RESUMO
One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Progressão da Doença , Hemoglobinas Glicadas/metabolismo , Proteínas de Membrana/genética , Metformina/uso terapêutico , Proteínas de Transporte de Cátions Orgânicos/genética , Variantes Farmacogenômicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Transportador 2 de Cátion Orgânico , Polimorfismo de Nucleotídeo Único/genética , Proteínas Supressoras de Tumor , Adulto JovemRESUMO
The world is facing an explosive increase in the incidence of diabetes mellitus and cost-effective complementary therapies are needed. The effects of Eugenia jambolana, a household remedy for diabetes, were studied. Streptozotocin diabetic female albino Wistar rats weighing 150-200 g (N = 6) were fed E. jambolana seed powder (250, 500 or 1000 mg/kg) for 15 days. Diabetic rats fed 500 and 1000 mg/kg seed powder showed an increase in body weight on day 20 in relation to day 5 (6 +/- 4.7, 9 +/- 7.8 vs diabetic control -16 +/- 7.1 g, P < 0.001), a decrease in fasting blood glucose (75 +/- 11.9, 123 +/- 14.4 vs diabetic control -34 +/- 12.1 mg/dl, P < 0.001), a difference in post-treatment fasting and peak blood glucose (38 +/- 11.9, 36 +/- 14.2 vs diabetic control 78 +/- 11.9 mg/dl, P < 0.001), and a difference in liver glycogen (50 +/- 6.8, 52 +/- 7.5 vs normal control 90 +/- 6.6 microg/g of liver tissue, P < 0.001). Tri-terpenoids, tannins, gallic acid, and oxalic acid were the chemical constituents detected in E. jambolana seed. The best results were obtained with an oral dose of 500 mg/kg. Subacute toxicity studies with a single administration of 2.5 and 5.0 g/kg seed powder showed no mortality or abnormality. These data on the antidiabetic effect of E. jambolana seed are adequate for approval of phase 2 clinical trials to evaluate this seed powder as complementary therapy in type 2 and type 1 diabetes.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Sementes/química , Syzygium , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Teste de Tolerância a Glucose , Glicogênio Hepático/análise , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , EstreptozocinaRESUMO
The world is facing an explosive increase in the incidence of diabetes mellitus and cost-effective complementary therapies are needed. The effects of Eugenia jambolana, a household remedy for diabetes, were studied. Streptozotocin diabetic female albino Wistar rats weighing 150-200 g (N = 6) were fed E. jambolana seed powder (250, 500 or 1000 mg/kg) for 15 days. Diabetic rats fed 500 and 1000 mg/kg seed powder showed an increase in body weight on day 20 in relation to day 5 (6 ± 4.7, 9 ± 7.8 vs diabetic control -16 ± 7.1 g, P < 0.001), a decrease in fasting blood glucose (75 ± 11.9, 123 ± 14.4 vs diabetic control -34 ± 12.1 mg/dl, P < 0.001), a difference in post-treatment fasting and peak blood glucose (38 ± 11.9, 36 ± 14.2 vs diabetic control 78 ± 11.9 mg/dl, P < 0.001), and a difference in liver glycogen (50 ± 6.8, 52 ± 7.5 vs normal control 90 ± 6.6 æg/g of liver tissue, P < 0.001). Tri-terpenoids, tannins, gallic acid, and oxalic acid were the chemical constituents detected in E. jambolana seed. The best results were obtained with an oral dose of 500 mg/kg. Subacute toxicity studies with a single administration of 2.5 and 5.0 g/kg seed powder showed no mortality or abnormality. These data on the antidiabetic effect of E. jambolana seed are adequate for approval of phase 2 clinical trials to evaluate this seed powder as complementary therapy in type 2 and type 1 diabetes.
