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1.
PLoS One ; 9(11): e113366, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25412338

RESUMO

BACKGROUND AND AIMS: L-glutamine is an efficacious glucagon-like peptide (GLP)-1 secretagogue in vitro. When administered with a meal, glutamine increases GLP-1 and insulin excursions and reduces postprandial glycaemia in type 2 diabetes patients. The aim of the study was to assess the efficacy and safety of daily glutamine supplementation with or without the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin in well-controlled type 2 diabetes patients. METHODS: Type 2 diabetes patients treated with metformin (n = 13, 9 men) with baseline glycated hemoglobin (HbA1c) 7.1±0.3% (54±4 mmol/mol) received glutamine (15 g bd)+ sitagliptin (100 mg/d) or glutamine (15 g bd) + placebo for 4 weeks in a randomized crossover study. RESULTS: HbA1c (P = 0.007) and fructosamine (P = 0.02) decreased modestly, without significant time-treatment interactions (both P = 0.4). Blood urea increased (P<0.001) without a significant time-treatment interaction (P = 0.8), but creatinine and estimated glomerular filtration rate (eGFR) were unchanged (P≥0.5). Red blood cells, hemoglobin, hematocrit, and albumin modestly decreased (P≤0.02), without significant time-treatment interactions (P≥0.4). Body weight and plasma electrolytes remained unchanged (P≥0.2). CONCLUSIONS: Daily oral supplementation of glutamine with or without sitagliptin for 4 weeks decreased glycaemia in well-controlled type 2 diabetes patients, but was also associated with mild plasma volume expansion. TRIAL REGISTRATION: ClincalTrials.gov NCT00673894.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glutamina/administração & dosagem , Glutamina/efeitos adversos , Hipoglicemiantes/administração & dosagem , Fosfato de Sitagliptina/administração & dosagem , Administração Oral , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Glutamina/uso terapêutico , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Pessoa de Meia-Idade , Volume Plasmático/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Resultado do Tratamento
2.
Mol Ther ; 17(8): 1340-6, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19384294

RESUMO

Ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, is associated with severe hyperammonemia accompanied by a high risk of neurological damage and death in patients presenting with the neonatal-onset form. Contemporary therapies, including liver transplantation, remain inadequate with considerable morbidity, justifying vigorous investigation of alternate therapies. Clinical evidence suggests that as little as 3% normal enzyme activity is sufficient to ameliorate the severe neonatal phenotype, making OTC deficiency an ideal model for the development of liver-targeted gene therapy. In this study, we investigated metabolic correction in neonatal and adult male OTC-deficient Spf(ash) mice following adeno-associated virus (AAV)2/8-mediated delivery of the murine OTC complementary DNA under the transcriptional control of a liver-specific promoter. Substantially supraphysiological levels of OTC enzymatic activity were readily achieved in both adult and neonatal mice following a single intraperitoneal (i.p.) injection, with metabolic correction in adults being robust and life-long. In the neonates, however, full metabolic correction was transient, although modest levels of OTC expression persisted into adulthood. Although not directly testable in Spf(ash) mice, these levels were theoretically sufficient to prevent hyperammonemia in a null phenotype. This loss of expression in the neonatal liver is the consequence of hepatocellular proliferation and presents an added challenge to human therapy.


Assuntos
Dependovirus/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/metabolismo , Doença da Deficiência de Ornitina Carbomoiltransferase/terapia , Animais , Animais Recém-Nascidos , Western Blotting , Linhagem Celular , DNA Complementar/genética , Feminino , Humanos , Imuno-Histoquímica , Fígado/metabolismo , Masculino , Camundongos , Ornitina Carbamoiltransferase/genética , Ornitina Carbamoiltransferase/metabolismo , Ornitina Carbamoiltransferase/fisiologia , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/urina , Ácido Orótico/urina
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