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1.
Bioorg Med Chem ; 17(15): 5426-32, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19595600

RESUMO

Endothelial dysfunction and consequent reduction of biosynthesis of endogenous nitric oxide (NO) play an important pathogenetic role in the cardiovascular complications associated with type II diabetes. In this work, the hybrid drugs 3a and 3b, nitrooxymethylbenzoate-derivatives of 1 (which is a hydroxylated active metabolite of glibenclamide 2), are reported. The pharmacodynamic characterization of 3b showed that its hypoglycaemic activity is enriched with additional NO-donor effects, conferring vasorelaxing and anti-platelet properties of potentially great usefulness for diabetes-related cardiovascular disorders.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Diabetes Mellitus Tipo 2/induzido quimicamente , Glibureto/química , Glibureto/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Ratos Wistar , Vasodilatadores/química , Vasodilatadores/farmacologia
2.
Diabetes ; 54(3): 727-35, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15734849

RESUMO

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy.


Assuntos
Desoxiguanosina/análogos & derivados , Diabetes Mellitus Tipo 2/fisiopatologia , Ilhotas Pancreáticas/fisiopatologia , Tirosina/análogos & derivados , 8-Hidroxi-2'-Desoxiguanosina , Proteínas Quinases Ativadas por AMP , Adulto , Idoso , Desoxiguanosina/metabolismo , Feminino , Expressão Gênica , Glucose/metabolismo , Glutationa/fisiologia , Humanos , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/metabolismo , Estresse Oxidativo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Tempo , Tirosina/metabolismo
3.
Eur J Endocrinol ; 154(2): 355-61, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16452552

RESUMO

OBJECTIVE: Data from prospective studies suggest a significant reduction in the risk of new diabetes from drug therapies containing angiotensin-converting enzyme (ACE) inhibitors. Since the renin-angiotensin system (RAS) has been found locally in several tissues and cells, including pancreatic islets, we hypothesized that the positive metabolic effects of ACE inhibitors may be due to a beneficial action of these compounds on insulin-secreting beta-cells. DESIGN AND METHODS: Isolated human pancreatic islets were studied after 24 h of incubation with 22.2 mmol/l glucose, with or without the presence in the incubation medium of 0.5-6.0 mmol/l zofenoprilat or enalaprilat, ACE inhibitor drugs which differ by the presence of a sulphydryl or a carboxyl group in their structural formula. Functional and molecular studies were then performed to assess insulin secretion, redox balance, mRNA and protein expression. RESULTS: Angiotensinogen, ACE and angiotensin type 1 receptor mRNA expression increased in islets cultured in high glucose; this was similarly prevented by the presence of either ACE inhibitor. As expected, preculture of human islets in high glucose determined a marked reduction in insulin secretion which was associated with enhanced oxidative stress, as shown by increased nitrotyrosine concentrations, and enhanced expression of protein kinase C beta and NADPH oxidase. The presence of either of the ACE inhibitors counteracted several of the deleterious effects of high glucose exposure, including reduction of insulin secretion and increased oxidative stress; zofenoprilat showed significantly more marked effects. CONCLUSIONS: These results showed that: (a) RAS molecules are present in human islets and their expression is sensitive to glucose concentration, (b) ACE inhibitors, and in particular zofenoprilat, protect human islets from glucotoxicity and (c) the effects of ACE inhibition are associated with decreased oxidative stress. Together, these findings provide evidence that the possible beneficial effects of ACE inhibitors in human diabetes are due, at least in part, to a protective action on pancreatic beta-cells.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/análogos & derivados , Enalaprilato/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Captopril/farmacologia , Feminino , Glucose/metabolismo , Humanos , Técnicas In Vitro , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA/química , RNA/genética , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tirosina/análogos & derivados , Tirosina/análise
5.
Diabetes Metab Res Rev ; 23(3): 215-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16874846

RESUMO

BACKGROUND: Recent data have demonstrated that pro-insulin-derived C-peptide can affect the function of several different cell types. We hypothesized that C-peptide might have an influence on the function and survival of isolated human islets. METHODS: Islets were prepared by combining enzymatic digestion and density gradient centrifugation, and the effects of human C-peptide were evaluated acutely and after 24-h incubation. Insulin secretion, apoptosis, quantitative RT-PCR and western-blotting experiments were then performed. RESULTS: Glucose-stimulated insulin secretion was not affected by C-peptide and, accordingly, mRNA expression of glucose transporter 2 and glucokinase did not differ between islets pre-cultured or not with the hormone. However, apoptosis was significantly lower in islets exposed to C-peptide than in control islets. This was accompanied by a significant increase of mRNA and protein expression of Bcl2, an anti-apoptotic molecule, with no change in the expression of Bax, a pro-apoptotic molecule. CONCLUSION: These results show that in human islets pro-insulin C-peptide has no direct effects on insulin secretion, but it decreases islet cell apoptosis. A direct role of C-peptide on beta-cell mass regulation is therefore suggested.


Assuntos
Peptídeo C/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Apoptose/efeitos dos fármacos , Feminino , Humanos , Secreção de Insulina , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , RNA Mensageiro/metabolismo , Proteína X Associada a bcl-2/biossíntese
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