RESUMEN
The aim of this study was to determine the relation between the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 (rs1862513) and glycemic control by pioglitazone in type 2 diabetes. In Study 1, 121 type 2 diabetic patients were treated with pioglitazone (15 or 30 mg/day) for 12 weeks, in addition to previous medication. In Study 2, 63 patients who had been treated with pioglitazone for 12 weeks were examined retrospectively. In Study 1, multiple regression analysis revealed that the G/G but not C/G genotype was correlated with a reduction in fasting plasma glucose (FPG) and homeostasis model assessment of insulin resistance (HOMA-IR) compared to C/C. When adjusted for age, gender, and BMI, the G/G genotype was an independent factor for the reduction of FPG (P=0.020) and HOMA-IR (P =0.012). When studies 1 and 2 were combined by adjusting the studies, age, gender, and BMI, the reduction of HbA1c was correlated with the G/G genotype (beta=-0.511, P=0.044). Therefore, this pilot study suggests that the G/G genotype of resistin SNP -420 may be an independent predictor of the reduction of fasting plasma glucose and HOMA-IR by pioglitazone.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Regiones Promotoras Genéticas/genética , Resistina/genética , Tiazolidinedionas/uso terapéutico , Adulto , Anciano , Femenino , Hemoglobina Glucada/análisis , Homeostasis/efectos de los fármacos , Homocigoto , Humanos , Hiperglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Farmacogenética/métodos , Proyectos Piloto , Pioglitazona , Polimorfismo de Nucleótido Simple , Resistina/sangre , Estudios Retrospectivos , Tiazolidinedionas/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVE: To clarify the natural course and factors involved in beta cell failure in Japanese latent autoimmune diabetes in adults (LADA) patients. RESEARCH DESIGN AND METHODS: Insulin secretion in 57 LADA patients identified from among 4980 adult-onset diabetic patients in a hospital-based Ehime study were examined over a 5-year period. Postprandial serum C-peptide levels below 0.33 nmol/l were defined as beta cell failure. The involvement of clinical and immunological factors in the progression to beta cell failure were evaluated. RESULTS: Forty-two of the fifty-seven LADA patients completed the 5-year follow-up. Eleven (26.2%) required insulin treatment and five (11.9%) progressed to beta cell failure. A Cox regression analysis revealed that positive anti-thyroid peroxidase antibody (TPOAb) and insulinoma-associated protein 2 (IA-2Ab) were associated with the need for insulin treatment (p<0.05 and p<0.01, respectively). Positive TPOAb, anti-thyroglobulin antibody (TGAb), IA-2 antibody (p<0.01 for each), and lower serum fasting C-peptide levels (p<0.05) were contributors to the progression to beta cell failure. Involvement of type 1 diabetes susceptible HLA class II genes was not evident. CONCLUSIONS: Japanese LADA patients are a heterogeneous population. In addition to IA-2 antibody, presence of TPOAb and fasting C-peptide level could indicate an oncoming deterioration of beta cell function.
Asunto(s)
Autoanticuerpos/sangre , Biomarcadores/sangre , Péptido C/sangre , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/inmunología , Yoduro Peroxidasa/inmunología , Adulto , Anciano , Pueblo Asiatico/genética , Pueblo Asiatico/estadística & datos numéricos , Diabetes Mellitus Tipo 1/genética , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad/epidemiología , Antígenos HLA-DQ/genética , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Haplotipos , Humanos , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de RiesgoRESUMEN
Glutamate dehydrogenase (GDH) is important in normal glucose homeostasis. Mutations of GDH result in hyperinsulinism/hyperammonemia syndrome. Using PCR/single-strand conformation polymorphism analysis of the gene encoding GDH in 12 Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we found a mutation (Y266C) in one PHHI patient. This mutation was not found in any of the control or type 2 diabetic subjects. The activity of the mutant GDH (GDH266C), expressed in COS-7 cells, was constitutively elevated, and allosteric regulations by ADP and GTP were severely impaired. The effect of the unregulated increase in GDH activity on insulin secretion was examined by overexpressing GDH266C in an insulinoma cell line, MIN6. Although glutamine alone did not stimulate insulin secretion from control MIN6-lacZ, it remarkably stimulated insulin secretion from MIN6-GDH266C. This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to alpha-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion. Interestingly, insulin secretion is also exaggerated significantly at low glucose concentrations (2 and 5 mmol/l) but not at higher glucose concentrations (8--25 mmol/l). Our results directly illustrate the importance of GDH in the regulation of insulin secretion from pancreatic beta-cells.