A Prospective Cohort Study on IRS Gene Polymorphisms in Type 2 Diabetes Mellitus Patients during Severe/Acute Hyperglycemia Phase 1: Association with Insulin Resistance

Purpose: To investigate the genetic polymorphisms that may contribute to the worsening of insulin resistance in type 2 diabetes mellitus (T2DM) with severe or acute hyperglycemia.Methods: This is a prospective cohort study involving 156 T2DM patients with severe or acute hyperglycemia from all medical wards of the National University of Malaysia Medical Centre (UKMMC) that were placed on insulin therapy. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to determine the genetic association of insulin receptor substrate (IRS) gene with insulin resistance. Insulin resistance status was determined using the homeostatic model assessment for insulin resistance (HOMA-IR) index.Results: IRS1 polymorphisms were associated with increased insulin resistance (X2 = 5.09, p = 0.023) in T2DM patients with severe/acute hyperglycemia. IRS2 polymorphisms were not associated with insulin resistance (X2 = 0.69, p = 0.406) in this group of patients.Conclusion: IRS1 genetic factor alone may be a significant genetic determinant for insulin resistance in T2DM patients during severe/acute phase hyperglycemia.Keywords: Insulin receptor substrate, Genetic, Polymorphism, Diabetes, Insulin resistance, Hyperglycemia, IRS1, IRS

Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of Kosovar Albanian epileptic patients

Aim The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy. Materials & Methods Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A (sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight. Results The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71±0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76±0.16 vs 0.94±0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; PG showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13±0.08 to 0.26±0.17, pT SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657±285 vs 489±231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84±4.37 vs 7.41±3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated. Conclusions The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy

Effect of Interaction between Polymorphisms in Insulin Receptor Substrate Genes in Type 2 Diabetes Mellitus Patients with Severe/Acute Hyperglycemia

Purpose: To investigate whether there are interactions between insulin receptor substrate 1 (IRS1) and insulin receptor substrate 2 (IRS2) that are associated with increased insulin resistance during such episodes.Methods: Testing Haplotype EffectS in Association Studies (THESIAS) software was used to investigate allelic and haplotype interactions between the polymorphisms in 156 T2DM patients with severe or acute hyperglycemia.Results: Binary analysis showed there were significant differences in the haplotype frequencies for the IRS1 and IRS2 polymorphisms based on the insulin resistance status. Nevertheless, estimation of haplotype effects by equality analysis showed no significant interactions (likelihood ratio tests: all p &gt; 0.05) in increased insulin resistance in T2DM patients with severe/acute hyperglycemia.Conclusion: There are no interactions between IRS1 rs1801278 (p.Gly972Arg) and IRS2 rs1805097 (p.Gly1057Asp) polymorphisms that would affect insulin resistance in T2DM patients with severe/acute hyperglycemia.Keywords: Insulin receptor substrate, Proteins, Insulin resistance, Diabetes mellitus, Hyperglycemia, Haplotype, Genetic polymorphis

A Prospective Cohort Study of IRS Genes Polymorphisms in Type 2 Diabetes Mellitus Patients during Severe/Acute Hyperglycemia Phase. 2: Association with Glycemic Control

Purpose: To investigate the genetic polymorphisms that may contribute to the worsening of glycemic control in type 2 diabetes mellitus (T2DM) with severe or acute hyperglycemia.Methods: The prospective cohort study included 156 T2DM patients with severe or acute hyperglycemia from all medical wards of the National University of Malaysia Medical Centre (UKMMC) that were treated with insulin therapy. For the genetic association study, we used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The glycemic control assessment during the acute phase was based on the degree to which the patient achieved the targeted glucose levels. The primary outcome was the influence of IRS gene on glycemic control in T2DM patients with severe/acute phase hyperglycemia.Results: Insulin Receptor Substrate 1 (IRS1) (R2 = -0.023, p = 0.771) and Insulin Receptor Substrate 2 (IRS2) gene polymorphisms (R2 = -0.160, p = 0.046) were not associated with glycemic control in T2DM patients with severe/acute hyperglycemia.Conclusion: The IRS1 and IRS2 genetic factors may not be significant genetic determinant for glycemic control in T2DM patients during severe/acute phase hyperglycemia.Keywords: Insulin receptor substrate, Gene, Polymorphism, Diabetes, Insulin resistance,Hyperglycemia, IRS 1, IRS

Antibiotic and shared decision-making preferences among adolescents in Malaysia

Irma Wati Ngadimon, Farida Islahudin, Ernieda Hatah, Noraida Mohamed Shah, Mohd Makmor-Bakry Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia Background: The purpose of this study was to establish baseline information on the current level of knowledge about, attitude toward, and experience with antibiotic usage, and preferences for shared decision making among adolescents in Malaysia. Methods: A cross-sectional survey, involving 1,105 respondents who were aged between 13 and 17&nbsp;years and who lived in Malaysia, was conducted using a validated questionnaire. The survey assessed knowledge, attitude, and experience with regard to antibiotic usage, and adolescents&rsquo; preferences for the style of shared decision-making process. Results: The majority (n=786 [71.13%]) of the respondents had a low level of knowledge, 296 (26.79%) had a moderate level of knowledge, and 23 (2.08%) had a high level of knowledge. Further, they demonstrated a slightly negative attitude mean score of 3.30&plusmn;0.05 (range: 0&ndash;8 points) but a positive experience mean score of 2.90&plusmn;0.029 (range: 0&ndash;4 points). There was a positive correlation between knowledge and attitude scores, with a higher knowledge level associated with a more positive attitude toward antibiotic usage (r=0.257, P&lt;0.001). Higher knowledge scores were associated with a more negative experience with antibiotic usage (r=-0.83, P=0.006). When assessing preference in shared decision making, more adolescents preferred an active role (n=408 [37%]) compared with collaborative (n=360 [32.6%]) or passive (n=337 [30.5%]) (P=0.028) roles.Conclusion:&nbsp;Current health care settings should involve adolescents in the decision-making process. Education packages can be introduced to improve adolescents&rsquo; knowledge of and practice of taking antibiotics, as well as to encourage their participation in decision making, in an attempt to reduce misuse of antibiotics. Keywords: antibiotic usage, knowledge, attitude, experienc