Assuntos
Bilirrubina/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Retinopatia Diabética/epidemiologia , Regulação para Baixo , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Bilirrubina/antagonistas & inibidores , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/fisiopatologia , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/fisiopatologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Hospitais de Ensino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Japão , Modelos Logísticos , Masculino , Microvasos/efeitos dos fármacos , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
AIM: We investigated the molecular mechanisms by which vildagliptin preserved pancreatic ß cell mass and function. METHODS: Morphological, biochemical and gene expression profiles of the pancreatic islets were investigated in male KK-A(y) -TaJcl(KK-A(y) ) and C57BL/6JJcl (B6) mice aged 8 weeks which received either vildagliptin or a vehicle for 4 weeks. RESULTS: Body weight, food intake, fasting blood glucose, plasma insulin and active glucagon-like peptide-1 were unchanged with vildagliptin treatment in both mice. In KK-A(y) mice treated with vildagliptin, increased plasma triglyceride (TG) level and islet TG content were decreased, insulin sensitivity significantly improved, and the glucose tolerance ameliorated with increases in plasma insulin levels. Furthermore, vildagliptin increased glucose-stimulated insulin secretion, islet insulin content and pancreatic ß cell mass in both strains. By vildagliptin, the expression of genes involved in cell differentiation/proliferation was upregulated in both strains, those related to apoptosis, endoplasmic reticulum stress and lipid synthesis was decreased and those related to anti-apoptosis and anti-oxidative stress was upregulated, in KK-A(y) mice. The morphological results were consistent with the gene expression profiles. CONCLUSION: Vildagliptin increases ß cell mass by not only directly affecting cell kinetics but also by indirectly reducing cell apoptosis, oxidative stress and endoplasmic reticulum stress in diabetic mice.
Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Experimental/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Nitrilas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pirrolidinas/farmacologia , Triglicerídeos/metabolismo , Adamantano/farmacologia , Animais , Apoptose , Glicemia/metabolismo , Proliferação de Células , Diabetes Mellitus Experimental/tratamento farmacológico , Regulação da Expressão Gênica no Desenvolvimento , Imuno-Histoquímica , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima , VildagliptinaRESUMO
AIMS/HYPOTHESIS: We investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice. METHODS: Male db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR. RESULTS: Liraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/db mice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/db mice, but GSIS, insulin and triacylglycerol content were not affected. In db/db mice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/db mice islets were consistent with the results of the gene expression analysis. CONCLUSIONS/INTERPRETATION: Liraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.