RESUMO
BACKGROUND AND PURPOSE: The AT2 receptor plays a role in metabolism by opposing the actions triggered by the AT1 receptors. Activation of AT2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT2 receptors activation improves metabolism in diabetic mice. EXPERIMENTAL APPROACH: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT2 agonist, compound 21 (C21, 0.3 mg·kg-1 ·day-1 , s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml-1 , drinking water). KEY RESULTS: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME. CONCLUSION AND IMPLICATIONS: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.
Assuntos
Complicações do Diabetes , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Receptor Tipo 2 de AngiotensinaRESUMO
Obesity is considered an important risk factor for several disorders, such as diabetes mellitus, systemic arterial hypertension, dyslipidemia, and atherosclerosis, which are associated with inflammation and oxidative stress as a trigger factor. Passiflora edulis contains important bioactive compounds, such as phenolics, carotenoids, vitamin C, and polyamines in pulp, leaves, seeds, and bark. Aim: To evaluate the effect of bark of Passiflora edulis (BPe) on body composition, and metabolic and oxidative stress parameters in genetically obese mice. Methods: Obese male db/db mice (n = 14 animals) received normal feeds and water ad libitum for 8 weeks. Then, animals were randomly divided to continue either receiving standard chow (obese, n = 7 (OB)) or feed with standard chow plus bark Passiflora edulis (BPe) (obese + BPe, n = 7 (OB + BPe)) for 8 more weeks, totaling 16 weeks. BPe was added to chow (7 g of BPe/kg of chow corresponding to 1.5 g/kg of body weight). The parameters evaluated in animals included food and caloric intake, body weight, body fat, plasma glucose, triglycerides, and total cholesterol. Malondialdehyde and antioxidant capacity were evaluated in plasma and organs. Groups were compared by Student t-test, with p < 0.05. Results: BPe reduced visceral and subcutaneous fat deposit and adiposity index, cholesterol and triglyceride levels, ameliorated the antioxidant capacity, and reduced malondialdehyde (MDA) levels. Conclusion: the bark of Passiflora edulis was effective in improving body composition, and metabolic and antioxidant parameters in obese mice.
RESUMO
BACKGROUND: A number of dysregulated miRNAs have been identified and are proposed to have significant roles in the pathogenesis of type 2 diabetes mellitus or renal pathology. Alpinia oxyphylla has shown significant anti-inflammatory properties and play an anti-diabetes role. The objective of this study was to detect the alteration of miRNAs underlying the anti-diabetes effects of A. oxyphylla extract (AOE) in a type II diabetic animal model (C57BIKsj db-/db-). RESULTS: Treatment with AOE for 8 weeks led to lower concentrations of blood glucose, urine albumin, and urine creatinine. 17 and 13 miRNAs were statistically identified as differentially regulated in the DB/DB and db-/db- AOE mice, respectively, compared to the untreated db-/db- mice. Of these, 7 miRNAs were identified in both comparison groups, and these 7 miRNAs were verified by quantitative real-time PCR. Functional bioinformatics showed that the putative target genes of 7 miRNAs were associated with several diabetes effects and signaling pathways. CONCLUSIONS: These founding suggest that the potential of AOE as a medicinal anti-diabetes treatment through changes in the expressions of specific miRNAs. The results provide a useful resource for future investigation of the role of AOE-regulated miRNAs in diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , Extratos Vegetais/farmacologia , Albuminúria , Alpinia , Animais , Glicemia/análise , Creatinina/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: A number of dysregulated miRNAs have been identified and are proposed to have significant roles in the pathogenesis of type 2 diabetes mellitus or renal pathology. Alpinia oxyphylla has shown significant anti-inflammatory properties and play an anti-diabetes role. The objective of this study was to detect the alteration of miRNAs underlying the anti-diabetes effects of A. oxyphylla extract (AOE) in a type II diabetic animal model (C57BIKsj db-/db-). RESULTS: Treatment with AOE for 8 weeks led to lower concentrations of blood glucose, urine albumin, and urine creatinine. 17 and 13 miRNAs were statistically identified as differentially regulated in the DB/DB and db-/db- AOE mice, respectively, compared to the untreated db-/db- mice. Of these, 7 miRNAs were identified in both comparison groups, and these 7 miRNAs were verified by quantitative real-time PCR. Functional bioinformatics showed that the putative target genes of 7 miRNAs were associated with several diabetes effects and signaling pathways. CONCLUSIONS: These founding suggest that the potential of AOE as a medicinal anti-diabetes treatment through changes in the expressions of specific miRNAs. The results provide a useful resource for future investigation of the role of AOE-regulated miRNAs in diabetes mellitus.
Assuntos
Animais , Masculino , Camundongos , Extratos Vegetais/farmacologia , MicroRNAs/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Fatores de Tempo , Glicemia/análise , Regulação da Expressão Gênica , Reprodutibilidade dos Testes , Resultado do Tratamento , Análise de Sequência de RNA , Creatinina/sangue , MicroRNAs/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Albuminúria , Reação em Cadeia da Polimerase em Tempo Real , Rim/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Mineralocorticoid receptors (MRs), which are activated by mineralocorticoids and glucocorticoids, actively participate in mechanisms that affect the structure and function of blood vessels. Although experimental and clinical evidence shows that vascular damage in diabetes is associated with structural alterations in large and small arteries, the role of MR in this process needs further studies. Thus, we tested the hypothesis that MR, through redox-sensitive mechanisms, plays a role in diabetes-associated vascular remodelling. Male, 12-14-weeks-old db/db mice, a model of type 2 diabetes and their non-diabetic counterpart controls (db/+) were treated with spironolactone (MR antagonist, 50 mg/kg/day) or vehicle for 6 weeks. Spironolactone treatment did not affect blood pressure, fasting glucose levels or weight gain, but increased serum potassium and total cholesterol in both, diabetic and control mice. In addition, spironolactone significantly reduced serum insulin levels, but not aldosterone levels in diabetic mice. Insulin sensitivity, evaluated by the HOMA (homoeostatic model assessment)-index, was improved in spironolactone-treated diabetic mice. Mesenteric resistance arteries from vehicle-treated db/db mice exhibited inward hypertrophic remodelling, increased number of smooth muscle cells and increased vascular stiffness. These structural changes, determined by morphometric analysis and with a myography for pressurized arteries, were prevented by spironolactone treatment. Arteries from vehicle-treated db/db mice also exhibited augmented collagen content, determined by Picrosirius Red staining and Western blotting, increased reactive oxygen species (ROS) generation, determined by dihydroethidium (DHE) fluorescence, as well as increased expression of NAD(P)H oxidases 1 and 4 and increased activity of mitogen-activated protein kinases (MAPKs). Spironolactone treatment prevented all these changes, indicating that MR importantly contributes to diabetes-associated vascular dysfunction by inducing oxidative stress and by increasing the activity of redox-sensitive proteins.