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1.
Diabetes Obes Metab ; 12(9): 790-7, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20649631

RESUMO

AIM: The aim of this study was to evaluate the efficacy of two group-based lifestyle interventions in ameliorating the risk factors of metabolic syndrome (MS) and insulin resistance. METHODS: Ninety-eight subjects who had at least one component of MS were randomized into standard intervention (SI) (4-month intervention; n = 50) and extended intervention (EI) (10-month intervention; n = 48) groups, and 39 subjects were followed up for a control group. The effects of intervention were evaluated after 10, 22 and 34 months. RESULTS: At month 10, the standard and EI groups showed improved body mass index (BMI) (SI, -0.28; EI, -0.47; control, -0.09), high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and A1c and a decreased mean number of components of MS (SI, -0.37; EI, -0.51; control, 0.08). At month 34, the effects on BMI (SI, -0.66; EI, -0.60; control, -0.05) and HDL-cholesterol were sustained for both the intervention groups. In controls, the increases in fasting plasma glucose and the mean number of components of MS from the baseline to month 34 were greater than those in the standard and EI groups. Whole body insulin sensitivity index and hepatic insulin resistance index were also improved at month 10. CONCLUSIONS: Group-based lifestyle intervention could be an efficient way to prevent MS. Its effects were sustainable, at least in part, for 2 years. These effects may be mediated by an improvement in insulin sensitivity.


Assuntos
Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Síndrome Metabólica/prevenção & controle , Comportamento de Redução do Risco , Adulto , Idoso , Feminino , Humanos , Japão/epidemiologia , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Fatores de Risco
2.
Eur J Endocrinol ; 138(3): 344-52, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9539311

RESUMO

Previously we demonstrated that bradykinin infusion could increase glucose uptake into dog peripheral tissues, and that bradykinin could potentiate insulin-induced glucose uptake through glucose transporter 4 (GLUT4) translocation in dog adipocytes. However, skeletal muscle is the predominant tissue for insulin-mediated glucose disposal. The aim of this study was to determine how bradykinin affected insulin-stimulated glucose uptake in dog skeletal muscle and myotubes transformed from rat L6 myoblasts. The bradykinin receptor binding studies revealed that dog skeletal muscle and rat L6 myoblasts possessed significant numbers of bradykinin receptors (Kd = 88 and 76 pmol/l, Bmax = 82.5 and 20 fmol/mg protein respectively). An RT-PCR (reverse transcriptase-polymerase chain reaction) amplification showed mRNA specific for bradykinin B2 receptor in both cells. Bradykinin significantly increased 2-deoxyglucose uptake in isolated muscle and L6 myoblasts in the presence of insulin (10(-7) mol/l) in a dose-dependent manner, but not in the absence of insulin. Bradykinin also enhanced insulin-stimulated GLUT4 translocation, and insulin-induced phosphorylation of insulin receptor beta subunit and insulin receptor substrate-1 (IRS-1) without affecting the binding affinities or numbers of cell surface insulin receptors in both cells. It is concluded that bradykinin could potentiate the insulin-induced glucose uptake through GLUT4 translocation in dog skeletal muscle and rat L6 myoblasts. This effect could be explained by the potency of bradykinin to upregulate the insulin receptor tyrosine kinase activity which stimulates phosphorylation of IRS-1, followed by an increase in GLUT4 translocation.


Assuntos
Bradicinina/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , Receptor de Insulina/metabolismo , Receptores da Bradicinina/metabolismo , Transdução de Sinais/fisiologia , Animais , Sequência de Bases , Sítios de Ligação , Ligação Competitiva , Bradicinina/análise , Bradicinina/farmacologia , Linhagem Celular , Primers do DNA/química , Cães , Relação Dose-Resposta a Droga , Insulina/farmacologia , Proteínas Substratos do Receptor de Insulina , Masculino , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Receptor de Insulina/efeitos dos fármacos , Receptores da Bradicinina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Trítio
3.
Eur J Endocrinol ; 134(6): 689-98, 1996 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8766937

RESUMO

To investigate the association of mutations in the arginine vasopressin receptor type II (V2R) gene with congenital nephrogenic diabetes insipidus (CNDI) in the Japanese, we analyzed the V2R gene, located on the X chromosome, in three Japanese pedigrees with CNDI. In one pedigree, a large deletion spanning the entire coding region of the V2R gene was identified. In another pedigree, a G to A transition responsible for a substitution of Met88 (ATG) for Val88 (GTG) was detected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed that this was a de novo mutation that had occurred in the proband's mother. Because CNDI was observed only in those with this mutation, the pathogenicity of this mutation seemed clear. In the last pedigree, only a silent mutation at Leu309 (CTA-->CTG) was found. All the individuals studied in this pedigree by allele-specific oligonucloetide-polymerase chain reaction (ASO-PCR) analysis showed a complete association of this mutation to the clinical symptoms. Because the silent mutation detected was unlikely to be a direct cause of CNDI, mutations in other regions of the V2R gene, such as a promoter region or other regulatory regions, may be responsible for the cause of CNDI in this pedigree. Thus, association of the V2R gene abnormality to clinical symptoms of CNDI was confirmed in three Japanese pedigrees, and a strong contribution of the V2R gene mutation to the development of CNDI was suggested.


Assuntos
Diabetes Insípido Nefrogênico/genética , Deleção de Genes , Genes , Receptores de Vasopressinas/genética , Adulto , Alelos , Sequência de Aminoácidos , Sequência de Bases , Southern Blotting , Criança , Pré-Escolar , DNA/genética , Genoma , Humanos , Masculino , Sondas Moleculares/genética , Dados de Sequência Molecular , Oligonucleotídeos/genética , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição
4.
Diabetologia ; 39(5): 600-8, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8739921

RESUMO

Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM). In this study, we have identified IRS-1 gene polymorphisms, evaluated their frequencies in Japanese subjects, and analysed the contribution of these polymorphisms to the development of NIDDM. The entire coding region of the IRS-1 gene of 94 subjects (47 NIDDM and 47 control subjects) was screened by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) analysis. Seven SSCP polymorphisms were identified. These corresponded to two previously identified polymorphisms [Gly971 --> Arg (GGG --> AGG) and Ala804 (GCA --> GCG)] as well as five novel polymorphisms [Pro190 --> Arg (CCC --> CGC), Met209 --> Thr (ATG --> ACG), Ser809 --> Phe (TCT --> TTT), Leu142 (CTT --> CTC), and Gly625 (GGC --> GGT)]. Although the prevalence of each of these polymorphisms was not statistically different between NIDDM and control subjects, the prevalence of the four IRS-1 polymorphisms with an amino acid substitution together was significantly higher in NIDDM than in control subjects (23.4 vs 8.5%, p < 0.05), and two substitutions (Met 209 --> Thr and Ser809 --> Phe) were found only in NIDDM patients. Equilibrium glucose infusion rates during a euglycaemic clamp in NIDDM and control subjects with the IRS-1 polymorphisms decreased by 29.5 and 22.0%, respectively on the average when compared to those in comparable groups without polymorphisms, although they were not statistically significant. Thus, IRS-1 polymorphisms may contribute in part to the insulin resistance and development of NIDDM in Japanese subjects; however, they do not account for the major part of the decrease in insulin-stimulated glucose uptake which is observed in subjects with clinically apparent NIDDM.


Assuntos
Diabetes Mellitus Tipo 2/genética , Fosfoproteínas/genética , Polimorfismo Genético , Sequência de Aminoácidos , Sequência de Bases , Glicemia/metabolismo , Primers do DNA , Desoxirribonucleases de Sítio Específico do Tipo II , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Técnica Clamp de Glucose , Humanos , Proteínas Substratos do Receptor de Insulina , Íntrons , Japão , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Valores de Referência
5.
Diabetologia ; 39(4): 412-20, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8777990

RESUMO

It has been suggested that bradykinin stimulates glucose uptake in experiments in vivo and in cultured cells. However, its mechanism has not yet been fully elucidated. In this study, the effects of bradykinin on the insulin signalling pathway were evaluated in isolated dog adipocytes. The bradykinin receptor binding study revealed that dog adipocytes possessed significant numbers of bradykinin receptors (Kd = 83 pmol/l, binding sites = 1.7 x 10(4) site/ cell). Reverse transcription-polymerase chain reaction amplification showed the mRNA specific for bradykinin B2 receptor in the adipocytes. Bradykinin alone did not increase 2-deoxyglucose uptake in adipocytes; however, in the presence of insulin (10(-7) mol/l) it significantly increased 2-deoxyglucose uptake in a dose-dependent manner. Bradykinin also enhanced insulin stimulated GLUT4 translocation from the intracellular fraction to the cell membrane, and insulin induced phosphorylation of the insulin receptor beta subunit and insulin receptor substrate-1 (IRS-1) without affecting the binding affinities or numbers of cell surface insulin receptors in dog adipocytes. The time-course of insulin stimulated phosphorylation of the insulin receptor beta subunit revealed that phosphorylation reached significantly higher levels at 10 min, and stayed at the higher levels until 120 min in the presence of bradykinin, suggesting that bradykinin delayed the dephosphorylation of the insulin receptor. It is concluded that bradykinin could potentiate insulin induced glucose uptake through GLUT4 translocation. This effect could be explained by the potency of bradykinin to upregulate the insulin receptor tyrosine kinase activity which stimulates phosphorylation of IRS-1, followed by GLUT4 translocation.


Assuntos
Adipócitos/fisiologia , Bradicinina/farmacologia , Desoxiglucose/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Receptor de Insulina/metabolismo , Receptores da Bradicinina/fisiologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/fisiologia , Animais , Sequência de Bases , Transporte Biológico , Células Cultivadas , Sequência Conservada , Primers do DNA , Cães , Transportador de Glucose Tipo 4 , Humanos , Proteínas Substratos do Receptor de Insulina , Cinética , Masculino , Camundongos , Dados de Sequência Molecular , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Fosforilação , Reação em Cadeia da Polimerase , Receptor B2 da Bradicinina , Receptor de Insulina/efeitos dos fármacos , Receptores da Bradicinina/biossíntese , Receptores da Bradicinina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
6.
Diabetes Res Clin Pract ; 28(2): 103-17, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7587918

RESUMO

To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows; HbA1c < 6.5%, FBG < 110 mg/dl, and 2-h post-prandial blood glucose concentration < 180 mg/dl.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/prevenção & controle , Insulina/uso terapêutico , Albuminúria , Glicemia/metabolismo , Pressão Sanguínea , Peptídeo C/urina , Colesterol/sangue , HDL-Colesterol/sangue , Estudos de Coortes , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/prevenção & controle , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/fisiopatologia , Retinopatia Diabética/prevenção & controle , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Estudos Prospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Triglicerídeos/sangue
7.
Diabetologia ; 38(4): 422-9, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7796982

RESUMO

In pancreatic alpha cells, the existence and function of the insulin receptor has not yet been fully established. In this study, to confirm the expression of functional insulin receptors in pancreatic alpha cells, we performed: 1) insulin receptor binding assay, 2) Northern blot analysis and RT-PCR (reverse transcription-polymerase chain reaction) amplification of insulin receptor mRNA, 3) immunocytochemical staining, 4) biosynthetic labelling of insulin receptor protein using [35S]methionine, 5) analysis of insulin-stimulated autophosphorylation of the insulin receptor in glucagon secreting cell lines, In-R1-G9 and alpha TC clone 6 cells. Glucagon secretion decreased with the addition of insulin in both cells. The receptor binding studies using [125I-Tyr-A14] insulin revealed that both cells possessed a significant number of insulin receptors (In-R1-G9:K1 = 2.1 x 10(9) mol/l-1, K2 = 6.2 x 10(7) mol/l-1, R1 = 0.27 x 10(4), R2 = 1.86 x 10(4) sites/cell; alpha TC clone 6: K1 = 2.1 x 10(9) mol/l-1, K2 = 7.3 x 10(7) mol/l-1, R1 = 0.27 x 10(4), R2 = 1.95 x 10(4) sites/cell). Northern blot analysis as well as RT-PCR amplification showed the mRNA specific for insulin receptor in both cells. By immunocytochemical staining using anti-insulin receptor alpha-subunit antibody, positive immunostaining for insulin receptor was observed in both cells. [35S]Methionine labelling of both cells followed by immunoprecipitation using anti-insulin receptor antibody showed the correct size of the insulin receptor protein. The insulin receptor expressed in these cells underwent autophosphorylation by insulin stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Expressão Gênica , Glucagon/metabolismo , Insulina/farmacologia , Receptor de Insulina/biossíntese , Animais , Sequência de Bases , Northern Blotting , Células Clonais , Cricetinae , Primers do DNA , Humanos , Imuno-Histoquímica , Insulinoma , Cinética , Metionina/metabolismo , Dados de Sequência Molecular , Neoplasias Pancreáticas , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Receptor de Insulina/análise , Receptor de Insulina/metabolismo , Radioisótopos de Enxofre , Células Tumorais Cultivadas
8.
Diabetologia ; 37(3): 300-7, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8174845

RESUMO

The present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol.kg-1) or orally (5.0 mmol.kg-1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol.kg-1) and oral administration of either delapril or enalapril (5.0 mmol.kg-1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-alpha-adamantane-acetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]-b bradykinin) (0.5 nmol.kg-1 x min-1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol.kg-1 x min-1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol.kg-1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/farmacologia , Resistência à Insulina/fisiologia , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Cães , Feminino , Técnica Clamp de Glucose , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Compostos de Sulfidrila/farmacologia
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