CYP2C9*3 gene variant contributes independently to glycaemic control in patients with type 2 diabetes treated with glibenclamide.

WHAT IS KNOWN AND OBJECTIVE: Glibenclamide is a prescribed glucose-lowering medication for diabetes, but there are interindividual variations in the therapeutic response. In this cross-sectional study, the aim was to explore the association of genetic variants in CYP2C9, ABCC8, KCNJ11 and TCF7L2 with good glycaemic control in Mexican type 2 diabetes (T2D) treated with glibenclamide. METHODS: Patients with T2D receiving treatment with glibenclamide or glibenclamide plus metformin were included. Patients with A1C ≤ 7% were considered to have good glycaemic control, whereas patients with A1C ≥ 8% were considered having poor glycaemic control. Genotyping was performed by real-time PCR using TaqMan probes for the genetic variants. Association was performed by calculating OR with 95% confidence intervals (95% CI). For the multivariate analysis, a multiple logistic regression was performed including the confounding variables age, exercised, BMI, glibenclamide dose, time with T2D and concomitant metformin. RESULTS AND DISCUSSION: Four hundred and four patients were included in the study, median age of the participants was 50 years (IQR 11.0), the median time with disease was 6 years (IQR 8.0), 118 (29.2%) were men, and 243 (60.1%) received glibenclamide in combination with metformin. CYP2C9*3 variant was associated with good glycaemic control (OR = 2.747 [95% CI, 1.194-6.324]), whereas the variants, CYP2C9*2, TCF7L2 rs7903146 and rs12255372, ABCC8 rs757110 and KCNJ11 rs5219, were not. In the multivariate analysis, the CYP2C9*3 variant maintained its association (OR = 2.779 [95% CI, 1.142-6.763]). WHAT IS NEW AND CONCLUSION: The findings suggest that CYP2C9*3 genetic variant independently contributes to good glycaemic control of patients with type 2 diabetes treated with glibenclamide.

Activation of TLR2 and TLR4 by minimally modified low-density lipoprotein in human macrophages and monocytes triggers the inflammatory response.

Oxidized low-density lipoproteins and Toll-like receptors (TLR) 2 and 4 are involved in the development of atherosclerosis. The TLR are important in the pro-inflammatory response. The aim of this research was to analyze the activation of CD14, TLR4, and TLR2 in response to minimally modified low-density lipoprotein (mmLDL). Human monocytes and macrophages secreted tumor necrosis factor (TNF)-alpha in response to mmLDL, and blocking CD14 or TLR4 resulted in a approximately 60% decrease in mmLDL-induced TNF-alpha secretion. We also observed similar inhibition of TNF-alpha synthesis in human monocytes ( approximately 65%) and macrophages ( approximately 70%) when both receptors were blocked simultaneously. When TLR2 was blocked, TNF-alpha synthesis was inhibited by approximately 70% in both cell types. Moreover mmLDL induced redistribution of CD14, TLR4, and TLR2 on the cell surface. This is the first evidence that TLR2 and TLR4 are upregulated in response to mmLDL. Our results suggest that mmLDL activates CD14, TLR4, and TLR2, inducing the production of TNF-alpha and increasing the expression of TLR2 and TLR4.

Rabies DNA vaccination by the intranasal route in dogs.

A DNA vaccine, using a pCl-neo plasmid encoding the glycoprotein gene of a Mexican isolate of rabies virus, was developed to induce long-lasting protective immunity against rabies virus in dogs. The aim of this work was to evaluate the intranasal (IN) vaccination route in mice and dogs. Mice and dogs were immunized via the intramuscular (IM) and IN routes. Mice received 50 microg of DNA vaccine, a booster on day 30, using the same doses and routes, and on day 90 they were challenged. Dogs received 100 microg of DNA vaccine, with a booster on day 180, and immune responses were studied on day 210. Virus-neutralizing antibodies were detected in blood sera (up to 0.5 IU) in animals immunized via the IN route and when the animals were submitted to a booster, the levels of neutralizing antibodies increased. Animals vaccinated via the IM route presented higher neutralizing antibody titres than those vaccinated IN. Control groups lacked anti-rabies antibodies. On day 90, mice were challenged. From these, a 100 % of the IM vaccinated mice, and an 80 % of the IN vaccinated mice survived the challenge. No animals from the control group survived. Dogs revealed significant virus-neutralizing antibody titres (up to 0.5 IU) on day 30 and, after booster, on day 210 neutralizing antibody titre was higher than 1.8 IU. The main advantage of using DNA vaccines over traditional live ones is that there is no contamination with viruses that could be disseminated in the environment and reproduced in susceptible animals. This study demonstrated that pGQH was succesful when administrated via the IN route. IN vaccination seems attractive due to its easy application and mucosal protection. This form of vaccination could also be advantageous in domestic animal vaccination campaigns, for it is less stressful than the parenteral route (no painful shots).