Browsing by Author "Fernandes, R."
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- Biochemical and histological effects of sitagliptin on Zucker Diabetic Fatty rat pancreasPublication . Mega, C.; Vala, Helena; Teixeira de Lemos, E.; Fernandes, R.; Oliveira, J.; Ferreira, L.; Teixeira, F.; Reis, F.Background: Inhibition of dipeptidyl peptidase-4 (DPP-4) activity by sitagliptin has been shown to improve glycemic control in patients with type 2 diabetes Mellitus (T2DM) by prolonging the actions of incretin hormones, but the really impact of low-dose sitagliptin treatment on pancreas lesions is almost unknown. This study aimed to evaluate the effects of sitagliptin on biochemical and histological (pancreas) parameters of Zucker Diabetic Fatty (ZDF, fa/fa) rats, an animal model of T2DM. Methods: Diabetic (fa/fa) ZDF male rats were treated with vehicle or sitagliptin (10 mg/kg BW/day) during 6 weeks (n=8 each). The following parameters were assessed: serum glycaemia, HbA1c, insulin and lipid profile; serum and pancreas oxidative stress (MDA) and endocrine and exocrine pancreas histology, estimating and rating inflammatory infiltrate, fibrosis, vacuolization and congestion in a semiquantitative score ranging from 0 (minimal) to 3 (severe and extensive damage). Results: Sitagliptin in diabetic ZDF rats promoted beneficial effects on dysglycaemia, dyslipidaemia, inflammatory profile and pancreatic oxidative stress. Endocrine and exocrine pancreas presented a reduction/amelioration of fibrosis severity, inflammatory infiltrate, intra-islet vacuolation, and congestion vs the vehicle-treated diabetic rats. Conclusions: The favourable biochemical profile promoted by sitagliptin in the diabetic rats, together with a protection against endocrine and exocrine pancreas lesions, might represent a further advantage of low doses of sitagliptin in the management of T2DM.
- Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker Diabetic Fatty rat)Publication . Mega, C.; Teixeira de Lemos, E.; Vala, Helena; Fernandes, R.; Oliveira, J.; Mascarenhas-Melo, F.; Teixeira, F.; Reis, F.This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker Diabetic Fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semi-quantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0-2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.
- Pancreatic lesions and metabolic aggravation are prevented by low doses of sitagliptin in a rat model of type 2 diabetesPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Teixeira de Lemos, E.; Reis, F.Introduction: The management of type 2 diabetes is designed to reduce disease-related complications and improve long-term outcomes. Inhibition of dipeptidyl peptidase-4 (DPP-4) activity by sitagliptin has been shown to improve glycaemic control in patients with type 2 diabetes Mellitus (T2DM) by prolonging the actions of incretin hormones, but the real impact of low-dose sitagliptin treatment on cardiometabolic risk factors and pancreatic lesions is almost unknown. This study aimed to evaluate the effects of low doses of sitagliptin on cardiovascular risk factors and histological pancreas parameters in Zucker Diabetic Fatty rats (ZDF (fa/fa)) an animal model of T2DM. Materials and Methods: Twenty weeks old diabetic obese (fa/fa) ZDF male rats were treated with vehicle or sitagliptin (10 mg/kg BW/day) during 6 weeks (n=8 each). The following parameters were assessed: glycaemia, HbA1c, insulin, lipidic profile; blood pressure. Specimens for pancreatic histopathology were stained with haematoxylin-eosin and periodic-acid-Shiff, examined by light microscopy. Endocrine and exocrine pancreas was evaluated semiquantitatively concerning inflammatory infiltrate, fibrosis, vacuolization and congestion, and scored from 0 (absent) to 3 (severe and extensive damage). Results: Sitagliptin in diabetic obese ZDF rats promoted a positive effect on dysglycaemia, dyslipidaemia and prevented the increase of blood pressure. Endocrine and exocrine pancreas presented a reduction/amelioration of fibrosis severity, inflammatory infiltrate, intra-islet vacuolation, and congestion vs the vehicle-treated diabetic rats. Conclusion: Simultaneous improvement of a sustainable glycaemic profile and of pancreatic histopathological lesions supports the favorable cardiovascular risk profile and may prove beneficial in decreasing long-term complications of T2DM.
- Pancreatic protection afforded by sitagliptin in a rat model of type 2 diabetes: putative mechanismsPublication . Mega, C.; Vala, Helena; Oliveira, J.; Teixeira, F.; Fernandes, R.; Teixeira de Lemos, E.; Reis, F.
- Progression of renal disease in the Zucker Diabetic Fatty rat, an experimental model of Type2 DiabetesPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Reis, F.; Teixeira de Lemos, E.
- Renal structure modification in an animal model of type 2 diabetes with aging: focus on hydronephrosisPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Teixeira de Lemos, E.; Reis, F.Background and aims: The Zucker Diabetic Fatty (ZDF-fa/fa) rat is one of the most used models for the study of type 2 diabetes (T2DM). Characterization of renal morphology in this model may provide useful insights into the mechanism of diabetic nephropathy progression. The purpose of the present study was to determine renal morphology, identify and characterize renal dysfunction complications such as hydronephrosis, in Zucker Diabetic fatty (ZDF) rat through T2DM evolution. Material and Methods: Male diabetic obese ZDF (fa/fa) rats were sacrificed at 8, 20 and 26 weeks of age and compared with their lean counterparts ZDF (+/+) with de same age. Biochemistry in serum for metabolic assessment was also performed. Kidney slices stained with hematoxylin-eosin and periodic acid-Schiff were evaluated. A semiquantitative rating was assigned for hydronephrosis and scored from 0 (normal) to 3 (severe), based on conformational aspects of the papilla and calyx and cortex compression. Results: A striking progression in the severity of hydronephrosis was observed. All end-disease state rats, 26 weeks of age, showed hydronephrosis, which was more severe in the diabetic rats (scoring: 2, 3) when compared to lean controls (scoring 1). No significant cortical atrophy was found. These abnormalities accompanied aggravation in diabetic desmetabolism. Conclusions: The present study indicates that ZDF rats present nephropathy with hydronephrosis. Lesions are age-related and aggravated by diabetic desmetabolism but don’t hinder morphological evaluation. Therefore the ZDF rat might represent a useful model for the preclinical study of therapeutic interventions in diabetic nephropathy.
- Sitagliptin ameliorates kidney lesions in a rat model of type 2 diabetes due to anti-inflammatory and anti-apoptotic effectsPublication . Marques, C.; Mega, C.; Gonçalves, A.; Rodrigues-Santos, P.; Vala, Helena; Teixeira-Lemos, E.; Teixeira, F.; Fontes-Ribeiro, C.; Reis, F.; Fernandes, R.Objective: This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of T2DM, the Zucker Diabetic Fatty (ZDF) rat. Methods: ZDF rats (aged 20 weeks) were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia, HbA1c, urea and creatinine levels were monitored. Kidney glomerular and tubulointerstitial lesions were assessed using a semiquantitative rating. Kidney mRNA and/or protein content of DPP-IV, GLP-1, TNF-α, IL-1β, BAX, Bcl-2 and Bid were evaluated by RT-PCR and/or WB. Protein distribution was evaluated by immunohistochemistry. Results: Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and HbA1c, and prevented the diabetes-induced increase in DPP-IV levels and decrease in GLP-1 levels. Sitagliptin ameliorated diabetes-induced glomerular atrophy and IFTA, and the increased urea levels. Sitagliptin decreased kidney IL-1β and TNF-α, and prevented the increase of BAX/Bcl-2 ratio and Bid protein levels, which indicates protective effects against inflammation and pro-apoptotic state in the kidney of diabetic rats, respectively. Conclusion: Sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and anti-apoptotic properties.
- Sitagliptin delays progression of renal lesions in a rodent model of type 2 diabetesPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Reis, F.; Lemos, E. T.
- Sitagliptin delays progression of renal lesions in a rodent model of type 2 diabetesPublication . Cristina, M.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Reis, F.; Teixeira de Lemos, E.
- Sitagliptin prevents aggravation of endocrine and exocrine pancreatic damage in the Zucker Diabetic Fatty rat - focus on amelioration of metabolic profile and tissue cytoprotective propertiesPublication . Mega, C.; Vala, Helena; Rodrigues-Santos, P.; Oliveira, J.; Teixeira, F.; Fernandes, R.; Reis, F.; Lemos, ETBACKGROUND: The purpose of this study was to investigate some of the possible mechanisms underlying the protective effects of a dipeptidyl peptidase IV (DPP-IV) inhibitor, sitagliptin, on pancreatic tissue in an animal model of type 2 diabetes mellitus (T2DM), the Zucker Diabetic Fatty(ZDF) rat, focusing on glycaemic, insulinic and lipidic profiles, as well as, on apoptosis, inflammation, angiogenesis and proliferation mediators. METHODS: Male obese diabetic ZDF (fa/fa) rats, aged 20 weeks, were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks and compared to untreated diabetic and lean control littermates. Metabolic data was evaluated at the beginning and at the end of the treatment, including glycaemia, HbA1c, insulinaemia, HOMA-beta and TGs. Endocrine and exocrine pancreas lesions were assessed semiquantitatively by histopathological methods. Pancreas gene (mRNA) and protein expression of mediators of apoptotic machinery, inflammation and angiogenesis/proliferation (Bax, Bcl2, IL-1β, VEGF, PCNA and TRIB3) were analyzed by RT-qPCR and/or by immunohistochemistry. RESULTS: Sitagliptin treatment for 6 weeks (between 20 and 26 week-old) was able to significantly (p < 0.001) ameliorate all the metabolicparameters, by preventing the increase in blood glucose and in serum TGs contents (16.54% and 37.63%, respectively, vs untreated), as well as, by preventing the decrease in serum insulin levels and in the functional beta cells capacity accessed via HOMA-beta index (156.28% and 191.74%, respectively, vs untreated). Sitagliptin-treated diabetic rats presented a reduced pancreas Bax/Bcl2 ratio, suggestive of an antiapoptotic effect; in addition, sitagliptin was able to completely reduce (p < 0.001) the pancreas overexpression of IL-1β and TRIB3 found in the untreated diabeticanimals; and promoted a significant (p < 0.001) overexpression of VEGF and PCNA. CONCLUSION: In this animal model of obese T2DM (the ZDF rat), sitagliptin prevented β-cell dysfunction and evolution of pancreatic damage. The protective effects afforded by this DPP-IV inhibitor may derive from improvement of the metabolic profile (viewed by the amelioration of glucose and TGs levels and of insulin resistance) and from cytoprotective properties, such as antiapoptotic, anti-inflammatory, pro-angiogenic and pro-proliferative.