Oral formulation of DPP-4 inhibitor plus Quercetin improves metabolic homeostasis in type 1 diabetic rats.

This study aimed to investigate the potential of an oral formulation (QV formulation) containing Quercetin and a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), Vildagliptin, in improving metabolic homeostasis in type 1 diabetes model. Female albino Fischer rats were divided into four groups: untreated control animals (C), untreated diabetic animals (D), diabetic animals treated with QV formulation (DQV), and diabetic animals treated with insulin (DI). Diabetes was induced by injection of alloxan (135?mg?kg body mass)?1 and confirmed by glycemic test. After the 30-day treatment period, biochemical parameters were analyzed in the pancreas, liver, and serum. Histopathological changes in pancreatic tissue were examined by Hematoxyline & Eosin staining and the insulin content in the islet measured by immunohistochemistry with anti-insulin antibody. The glycogen content in the hepatocytes was quantified by Periodic Schiff Acid staining. The QV formulation reduced the glycemia, preserved the pancreatic architecture, increased insulin levels, furthermore ameliorated lipid profile and to promote higher survival rate of animals. Together, our data suggest that the QV formulation treatment was able to normalize metabolic homeostasis in type 1 diabetic rats

Potencial terap?utico de formula??o antidiab?tica oral em modelo experimental de diabetes tipo 1 : avalia??es hep?ticas e renais.

Programa de P?s-Gradua??o em Ci?ncias Biol?gicas. N?cleo de Pesquisas em Ci?ncias Biol?gicas, Pr?-Reitoria de Pesquisa de P?s Gradua??o, Universidade Federal de Ouro Preto.O diabetes mellitus 1 (DM1) compreende um conjunto de altera??es em c?lulas ?-pancre?ticas, que, de maneira cr?nica, acarreta efeitos em diversos ?rg?os, dentre eles f?gado e rins. A Vildagliptina (V) tem sido usada no controle terap?utico da glicemia em diab?ticos do tipo 2. Outro candidato terap?utico, a Quercetina (Q) ? um antioxidante com potencial protetor de diversos tecidos, sendo demonstrados efeitos ben?ficos em f?gado e rins. Neste projeto visamos analisar o efeito do tratamento com a formula??o antidiab?tica oral (QV) no f?gado e rins de animais DM1. Os procedimentos foram aprovados pela CEUA-UFOP (#2014/17). Ratas Fisher f?meas (n=39), 120 dias, 200g foram divididas nos grupos: Controle (C), Diab?tico (D), Diab?tico tratado com formula??o QV (DQV) e Diab?tico tratado com insulina (DI). O diabetes foi induzido por inje??o intraperitonial de Aloxano (135mgKg). O tratamento foi realizado diariamente, por via orogr?strica por 30 dias. Ap?s este per?odo realizou-se a eutan?sia e coleta de materiais. O sangue foi coletado para an?lise dos n?veis glic?micos. O f?gado e rins foram destinados a an?lises histol?gicas e avalia??o de biomarcadores do processo redox. Os resultados foram analisados pelo Software Graphpad Prism 6.0, com n?vel de signific?ncia de 5%. As an?lises hep?ticas mostraram que a formula??o QV restaurou os dep?sitos de glicog?nio hep?tico nos animais DQV (100,8?7,466?m?) em n?vel dos animais C (126,3?3,487 ?m?). Houve tamb?m redu??o do n?mero de c?lulas de Kupffer nos animais DQV (52,34?2,53), comparado a animais do grupo D (74,45?7,18), acompanhado por redu??o das ?reas de fibrose, tamb?m reduzidas no grupo DQV (334,9?47,9 ?m?) e DI (437,8?74,20 ?m?) quando comparado ao grupo D (1752?434,7 ?m?). As ?reas de col?geno 1 tamb?m foram reduzidas em animais DQV (270,5?79,50 ?m?) quando comparado ao grupo D (2970?1409 ?m?), entretanto a quantifica??o de col?geno 3 e de fibras el?sticas n?o apresentaram diferen?as significativas. O modelo de diabetes induzido pelo aloxano, bem como o tratamento com a formula??o n?o promoveu diferen?as significativas na atividade enzim?tica de SOD e CAT, bem como na gera??o de prote?na carbonilada. As an?lises em rins mostraram que o tratamento com a formula??o foi eficaz em preservar os tecidos de hemorragia em ?reas glomerulares e tubulares, al?m de reduzir ?reas de fibrose nos animais DQV (2004?397,6 ?m?) quando comparado a animais D (3840?694,8 ?m?), esta redu??o se mostrou ao n?vel dos animais DI (1502?256,6 ?m?). Resultado semelhante foi encontrado na quantifica??o de col?geno 1, os grupos DQV (808,3?240,3 ?m?) e DI (3233?817,7 ?m?) exibiram ?reas de col?geno 1 reduzidas a n?vel dos animais controle C (1624?430,2 ?m?), por?m n?o foram encontradas diferen?as significativas na quantifica??o de col?geno 3 e apenas animais DI apresentaram fibras el?sticas elevadas. A atividade de CAT foi reduzida em animais DQV (58,39?4,28) em rela??o aos animais C (88,59?7,66), entretanto a atividade de SOD, TBARS e MMP-2 n?o apresentaram diferen?as significativas. Nossas considera??es finais ressaltam que a formula??o possui propriedades que preservam a integridade histol?gica hep?tica e renal, o que aliado a seu efeito na regula??o da glicemia, mostra-se um importante alvo terap?utico coadjuvante para tratamento do DM1.Diabetes mellitus 1 (DM1) comprises a set of alterations in ?-pancreatic cells, which, in a chronic way, has effects in several organs, among them liver and kidneys. Vildagliptin (V) has been used in the therapeutic control of glycemia in type 2 diabetics. Another therapeutic candidate, Quercetin (Q) is an antioxidant with protective potential of several tissues and beneficial effects on liver and kidneys have been demonstrated. We aimed to analyze the effect of treatment with the oral antidiabetic formulation (QV) in the liver and kidneys of DM1 animals. The procedures were approved by CEUA-UFOP (# 2014/17). Female Fisher rats (n = 39), 120 days, 200g were divided into the groups: Control (C), Diabetic (D), Diabetic treated with QV formulation (DQV) and Diabetic treated with insulin (DI). Diabetes was induced by intraperitoneal injection of Aloxane (135mg kg). The treatment was performed daily by orogastric route for 30 days. After this period, euthanasia and material collection were performed. Blood was collected for analysis of glycemic levels. The liver and kidneys were targeted for histological and oxidative stress analyzes. The results were analyzed by Graphpad Prism 6.0 Software, with significance level of 5%. Hepatic analyzes showed that the QV formulation restored hepatic glycogen stores in DQV animals (100.8 ? 7.466?m) at C animals level (126.3 ? 3.487 ?m). There was also a reduction in the number of Kupffer cells in DQV animals (52.34 ? 2.53), compared to animals in group D (74.45 ? 7.18), accompanied by reduction of fibrosis areas, also reduced in the group DQV (334.9 ? 47.9 ?m) and DI (437.8 ? 74.20 ?m) when compared to group D (1752 ? 434.7 ?m). Collagen 1 areas were also reduced in DQV animals (270.5 ? 79.50 ?m) when compared to group D (2970 ? 1409 ?m). However, quantification of collagen 3 and elastic fibers showed no significant differences. Diabetes as well as the formulation did not promote significant differences in the enzymatic activity of SOD and CAT, as well as in the generation of carbonylated protein. Kidney analyzes showed that treatment with the formulation was effective in preserving bleeding tissues in glomerular and tubular areas, as well as reducing areas of fibrosis in DQV animals (2004 ? 397.6 ?m) when compared to D animals (3840 ? 694.8 ?m), this reduction was shown in the DI animals (1502 ? 256.6 ?m). A similar result was found in the quantification of collagen 1, DQV group (808.3 ? 240.3 ?m) and DI (3233 ? 817.7 ?m) showed reduced collagen 1 areas at control C animals (1624 ? 430.2 ?m), but no significant differences were found in the quantification of collagen 3 and only DI animals presented high elastic fibers. CAT activity was reduced in DQV animals (58.39 ? 4.28) compared to C animals (88.59 ? 7.66), although the SOD, TBARS and MMP-4 activity did not present significant differences. Our final considerations emphasize that the formulation has properties that preserve liver and renal histological integrity, which, together with the blood glucose reduction, is an important therapeutic target for the treatment of DM