Bloqueio do sistema renina-angiotensina atenua lesões em órgãos-alvo em modelo de diabetes mellitus tipo 2 e hipercolesterolemia induzidos por dieta
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Arquivos
Data
2009
Autores
Helfenstein, Tatiana [UNIFESP]
Orientadores
Izar, Maria Cristina de Oliveira [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
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Resumo
Com o crescente aumento da prevalência mundial de diabetes mellitus, tem-se buscado modelos
experimentais para melhor compreensão de sua fisiopatologia e tratamento que atendam de maneira
mais adequada à preservação de células beta, proteção de órgãos-alvo e atenuação da aterosclerose.
Objetivos: Desenvolver modelo experimental de diabetes mellitus tipo 2 induzido por meio de dieta, e
utilizá-lo para examinar os efeitos de um inibidor da enzima conversora de angiotensina (IECA) e de um
bloqueador do receptor de angiotensina (BRA) na proteção de órgãos-alvo. Métodos: Coelhos machos
Nova Zelândia (n=49) receberam dieta acrescida de banha (10%), sacarose (40%) durante todo o
protocolo do estudo além de colesterol (0,5% nos três primeiros meses e 0,1% nos meses
subseqüentes). Os animais receberam aleatoriamente: apenas a dieta sem fármacos (G1), olmesartana
5 mg (G2), quinapril 30 mg (G3), ou a combinação de ambos (G4), acrescidos à mesma dieta por seis
meses. Foram analisados lípides, frutosamina, glicose e insulina em jejum com cálculo dos índices para
resistência à insulina e função de células beta pancreáticas. Foram ainda examinadas as áreas sob as
curvas de insulina e glicose, após infusão de glicose intraperitoneal. Angiofluoresceinografias e análises
histopatológicas avaliaram lesões em órgãos-alvo. Resultados: Os coelhos ganharam peso, e houve
aumento dos níveis de glicose, colesterol total, LDL-C e triglicérides e redução do HDL-C (p <0,05 vs.
basal). A frutosamina e o HOMA-IR se elevaram, enquanto houve redução do HOMA-β (p <0,05 vs.
basal). Sinais precoces de retinopatia diabética foram observados a partir do terceiro mês, progredindo
até o final do experimento (p<0,0005). Lesões ateroscleróticas em aorta, esteatofibrose hepática e
infiltrado glomerular de macrófagos constituíram os principais achados histomorfológicos. O bloqueio do
sistema renina-angiotensina modificou favoravelmente a glicemia e o HOMA-β (p<0,05) e houve
atenuação do número e grau dos microaneurismas pelo tratamento com BRA isoladamente ou
combinado com IECA (p<0,05 vs. G1). Conclusões: Nosso modelo reproduziu várias características
glucometabólicas do diabetes mellitus tipo 2 humanóide, incluindo déficit de secreção e resistência à
insulina. O bloqueio do sistema renina-angiotensina atenuou algumas alterações bioquímicas e as lesões
microvasculares em retina.
With the increasing prevalence of diabetes mellitus worldwide, new experimental models are required to better understand the pathophysiology of this disease and to offer therapeutic options that can preserve pancreatic beta-cells, protect target organs and attenuate atherosclerosis. Objective: The aims of this study were to develop an experimental model of type 2 diabetes mellitus induced by diet and assess on this model the effects of an angiotensin-converting enzyme inhibitor (ACEI) and an antagonist of the angiotensin II type1 receptor (AT1R) on target organ protection. Methods: New Zealand male white rabbits (n=49) were fed high-fat/high-sucrose (10/40%) during the study protocol and cholesterol-enriched diet (0.5% in the first three months followed by 0.1% until the end of the study). These animals were randomized to receive: diet alone (G1), olmesartan 5 mg (G2), quinapril 30mg (G3), or combination of both drugs (G4), added to the same diet for six months. Fasting lipids, fructosamine, glucose and insulin, with calculation of insulin resistance and beta-cell function indexes were evaluated. The areas under the curves for glucose and insulin were obtained after intraperitoneal glucose bolus injection. Fluorescein angiography and histopathological analyses were performed to assess target-organs lesions. Results: The animals gained weight, and there were increases in blood glucose, total cholesterol, LDL-C and triglycerides, and decrease in HDL-C (p<0.05 vs. baseline). Fructosamine levels and the homeostasis model assessment of insulin resistance (HOMA-IR) were increased, while there was a reduction in the HOMA-β (p<0.05 vs. baseline). Early clinical features of diabetic retinopathy were seen since the third month, progressing up to the end of the experiment (p<0.0005). Aortic atherosclerosis, hepatic steatofibrosis and glomerular macrophage infiltration were the main histomorphologic findings of this study. The renin-angiotensin system (RAS) blockade favorably modified blood glucose and the HOMA- β (p<0.05) and promoted attenuation of the number and grade of microaneurysms in retina in the group of animals receiving AT1R antagonist or combined therapy with the ACEI (p<0.05 vs. G1). Conclusion: Our model reproduced several glucometabolic characteristics of humanoid type 2 diabetes, including decreased insulin secretion and insulin resistance. The RAS blockade attenuated some biochemical abnormalities and the diabetic retinopathy.
With the increasing prevalence of diabetes mellitus worldwide, new experimental models are required to better understand the pathophysiology of this disease and to offer therapeutic options that can preserve pancreatic beta-cells, protect target organs and attenuate atherosclerosis. Objective: The aims of this study were to develop an experimental model of type 2 diabetes mellitus induced by diet and assess on this model the effects of an angiotensin-converting enzyme inhibitor (ACEI) and an antagonist of the angiotensin II type1 receptor (AT1R) on target organ protection. Methods: New Zealand male white rabbits (n=49) were fed high-fat/high-sucrose (10/40%) during the study protocol and cholesterol-enriched diet (0.5% in the first three months followed by 0.1% until the end of the study). These animals were randomized to receive: diet alone (G1), olmesartan 5 mg (G2), quinapril 30mg (G3), or combination of both drugs (G4), added to the same diet for six months. Fasting lipids, fructosamine, glucose and insulin, with calculation of insulin resistance and beta-cell function indexes were evaluated. The areas under the curves for glucose and insulin were obtained after intraperitoneal glucose bolus injection. Fluorescein angiography and histopathological analyses were performed to assess target-organs lesions. Results: The animals gained weight, and there were increases in blood glucose, total cholesterol, LDL-C and triglycerides, and decrease in HDL-C (p<0.05 vs. baseline). Fructosamine levels and the homeostasis model assessment of insulin resistance (HOMA-IR) were increased, while there was a reduction in the HOMA-β (p<0.05 vs. baseline). Early clinical features of diabetic retinopathy were seen since the third month, progressing up to the end of the experiment (p<0.0005). Aortic atherosclerosis, hepatic steatofibrosis and glomerular macrophage infiltration were the main histomorphologic findings of this study. The renin-angiotensin system (RAS) blockade favorably modified blood glucose and the HOMA- β (p<0.05) and promoted attenuation of the number and grade of microaneurysms in retina in the group of animals receiving AT1R antagonist or combined therapy with the ACEI (p<0.05 vs. G1). Conclusion: Our model reproduced several glucometabolic characteristics of humanoid type 2 diabetes, including decreased insulin secretion and insulin resistance. The RAS blockade attenuated some biochemical abnormalities and the diabetic retinopathy.
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Citação
HELFENSTEIN, Tatiana. Bloqueio do sistema renina-angiotensina atenua lesões em órgãos-alvo em modelo de diabetes mellitus tipo 2 e hipercolesterolemia induzidos por dieta. 2009. 97 f. Tese (Doutorado em Ciências) – Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2009.