Dataset Information

Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1.

ABSTRACT: The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1-induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on ?-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.

SUBMITTER: Smushkin G

PROVIDER: S-EPMC3331759 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1.

Smushkin Galina G Sathananthan Matheni M Sathananthan Airani A Dalla Man Chiara C Micheletto Francesco F Zinsmeister Alan R AR Cobelli Claudio C Vella Adrian A

Diabetes 20120328 5

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1-induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp a ...[more]

PMID: 22461567

Similar Datasets

Project description:IntroductionPositive hemodynamic response to vasopressin after 6 hours of infusion was independently associated with lower mortality in a previous retrospective study of patients with septic shock. However, factors previously associated with higher plasma vasopressin concentration were not associated with response, and the relationship between plasma vasopressin concentration and hemodynamic response has not been evaluated.ObjectivesThis cross-sectional study compared plasma vasopressin concentrations in hemodynamic responders and nonresponders to vasopressin in patients with septic shock to evaluate plasma vasopressin concentration as a therapeutic target for hemodynamic response to vasopressin.MethodsAdult patients with septic shock were included if they were treated with fixed-dose vasopressin as an adjunct to catecholamines for at least 3 hours. Patients were assigned to groups based on vasopressin response.ResultsTen hemodynamic responders to vasopressin and eight nonresponders were included. Blood samples for plasma vasopressin concentration were collected 3-6 hours after vasopressin initiation. Baseline characteristics were similar between groups. No difference was detected in plasma vasopressin concentrations between hemodynamic responders and nonresponders (median 88.6 pg/ml [interquartile range (IQR) 84.4-107.5 pg/ml] vs 89.9 pg/ml [IQR 67.5-157.4 pg/ml], p=0.79, respectively). We also did not detect a difference between groups after correcting for vasopressin dose; median vasopressin plasma concentration per 0.01 units/minute of vasopressin infusion for responders was 25.9 pg/ml (IQR 21.8-31.8 pg/ml) versus 29.5 pg/ml (IQR 23.0-57.5 pg/ml, p=0.48) for nonresponders. No difference in clinical outcomes was detected between groups. The findings were robust to multiple sensitivity analyses.ConclusionsThis study does not support the use of plasma vasopressin concentrations as a therapeutic target to predict hemodynamic response to exogenous vasopressin in septic shock.

Project description:BackgroundCurrently, there is a sense that the spatial orienting of attention is related to genotypic variations in cholinergic genes but not to variations in dopaminergic genes. However, reexamination of associations with both cholinergic and dopaminergic genes is warranted because previous studies used endogenous rather than exogenous cues and costs and benefits were not analyzed separately. Examining costs (increases in response time following an invalid pre-cue) and benefits (decreases in response time following a valid pre-cue) separately could be important if dopaminergic genes (implicated in disorders such as attention deficit disorder) independently influence the different processes of orienting (e.g., disengage, move, engage).Methodology/principal findingsWe tested normal subjects (N = 161) between 18 and 61 years. Participants completed a computer task in which pre-cues preceded the presence of a target. Subjects responded (with a key press) to the location of the target (right versus left of fixation). The cues could be valid (i.e., appear where the target would appear) or invalid (appear contralateral to where the target would appear). DNA sequencing assays were performed on buccal cells to genotype known genetic markers and these were examined for association with task scores. Here we show significant associations between visual orienting and genetic markers (on COMT, DAT1, and APOE; R(2)s from 4% to 9%).Conclusions/significanceOne measure in particular--the response time cost of a single dim, invalid cue - was associated with dopaminergic markers on COMT and DAT1. Additionally, variations of APOE genotypes based on the ε2/ε3/ε4 alleles were also associated with response time differences produced by simultaneous cues with unequal luminances. We conclude that individual differences in visual orienting are related to several dopaminergic markers as well as to a cholinergic marker. These results challenge the view that orienting is not associated with genotypic variation in dopaminergic genes.

Dataset Information

Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1.

Publications

Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets