Biomedical subjects

Nitai Mukhopadhyay

Publications and source records attributed to Nitai Mukhopadhyay.

5 recordsLinked to original sources

PubMed2004

Genetic polymorphisms in human proton-dependent dipeptide transporter PEPT1: implications for the functional role of Pro586.

The human proton-dependent dipeptide transporter (PEPT1, gene SLC15A1) is important for intestinal absorption of di- and tripeptides and a variety of peptidomimetic compounds. Using a DNA polymorphism discovery panel of 44 ethnically diverse individuals, nine nonsynonymous and four synonymous coding-region single-nucleotide polymorphisms (SNPs) were identified in PEPT1. HeLa cells were transiently transfected with plasmids constructed by site-directed mutagenesis for each of the nine nonsynonymous variants. Quantitative polymerase chain reaction showed that the mRNA transcription level of all of the mutants was comparable with the mRNA transcription level of the reference sequence in transfected HeLa cells. Functional analysis in transiently transfected HeLa cells revealed that all nonsynonymous variants retained similar pH-dependent activity and K(t) values for [glycyl-1,2-(14)C]glycylsarcosine (Gly-Sar) uptake as the reference PEPT1. In addition, a group of seven peptide-like drugs showed inhibitory effect on Gly-Sar uptake by these variants comparable with the reference, suggesting conserved drug recognition. Of the nine nonsynonymous SNPs, a single SNP (P586L) demonstrated significantly reduced transport capacity as evidenced by a much lower V(max) value. This was consistent with lower immunoactive protein level (Western analysis) and lower plasma membrane expression (immunocytochemical analysis). Therefore, Pro(586) may have profound effect on PEPT1 translation, degradation, and/or membrane insertion.

Alleles↗

PubMed2004

Retrospective analysis of risk factors in patients with treatment-emergent diabetes during clinical trials of antipsychotic medications.

AIMS: In this retrospective analysis, we assessed the short-term risk of treatment-emergent diabetes (TED) among patients with schizophrenia during clinical trials of antipsychotic medications. METHOD: From a non-diabetic cohort of patients with schizophrenia (n=5013), the relationship between baseline non-fasting glucose measurement, presence at baseline of risk factors for diabetes, weight gain and therapy assignment on the risk of treatment-emergent diabetes were assessed. RESULTS: At the baseline assessment, about a third of patients identified with TED during treatment had non-fasting glucose levels over 7.8 mmol/l and two-thirds had multiple diabetes risk factors. Both baseline non-fasting glucose level and the presence of multiple pre-existing diabetes risk factors appeared to have a major impact on the risk of developing diabetes. CONCLUSIONS: Overall, risk factors for diabetes in patients with schizophrenia overlap those in the general population. The results also suggest that many patients identified with TED might have had pre-existing glycaemic abnormalities or a high baseline burden of diabetes risk factors.

Adolescent↗

PubMed2003

Identification of genes for complex disease using longitudinal phenotypes.

Using the simulated data set from Genetic Analysis Workshop 13, we explored the advantages of using longitudinal data in genetic analyses. The weighted average of the longitudinal data for each of seven quantitative phenotypes were computed and analyzed. Genome screen results were then compared for these longitudinal phenotypes and the results obtained using two cross-sectional designs: data collected near a single age (45 years) and data collected at a single time point. Significant linkage was obtained for nine regions (LOD scores ranging from 5.5 to 34.6) for six of the phenotypes. Using cross-sectional data, LOD scores were slightly lower for the same chromosomal regions, with two regions becoming nonsignificant and one additional region being identified. The magnitude of the LOD score was highly correlated with the heritability of each phenotype as well as the proportion of phenotypic variance due to that locus. There were no false-positive linkage results using the longitudinal data and three false-positive findings using the cross-sectional data. The three false positive results appear to be due to the kurtosis in the trait distribution, even after removing extreme outliers. Our analyses demonstrated that the use of simple longitudinal phenotypes was a powerful means to detect genes of major to moderate effect on trait variability. In only one instance was the power and heritability of the trait increased by using data from one examination. Power to detect linkage can be improved by identifying the most heritable phenotype, ensuring normality of the trait distribution and maximizing the information utilized through novel longitudinal designs for genetic analysis.

Cardiovascular Diseases↗

PubMed2003

Evaluation of insulin sensitivity in healthy volunteers treated with olanzapine, risperidone, or placebo: a prospective, randomized study using the two-step hyperinsulinemic, euglycemic clamp.

The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.

Adult↗

PubMed2002

Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo.

The goal of this study was to evaluate the effect of olanzapine or risperidone treatment on beta-cell function in healthy volunteers. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d; n = 17), risperidone (4 mg/d; n = 13), or placebo (n = 18) for 15-17 d. Insulin secretion was quantitatively assessed at baseline and the end of the study period using the hyperglycemic clamp. Weight increased significantly (P < 0.01) in the olanzapine (2.8 +/- 1.7 kg) and risperidone (3.1 +/- 2.1 kg) treatment groups. An increase ( approximately 25%) in the insulin response to hyperglycemia and a decrease ( approximately 18%) in the insulin sensitivity index were observed after treatment with olanzapine and risperidone. The change in insulin response was correlated (r = 0.5576; P = 0.019) with a change in body mass index. When the impact of weight change was accounted for by multivariate regression analyses, no significant change in insulin response or insulin sensitivity was detected after treatment with olanzapine or risperidone. We found no evidence that treatment of healthy volunteers with olanzapine or risperidone decreased the insulin secretory response to a prolonged hyperglycemic challenge. The results of this study do not support the hypothesis that olanzapine or risperidone directly impair pancreatic beta-cell function.

Adult↗