1. Repositório Institucional - Universidade Federal de Uberlândia
2. Instituto de Biotecnologia (IBTEC)
3. TESE - Genética e Bioquímica

Tipo de documento:	Tese
Tipo de acceso:	Acesso Aberto
Título:	Análise do papel da metformina na via insulínica, não-insulínica e inflamatória
Autor:	Peixoto, Leonardo Gomes
Primer orientador:	Espindola, Foued Salmen
Primer miembro de la banca:	Silva, Robinson Sabino da
Segundo miembro de la banca:	Fernandes, Maria Luiza
Tercer miembro de la banca:	Mori, Rosana Cristina Tieko
Cuarto miembro de la banca:	Furuya, Daniela Tomie
Resumen:	CHAPTER II: Purpose: We performed a meta-analysis of randomized trials to assess the effect of metformin on inflammatory markers and metabolic parameters in subjects with diabetes. Methods: We performed comprehensive searches on NCBI, Cochrane, Science Direct databases from 1966 to Jun of 2015. We included randomized trials of at least 4 weeks duration that compared groups with diabetes before and after the treatment with metformin or metformin plus other drugs, and evaluated body mass index, blood glucose, HbA1c and inflammatory parameters such as C-reactive protein, tumor necrosis factor and adiponectin. Results: Pooled results of the 26 trials, with 1760 participants at the end of treatment reduce BMI in 0.9% p=0,0043, as well as, decrease of blood glucose level [SMD -0,411 mg/dL, 95%CI -0,463 to -0,369, I2= 56.62%], HbA1c [SMD -0.479%, 95%CI -0,568 to -0,390, I2= 55.02%], CRP levels [SMD -0,274mg/dL, 95%CI -0,419 to -0,129, I2= 72.78%], TNFα concentration [SMD -0,103pg/ml, 95%CI -0,514 to 0,309, I2= 87.67%] and increase of adiponectin [SMD 0,171μg/ml, 95%CI 0,098 to 0,440, I2= 81.09%] compared with pretreatment. Conclusion: The long-treatment with metformin monotherapy or metformin plus other drugs improves metabolic parameters and induced changes in inflammatory markers in diabetic subject. CHAPTER III: Background: Metformin increases insulin sensitivity by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle. However, modulation of inflammatory response and CaMKKβ/AMPK/Myosin V activation in gastrocnemius muscle by metformin treatment has not been demonstrated in hypoinsulinemic diabetic rats. Objective: The present study investigated how the metformin improve insulin sensitivity in skeletal muscle of hypoinsulinemic diabetic rats. Methods: Diabetes was induced by streptozotocin (45 mg/kg, intraperitoneally) 10 days prior treatments. On 11th day, diabetic rats were treated with metformin (500 mg/kg, oral gavage), insulin (2U at 08:00 h and 4U at 17:00 h, subcutaneously) or untreated. After 20 days, glycemia was measured and insulin sensitivity was determined by KITT. Serum Insulin, GLUT4, IRSthr, inflammatory markers (NF-κB, IκB, TNF-α and p-JNK) and CAMKK, AMPK and Myosin V in gastrocnemius muscle were determined by ELISA. Results: As expected, insulin and metformin improved the insulin sensitivity. Besides, metformin treatment promoted reduction in inflammatory response mediated by NF-κB, IκB, TNF-α and p-JNK, and that was accompanied by increased CaMKKβ/AMPK/Myosin V/GLUT4 pathway activity in gastrocnemius muscle of diabetic rats. Conclusion: Our findings suggest that metformin induces significant reductions in several inflammatory markers in skeletal muscle of diabetic rats. Metformin-induced increase in CaMKKβ/AMPK/Myosin V/GLUT4 pathway activity was associated with higher insulin sensitivity. CHAPTER IV: Diabetes is characterized by a proinflammatory state which can activate TLR2 and TLR4, and these receptors could induce NF-κB and JNK activation in skeletal muscle. In this study, we investigated the inflammatory and apoptotic signaling pathways triggered by TLRs/NF-κB and JNK activation in skeletal muscle of diabetic rats treated with metformin before and after an insulin tolerance test. Metformin treatment decreased p-JNK and NF-κB, and increased IκB concentrations. This attenuation leads to a decrease of TNFα and CXCL1/KC, and an increase of p-AMPK, BAX and Bcl2 concentration. Furthermore, KITT revealed an improvement of the insulin sensitivity in the diabetic rats treated with metformin. In addition, metformin was not capable of attenuating the changes in the inflammatory pathway triggered by insulin injection as the increase of TNFα and TLR4 in metformin treated rats, and IκB, CXCL1/KC, TNFα and p-AMPK increase in the untreated group. Taken together, these results point out that metformin may attenuate the activation of the inflammatory pathway TLRs/NF-κB/TNFα/CXCL1/KC and the apoptotic signaling BAX/Bcl2/p-JNK, which could be accompanied by a reduction of the inflammatory damage caused by hyperglycemia and an improvement of insulin sensitivity in diabetic rats.
Palabras clave:	C-reactive proteins Tumor necrosis factor (TNFα Adiponectin Blood glucose level Glycated hemoglobin (HbA1c) Inflammatory pathway Insulin sensitivity Insulin pathway Hypoinsulinemic rat Insulin resitance Toll like receptor NF-κ B/Iκ B pathway skeletal muscle Músculo esquelético Sensibilidade insulínica Captação de glicose
Área (s) del CNPq:	CNPQ::CIENCIAS BIOLOGICAS::GENETICA
Idioma:	eng
País:	BR
Editora:	Universidade Federal de Uberlândia
Sigla de la institución:	UFU
Departamento:	Ciências Biológicas
Programa:	Programa de Pós-graduação em Genética e Bioquímica
Cita:	PEIXOTO, Leonardo Gomes. Análise do papel da metformina na via insulínica, não-insulínica e inflamatória. 2015. 84 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Uberlândia, Uberlândia, 2015. DOI https://doi.org/10.14393/ufu.te.2015.97.
Identificador del documento:	https://doi.org/10.14393/ufu.te.2015.97
URI:	https://repositorio.ufu.br/handle/123456789/15755
Fecha de defensa:	28-jul-2015
Aparece en las colecciones:	TESE - Genética e Bioquímica

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