19 research outputs found
The Effect of Colesevelam Hydrochloride on Fasting and Postprandial Glucose Metabolism in Subjects with Type 2 Diabetes
Letter to the Editor: "Defects in GLP-1 Response to an Oral Challenge Do Not Play a Significant Role in the Pathogenesis of Prediabetes"
Defects in GLP-1 response to an oral challenge do not play a significant role in the pathogenesis of prediabetes.
CONTEXT:
There has been much speculation as to whether defects in glucagon-like peptide-1 (GLP-1) secretion play a role in the pathogenesis of type 2 diabetes and the progression from normal glucose tolerance to prediabetes and diabetes.
OBJECTIVE:
Our objective was to determine whether fasting and postchallenge concentrations of active and total GLP-1 decrease as glucose tolerance and insulin secretion worsen across the spectrum of prediabetes.
DESIGN:
This was a cross-sectional study.
SETTING:
The study was performed in the clinical research unit of an academic medical center.
PARTICIPANTS:
Participants included 165 subjects with a fasting glucose below 7.0 mmol/liter and not taking medications known to affect gastrointestinal motility or glucose metabolism.
INTERVENTION:
Intervention included a 2-h, 75-g oral glucose tolerance test with insulin, C-peptide, glucagon, and GLP-1 measurements at seven time points.
MAIN OUTCOME MEASURE:
We evaluated the association of integrated, incremental active, and total GLP-1 concentrations with integrated, incremental glucose response to 75 g oral glucose.
RESULTS:
After accounting for covariates, there was no evidence of a relationship of incremental glucose concentrations after oral glucose tolerance test with active and total GLP-1 (r(s) = -0.16 and P = 0.14, and r(s) = 0.00 and P > 0.9, respectively). There also was no association of GLP-1 concentrations with insulin secretion and action.
CONCLUSIONS:
The lack of association of GLP-1 concentrations with glucose tolerance status and with insulin secretion and action in a cohort encompassing the full spectrum of prediabetes strongly argues against a significant contribution of defects in GLP-1 secretion to the pathogenesis of prediabetes
Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1.
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 β-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
The effect of a bile Acid sequestrant on glucose metabolism in subjects with type 2 diabetes.
We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and \u3b2-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 \ub1 0.2 vs. 6.6 \ub1 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 \ub1 138 vs. 2,896 \ub1 127 mmol/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model-derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 \ub1 204 vs. 5,817 \ub1 204 \u3bcmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose