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1.
Diabetes ; 61(10): 2621-32, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22596048

RESUMO

We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes was induced in nude athymic mice by streptozotocin injections. At 9 weeks after hyperglycemia, 10(5) PB-MNCs from diabetic patients, pretreated by EFNB2, were intravenously injected in diabetic mice with hindlimb ischemia. Two weeks later, the postischemic neovascularization was evaluated. The mechanisms involved were investigated by flow cytometry analysis and in vitro cell biological assays. Paw skin blood flow, angiographic score, and capillary density were significantly increased in ischemic leg of diabetic mice receiving EFNB2-activated diabetic PB-MNCs versus those receiving nontreated diabetic PB-MNCs. EFNB2 bound to PB-MNCs and increased the adhesion and transmigration of PB-MNCs. Finally, EFNB2-activated PB-MNCs raised the number of circulating vascular progenitor cells in diabetic nude mice and increased the ability of endogenous bone marrow MNCs to differentiate into cells with endothelial phenotype and enhanced their proangiogenic potential. Therefore, EFNB2 treatment of PB-MNCs abrogates the diabetes-induced stem/progenitor cell dysfunction and opens a new avenue for the clinical development of an innovative and accessible strategy in diabetic patients with critical ischemic diseases.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Efrina-B2/farmacologia , Isquemia/terapia , Leucócitos Mononucleares/efeitos dos fármacos , Neovascularização Patológica/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Membro Posterior/irrigação sanguínea , Membro Posterior/fisiopatologia , Humanos , Isquemia/metabolismo , Isquemia/fisiopatologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/transplante , Masculino , Camundongos , Camundongos Nus , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/fisiologia
2.
Phys Sportsmed ; 39(2): 98-106, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21673489

RESUMO

In this article, we examine the results from meta-analyses of studies that have focused on the effects of supervised exercise in patients with established type 2 diabetes mellitus. Exercise has been clearly demonstrated to have benefits on blood glucose control (average reduction of glycated hemoglobin, 0.6%) and cardiovascular risk factors. These benefits are observed independently of any change in body mass index and fat mass, and are also seen in older populations. Multiple mechanisms are involved, and the improved insulin-sensitizing effect of exercise training is not restricted to muscle but extends to hepatic and adipose tissue. However, while the benefits of exercise in type 2 diabetes management are undisputable, it is not as easy to draw correlations between clinical benefit and the amount of physical activity included in daily life. Recent studies have shown encouraging results with moderate increases in physical activity, which are feasible for most patients and are sufficient to induce sustained positive changes for 2 years. Thus, the benefits of structured and supervised exercise in patients with type 2 diabetes have been consistently demonstrated. Currently, the primary challenge is to determine how long-term increased physical activity can be durably implemented in a patient's daily life.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Terapia por Exercício , Exercício Físico/fisiologia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos
3.
Diabetes ; 59(3): 653-61, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20007936

RESUMO

OBJECTIVE: Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved. RESEARCH DESIGN AND METHODS: The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin-green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal beta-cells by immunocytochemistry and proinsulin secretion, by radioimmunoassay. Spliced XBP1 and C/EBP homologous protein were quantitated by real-time PCR. RESULTS: A novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17-36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6 beta-cells, and ER exit was inhibited by approximately 50%. Two additional mutants, R55C (at the B/C junction) and R6H (in the signal peptide), were normally targeted to secretory granules, but nonetheless caused substantial ER stress. CONCLUSIONS: We describe three INS mutations cosegregating with early-onset diabetes whose clinical presentation is compatible with MODY. These led to the production of (pre)proinsulin molecules with markedly different trafficking properties and effects on ER stress, demonstrating a range of molecular defects in the beta-cell.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/metabolismo , Proinsulina/genética , Proinsulina/metabolismo , Adolescente , Adulto , Idade de Início , Saúde da Família , Feminino , França , Proteínas de Fluorescência Verde/genética , Heterozigoto , Humanos , Células Secretoras de Insulina/fisiologia , Masculino , Mutagênese Sítio-Dirigida , Linhagem , Mutação Puntual , Proinsulina/química , Dobramento de Proteína , Estrutura Terciária de Proteína , Transporte Proteico/fisiologia , RNA Mensageiro/metabolismo , Estresse Fisiológico/fisiologia , Adulto Jovem
4.
Presse Med ; 36(3 Pt 2): 467-74, 2007 Mar.
Artigo em Francês | MEDLINE | ID: mdl-17336855

RESUMO

Insulin secretagogues and insulin sensitizers can be combined with one another as well as with other treatments (described below). Alpha-glucosidase inhibitors delay intestinal absorption of carbohydrates and reduce postprandial glycemia. Orlistat and sibutramine improve insulin sensitivity by helping patients lose weight. Orlistat inhibits hydrolysis of dietary triglycerides. Sibutramine, a noradrenaline and serotonin reuptake inhibitor, reinforces feelings of satiety and increases energy expenditure. After approximately 10 years, insulin therapy is usually required together with oral antidiabetic agents (except glitazones) or alone if HbA(1c) (glycosylated hemoglobin) is>6.5%. New guidelines for management of type 2 diabetes were published in 2006.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Fármacos Antiobesidade/uso terapêutico , Inibidores de Glicosídeo Hidrolases , Humanos , Insulina/uso terapêutico
6.
Presse Med ; 36(2 Pt 2): 269-78, 2007 Feb.
Artigo em Francês | MEDLINE | ID: mdl-17258675

RESUMO

Drug treatment of 2 diabetes is intended to normalize glycosylated hemoglobin levels (HbA(1c)<6.5%) and thereby prevent the development of micro- and macrovascular complications. Oral antidiabetic agents target the metabolic abnormalities that cause diabetes. The two principal families of oral antidiabetic agents - insulin sensitizers and insulin secretagogues - can be taken together. Thiazolidinediones or glitazones (insulin sensitizers) improve peripheral tissue sensitivity to insulin. Metformin (an insulin sensitizer) reduces hepatic glucose production. Sulfonylureas and meglitinides (insulin secretagogues) stimulate insulin secretion and can cause hypoglycemia. GLP-1 (Glucagon-Like Peptide-1) analogs and DPP-IV (dipeptidyl-peptidase-IV) inhibitors are new drug classes currently under development.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
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