCLUSIONS: ACE2 activity increases with increasing vascular tone and when the patient with T1D has microvascular or macrovascular disease, indicating that ACE2 may participate as a compensatory mechanism in the regulation of vascular and renal function in patients with T1D.
Assuntos
Diabetes Mellitus Tipo 1/enzimologia , Angiopatias Diabéticas/enzimologia , Peptidil Dipeptidase A/sangue , Adulto , Enzima de Conversão de Angiotensina 2 , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Angiopatias Diabéticas/sangue , Feminino , Humanos , MasculinoRESUMO
Advanced glycation end products (AGEs) are important mediators of diabetic nephropathy that act through the receptor for AGEs (RAGE), as well as other mechanisms, to promote renal inflammation and glomerulosclerosis. The relative contribution of RAGE-dependent and RAGE-independent signaling pathways has not been previously studied in vivo. In this study, diabetic RAGE apoE double-knockout (KO) mice with streptozotocin-induced diabetes were treated with the AGE inhibitor, alagebrium (1 mg/kg/day), or the ACE inhibitor, quinapril (30 mg/kg/day), for 20 weeks, and renal parameters were assessed. RAGE deletion attenuated mesangial expansion, glomerular matrix accumulation, and renal oxidative stress associated with 20 weeks of diabetes. By contrast, inflammation and AGE accumulation associated with diabetes was not prevented. However, treatment with alagebrium in diabetic RAGE apoE KO mice reduced renal AGE levels and further reduced glomerular matrix accumulation. In addition, even in the absence of RAGE expression, alagebrium attenuated cortical inflammation, as denoted by the reduced expression of monocyte chemoattractant protein-1, intracellular adhesion molecule-1, and the macrophage marker cluster of differentiation molecule 11b. These novel findings confirm the presence of important RAGE-independent as well as RAGE-dependent signaling pathways that may be activated in the kidney by AGEs. This has important implications for the design of optimal therapeutic strategies for the prevention of diabetic nephropathy.
Assuntos
Apolipoproteínas E/genética , Produtos Finais de Glicação Avançada/metabolismo , Receptores Imunológicos/metabolismo , Tiazóis/farmacologia , Albuminúria , Animais , Diabetes Mellitus Experimental , Fibrose/etiologia , Mesângio Glomerular/efeitos dos fármacos , Glomerulonefrite/etiologia , Masculino , Camundongos , Camundongos Knockout , Nefrite/etiologia , Estresse Oxidativo/fisiologia , Quinapril , Receptor para Produtos Finais de Glicação Avançada , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
INTRODUCTION/AIMS: While patients with type 1 diabetes (T1D) are known to suffer from early cardiovascular disease (CVD), we examined associations between arterial stiffness and diabetic complications in a large patient group with T1D. METHODS: This study included 807 subjects (622 T1D and 185 healthy volunteers (age 40.6 ± 0.7 versus 41.6 ± 1.2 years; P = NS)). Arterial stiffness was measured by pulse wave analysis from each participant. Furthermore, information on diabetic retinopathy, nephropathy, and CVD was collected. The renal status was verified from at least two out of three urine collections. RESULTS: Patients with T1D without signs of diabetic nephropathy had stiffer arteries measured as the augmentation index (AIx) than age-matched control subjects (17.3% ± 0.6% versus 10.0% ± 1.2%; P < 0.001). Moreover, AIx (OR 1.08; 95% CI 1.03-1.13; P = 0.002) was associated with diabetic laser-treated retinopathy in patients with normoalbuminuria in a multivariate logistic regression analysis. The same was true for AIx and diabetic nephropathy (1.04 (1.01-1.08); P = 0.004) as well as AIx and CVD (1.06 (1.00-1.12); P = 0.01) in patients with T1D. CONCLUSIONS: Arterial stiffness was associated with microvascular and macrovascular complications in patients with T1D.
Assuntos
Albuminúria/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Rigidez Vascular/fisiologia , Adulto , Estudos de Casos e Controles , Feminino , Finlândia , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Análise de Regressão , Estatísticas não ParamétricasRESUMO
OBJECTIVE: A number of factors contribute to diabetes-associated vascular dysfunction. In the present study, we tested whether exposure to advanced glycation end-products (AGEs) impairs vascular reactivity independently of hyperglycemia and examined the potential mechanisms responsible for diabetes and AGE-associated vascular dysfunction. METHODS: Vasodilator function was studied using infusion of exogenous AGEs into Sprague-Dawley rats as compared with control and streptozotocin-induced diabetic rats all followed for 16 weeks (n = 10 per group). The level of arginine metabolites and expression of endothelial nitric oxide synthase (eNOS) and downstream mediators of nitric oxide-dependent signaling were examined. To further explore these mechanisms, cultured bovine aortic endothelial cells (BAECs) were exposed to AGEs. RESULTS: Both diabetic and animals infused with AGE-modified rat serum albumin (AGE-RSA) had significantly impaired vasodilatory response to acetylcholine. Unlike diabetes-associated endothelial dysfunction, AGE infusion was not associated with changes in plasma arginine metabolites, asymmetric dimethyl-L-arginine levels or eNOS expression. However, expression of the downstream mediator cGMP-dependent protein kinase 1 (PKG-1) was significantly reduced by both AGE exposure and diabetes. AGEs also augmented hyperglycemia-associated depletion in endothelial nitric oxide production and eNOS protein expression in vitro, and the novel AGE inhibitor, alagebrium chloride, partly restored these parameters. CONCLUSION: We demonstrate that AGEs represent a potentially important cause of vascular dysfunction, linked to the induction of nitric oxide resistance. These findings also emphasize the deleterious and potentially additive effects of AGEs and hyperglycemia in diabetic vasculature.
Assuntos
Produtos Finais de Glicação Avançada/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Doenças Vasculares/induzido quimicamente , Animais , Aorta Torácica/citologia , Arginina/análogos & derivados , Arginina/sangue , Arginina/metabolismo , Bovinos , Células Cultivadas , Diabetes Mellitus/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Hipoglicemiantes/metabolismo , Masculino , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Doenças Vasculares/complicações , Doenças Vasculares/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/metabolismo , Vasodilatadores/farmacologiaRESUMO
OBJECTIVE: Endocannabinoids (ECs) control metabolism via cannabinoid receptors type 1 (CB1). Their plasma levels are elevated in overweight type 2 diabetes (T2D) and in obese patients, and decrease postprandially in normoweight individuals. We investigated in two different cohorts of nonobese or obese volunteers whether oral glucose in glucose tolerance tests (OGTT) or acute insulin infusion during euglycemic hyperinsulinemic clamp affect plasma EC levels. DESIGN AND METHODS: OGTT was performed in ten obese hyperinsulinemic patients (body mass index (BMI)=35.8 kg/m2, fasting insulin=14.83 mU/l), and ten normoweight normoinsulinemic volunteers (BMI=21.9 kg/m2, fasting insulin=7.2 mU/l). Insulin clamp was performed in 19 mostly nonobese men (BMI=25.8 kg/m2) with varying degrees of liver fat and plasma triglycerides (TGs), with (n=7) or without T2D. Plasma levels of ECs (anandamide and 2-arachidonoylglycerol (2-AG)) were measured by liquid chromatography-mass spectrometry, before and 60 and 180 min after OGTT, and before and 240 and 480 min after insulin or saline infusion. RESULTS: Oral glucose load decreased anandamide plasma levels to an extent inversely correlated with BMI, waist circumference, subcutaneous fat, fasting insulin and total glucose, and insulin areas under the curve during the OGTT, and nonsignificantly in obese volunteers. Insulin infusion decreased anandamide levels to an extent that weakly, but significantly, correlated negatively with TGs, liver fat and fasting insulin, and positively with high density lipoprotein cholesterol. OGTT decreased 2-AG levels to a lower extent and in a way weakly inversely correlated with fasting insulin. CONCLUSIONS: We suggest that insulin reduces EC levels in a way inversely related to anthropometric and metabolic predictors of insulin resistance and dyslipidemia.
Assuntos
Ácidos Araquidônicos/metabolismo , Moduladores de Receptores de Canabinoides/metabolismo , Endocanabinoides , Glucose/metabolismo , Glicerídeos/metabolismo , Insulina/metabolismo , Obesidade/sangue , Alcamidas Poli-Insaturadas/metabolismo , Adulto , Alanina Transaminase/sangue , Antropometria , Apolipoproteínas B/sangue , Ácidos Araquidônicos/sangue , Gasometria , Composição Corporal/fisiologia , Moduladores de Receptores de Canabinoides/sangue , Colesterol/sangue , Estudos de Coortes , Feminino , Glucose/análise , Glicerídeos/sangue , Humanos , Insulina/sangue , Masculino , Obesidade/metabolismo , Alcamidas Poli-Insaturadas/sangue , Estatísticas não Paramétricas , Triglicerídeos/sangueRESUMO
OBJECTIVE: Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE(-/-) model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS: ApoE(-/-) and RAGE(-/-)/apoE(-/-) double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS: Although diabetic apoE(-/-) mice showed increased plaque accumulation (14.9 +/- 1.7%), diabetic RAGE(-/-)/apoE(-/-) mice had significantly reduced atherosclerotic plaque area (4.9 +/- 0.4%) to levels not significantly different from control apoE(-/-) mice (4.3 +/- 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-kappaB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE(-/-) mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE(-/-)/apoE(-/-) mice. CONCLUSIONS: This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.
Assuntos
Aterosclerose/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Produtos Finais de Glicação Avançada/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Animais , Apolipoproteínas E/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Biomarcadores , Colágeno/metabolismo , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/patologia , Metabolismo Energético/fisiologia , Expressão Gênica/fisiologia , Macrófagos/patologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Receptor Tipo 1 de Angiotensina/metabolismo , Linfócitos T/patologia , Vasculite/imunologia , Vasculite/patologia , Vasculite/fisiopatologiaRESUMO
HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Colesterol/metabolismo , Lipoproteínas HDL/metabolismo , Polimorfismo Genético , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , Células Cultivadas , Feminino , Frequência do Gene , Humanos , Hipolipoproteinemias/genética , Hipolipoproteinemias/metabolismo , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The study was aimed to compare inflammatory parameters between carriers of apoE4 isoforms (apoE4/3, apoE4/2, and apoE4/4 phenotypes) and those of carrying apoE3 isoform without apoE4 isoform (apoE3/3 phenotypes and apoE2/3 phenotypes). The concentrations of serum hsCRP, sVCAM-1, sICAM-1, and sE-selectin were measured in 211 subjects from Finnish low-HDL families and in 157 normolipidemic subjects. The subjects with apoE4 isoform had lower concentrations of serum hsCRP both in low-HDL family members (p < 0.05) and in normolipidemic subjects (p < 0.01). The differences in serum CRP values remained significant after adjustment for age, BMI, smoking status, hypertension, gender, lipoprotein variables, and family number. We conclude that apoE phenotype has a strong influence on serum CRP values.
Assuntos
Apolipoproteínas E/genética , Proteína C-Reativa/análise , Lipoproteínas HDL/sangue , Polimorfismo Genético , Moléculas de Adesão Celular/sangue , Feminino , Humanos , Lipídeos/sangue , Masculino , Análise de RegressãoRESUMO
BACKGROUND: Inhibition of cytokine-induced expression of adhesion molecules is one of the atheroprotective mechanisms of high-density lipoprotein (HDL). AIM: We investigated whether increased endothelial activation and low-grade inflammation are present in Finnish subjects with familial low HDL, and which factors contribute to the inflammatory parameters. METHOD: High-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin were measured in 91 subjects with low HDL-cholesterol from 41 low-HDL families and in 112 normolipidemic controls with comparable age- and gender distribution. Presence of the features of the metabolic syndrome (MetS) was recorded. RESULTS: sVCAM-1, sICAM-1, sE-selectin, and hsCRP were significantly higher in low-HDL subjects than in the controls (sVCAM-1: 560+/-147 ng/mL versus 496+/-95 ng/mL, P = 0.001; sICAM-1: 247+/-60 ng/mL versus 215+/-47 ng/mL, P<0.001; sE-selectin: 52+/-20 ng/mL versus 44+/-16 ng/mL, P = 0.022; and hsCRP: 1.73+/-2.05 mg/L versus 0.85+/-1.10 mg/L, P<0.001). Low-HDL subjects had increased body mass index (BMI) and waist, and elevated insulin and triglyceride levels. Adhesion molecules and hsCRP increased according to the number of the features of the MetS. CONCLUSIONS: The presence of the MetS in subjects with familial low HDL-cholesterol aggravates the low-grade inflammation and endothelial activation, and ultimately may add to the higher susceptibility for atherosclerotic disease in these individuals.
Assuntos
Endotélio Vascular/metabolismo , Síndrome Metabólica/complicações , Doença de Tangier/complicações , Doença de Tangier/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Moléculas de Adesão Celular/sangue , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Feminino , Finlândia , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Recent studies in the mouse have demonstrated that variations in lipin expression levels in adipose tissue have marked effects on adipose tissue mass and insulin sensitivity. In the mouse, lipin deficiency prevents normal adipose tissue development, resulting in lipodystrophy and insulin resistance, whereas excess lipin levels promote fat accumulation and insulin sensitivity. Here, we investigated the effects of genetic variation in lipin levels on glucose homeostasis across species by analyzing lipin transcript levels in human and mouse adipose tissues. A strong negative correlation was observed between lipin mRNA levels and fasting glucose and insulin levels, as well as an indicator of insulin resistance (HOMA-IR), in both mice and humans. We subsequently analyzed the allelic diversity of the LPIN1 gene in dyslipidemic Finnish families, as well as in a case-control sample of obese (n = 477) and lean (n = 821) individuals. Alleles were defined by genotyping seven single nucleotide polymorphisms (SNPs) of the critical DNA region over the LPIN1 gene. Intragenic SNPs and corresponding allelic haplotypes exhibited associations with serum insulin levels and body mass index (P = 0.002-0.04). Both the expression levels in adipose tissue across species and genetic data in human study samples highlight the importance of lipin in glucose homeostasis and imply that allelic variants of this gene have significance in human metabolic traits.