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1.
Diabetologia ; 54(3): 681-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21161164

RESUMO

AIMS/HYPOTHESIS: Formation of AGEs is increased in the diabetic milieu, which contributes to accelerated atherogenesis. We studied whether delayed treatment with AGE-inhibiting compounds, alagebrium chloride and pyridoxamine dihydrochloride, affected established atherosclerosis in experimental diabetes in comparison with the angiotensin-converting enzyme inhibitor, quinapril. METHODS: Streptozotocin-induced diabetic male Apoe (-/-) mice (n = 24 per group) received, by oral gavage, from week 10 to 20 of diabetes: no treatment; alagebrium (1 mg kg(-1) day(-1)); pyridoxamine (1 g/l in drinking water); or quinapril (30 mg kg(-1) day(-1)). Atherosclerotic lesion area (en face analysis) was evaluated for all groups. RESULTS: Delayed intervention with alagebrium decreased plaque area in the diabetic Apoe (-/-) mice compared with untreated mice (total plaque area: alagebrium 10.6 ± 1.6%, untreated, 15.1 ± 1.5%, p < 0.05). This anti-atherosclerotic effect was comparable with that achieved with quinapril (quinapril 8.4 ± 1.4%, vs untreated, p < 0.05). Pyridoxamine also attenuated plaque development in diabetic mice (5.7 ± 1.2% vs untreated 11.9 ± 1.1%, p < 0.05). The anti-atherosclerotic effect conferred by alagebrium and quinapril was associated with a significant reduction in vascular oxidative stress and circulating AGEs and methylglyoxal, although preformed AGEs were not removed from the vascular wall with either delayed intervention. CONCLUSIONS/INTERPRETATION: Inhibition of AGE accumulation, using a delayed intervention with alagebrium or pyridoxamine, significantly attenuated the progression of established diabetes-associated atherosclerosis, similar to results obtained with quinapril. These findings provide further evidence that blockade of AGE-mediated pathways may present a novel therapy for the prevention of atherosclerosis in diabetes.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Apolipoproteínas E/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Diabetes Mellitus Experimental/fisiopatologia , Animais , Apolipoproteínas E/genética , Aterosclerose/sangue , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Peptidil Dipeptidase A/sangue , Quinapril , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tetra-Hidroisoquinolinas/uso terapêutico
2.
Diabetologia ; 53(3): 584-92, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19957160

RESUMO

AIMS/HYPOTHESIS: Most of the known actions of angiotensin II have been considered primarily to be the result of angiotensin II subtype 1 receptor activation. However, recent data suggest that the angiotensin II subtype 2 receptor (AT(2)R) may modulate key processes linked to atherosclerosis. The aim of this study was to investigate the role of AT(2)R in diabetes-associated atherosclerosis using pharmacological blockade and genetic deficiency. METHODS: Aortic plaque deposition was assessed in streptozotocin-induced diabetic apolipoprotein E (Apoe) knockout (KO) and At ( 2 ) r (also known as Agtr2)/Apoe double-KO (DKO) mice. Control and diabetic Apoe-KO mice received an AT(2)R antagonist PD123319 (5 mg kg(-1) day(-1)) via osmotic minipump for 20 weeks (n = 7-8 per group). RESULTS: Diabetes was associated with a sixfold increase in plaque area (diabetic Apoe-KO: 12.7 +/- 1.4% vs control Apoe-KO: 2.3 +/- 0.4%, p < 0.001) as well as a significant increase in aortic expression of the gene At ( 2 ) r (also known as Agtr2). The increase in plaque area with diabetes was attenuated in AT(2)R antagonist-treated diabetic Apoe-KO mice (7.1 +/- 0.5%, p < 0.05) and in diabetic At ( 2 ) r/Apoe DKO mice (9.2 +/- 1.3%, p < 0.05). These benefits occurred independently of glycaemic control or BP, and were associated with downregulation of a range of pro-inflammatory cytokines, adhesion molecules, chemokines and various extracellular matrix proteins. CONCLUSIONS/INTERPRETATION: This study provides evidence for AT(2)R playing a role in the development of diabetes-associated atherosclerosis. These findings suggest a potential utility of AT(2)R blockers in the prevention and treatment of diabetic macrovascular complications.


Assuntos
Antagonistas de Receptores de Angiotensina , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/prevenção & controle , Diabetes Mellitus Experimental/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Peso Corporal , Adesão Celular , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piridinas/farmacologia , Receptores de Angiotensina/deficiência , Receptores CCR2/metabolismo
3.
Diabetologia ; 50(11): 2356-65, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17849096

RESUMO

AIMS/HYPOTHESIS: Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content. METHODS: A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group. RESULTS: The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased. CONCLUSIONS/INTERPRETATION: Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.


Assuntos
Tecido Adiposo/anatomia & histologia , Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina/fisiologia , Insulina/fisiologia , Lipoproteínas VLDL/metabolismo , Fígado/anatomia & histologia , Abdome , Tecido Adiposo/fisiologia , Adulto , Apolipoproteínas B/sangue , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Ácidos Graxos não Esterificados/metabolismo , Humanos , Insulina/sangue , Cinética , Lipoproteínas VLDL/antagonistas & inibidores , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Valores de Referência
4.
Curr Med Chem ; 13(15): 1777-88, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16787220

RESUMO

Diabetic patients have a two- to four-fold increased risk for the development of microvascular (renal, neuronal and retinal) and macrovascular complications. Unfortunately, these complications may develop in both Type 1 and Type 2 diabetic patients even with careful glycaemic, blood pressure and lipid control. With the worldwide increase in the incidence diabetes, new strategies to prevent the complications are urgently needed. Mediators of vascular damage of diabetes include poor glycemic control, lipoprotein abnormalities, hypertension, oxidative stress, inflammation and advanced glycation end-products (AGEs), which are modified proteins formed by non-enzymatic glycation. AGEs are resistant to enzymatic degradation and therefore very stable, thus their accumulation continues throughout aging. AGE accumulation causes arterial stiffening in the vessel wall, glomerulosclerosis in the kidney, and vascular hyperpermeability in the retina. Through their interaction with their putative receptor the so-called receptor for AGEs (RAGE), AGEs activate endothelial cells and macrophages, generate reactive oxygen species (ROS), induce overexpression of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1), and quench nitric oxide (NO). The pharmacological treatment currently available for either Type 1 or Type 2 diabetic patients does not directly address the excess accumulation of AGEs. Novel compounds that inhibit AGE formation, cleave AGE cross-links or reverse their interaction with RAGE are now accessible and could prove useful in meeting this challenge. Other strategies such as inhibition of the hexosamine pathway, vitamin therapy to reduce oxidation and AGE accumulation, reduction of the ROS, or blocking the actions of growth factors or intracellular messengers of cell differentiation are also currently under research. This review will recount recent advances in the development of therapeutic approaches for inhibiting and treating the development of diabetic end-organ damage.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Produtos Finais de Glicação Avançada , Humanos
5.
Diabetologia ; 49(4): 755-65, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16463046

RESUMO

AIMS/HYPOTHESIS: We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL(1) production. METHODS: A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. RESULTS: Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL(1) TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL(1) in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL(1) TG and ApoB pool sizes, adiponectin was not linked to VLDL(1) TG or ApoB production and thus was not a predictor of VLDL(1) production. However, adiponectin correlated negatively with the removal rates of VLDL(1) TG and ApoB. CONCLUSIONS/INTERPRETATION: We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL(1) particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.


Assuntos
Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Lipoproteínas VLDL/biossíntese , Adulto , Idoso , Apolipoproteínas B/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade
6.
J Med Genet ; 42(12): 932-9, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15827092

RESUMO

BACKGROUND: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. OBJECTIVE: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. METHODS: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. RESULTS: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. CONCLUSIONS: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.


Assuntos
Estatura/genética , Cromossomos Humanos Par 1 , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genoma Humano , Genótipo , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Fatores Sexuais
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