RESUMEN
Insulin resistance is a key feature of obesity and type 2 diabetes mellitus (T2DM). Interaction of insulin with the insulin receptor (IR) leads to both its auto-phosphorylation and phosphorylation of tyrosine residues on the IR substrate (IRS) proteins, initiating the activation of intracellular signaling cascades. The metabolic effects of IRS are known to be mediated through pathways involving phosphatidyl-inositol 3-kinase (PI-3K), which result in the activation of Akt signaling. The C-terminal region of the IR ectodomain is required to facilitate the conformational changes that are required for high-affinity binding to insulin. Furthermore, the CH2 and CH3 domains in the Fc fragments of immunoglobulins are responsible for their binding to the Fc receptor, which triggers transcytosis. In this study, we created a fusion peptide of the C-terminal end of the human IR ectodomain with the IgG4 Fc fragment, including an intervening polyG fragment to ensure enough space for insulin binding. We named this new peptide "Yiminsu", meaning an insulin sensitizer. The results of our analyses show that Yiminsu significantly facilitates insulin signaling via the activation of Akt in hepatocytes in a dose- and time-dependent manner. Further studies are required to determine whether Yiminsu can act as an insulin sensitizer.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fragmentos Fab de Inmunoglobulinas/farmacología , Inmunoglobulina G/farmacología , Insulina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Animales , Células CHO , Línea Celular , Clonación Molecular/métodos , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/genética , Inmunoglobulina G/química , Inmunoglobulina G/genética , Resistencia a la Insulina , Fosfatidilinositol 3-Quinasa/metabolismo , Fosforilación/efectos de los fármacos , Ingeniería de Proteínas , Estructura Terciaria de Proteína , Receptor de Insulina/metabolismo , Receptores Fc/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Transducción de Señal/efectos de los fármacos , Tirosina/metabolismoRESUMEN
We investigated type II deiodinase (DIO2) polymorphisms and serum thyroid hormone levels in subjects with mild cognitive impairment (MCI) in a Uygur population. We studied the DIO2 Thr92Ala (rs225014) and ORFa-Gly3Asp (rs12885300) polymorphisms of 129 unrelated MCI cases and 131 matched controls. All subjects were genotyped using SNaPshot SNP genotyping assays. Serum thyroid hormone levels were measured by radioimmunoassay. Levels of serum triiodothyronine and thyroxine in the MCI group were significantly lower than those in the control group. Genotype and allele frequencies in the DIO2 gene between the MCI and control groups were not significantly different. There was no association in genotype and allele frequencies of Thr92Ala between genders in both groups. ORFa-Gly3Asp genotype and allele frequencies were significantly different in patients and controls by gender. The Asp allele was less frequent among male MCI patients compared to controls (odds ratio = 0.471, 95% confidence interval = 0.261-0.848). However, female Asp carriers were more frequent among MCI patients than among controls (odds ratio = 2.842, 95% confidence interval = 1.326-6.09). Serum levels of triiodothyronine and thyroxine were lower in individuals of the Ala/Ala genotype than in those with the Thr/Thr or Thr/Ala genotype. Serum levels of triiodothyronine were lower in male Gly/Gly carriers than in Gly/Asp or Asp/Asp carriers. Decreased serum levels of triiodothyronine and thyroxine may influence the incidence of MCI in the Uygur population. DIO2 gene polymorphisms may play a role in the incidence of MCI in male patients.