Plasma Metabolic Signatures of Healthy Overweight Subjects Challenged With an Oral Glucose Tolerance Test

Abstract

Insulin secretion following ingestion of a carbohydrate load affects a multitude of metabolic pathways that simultaneously change direction and quantity of interorgan fluxes of sugars, lipids and amino acids. In the present study, we aimed at identifying markers associated with differential responses to an OGTT a population of healthy adults. By use of three metabolite profiling platforms, we assessed these postprandial responses of a total of 202 metabolites in plasma of 72 healthy volunteers undergoing comprehensive phenotyping and of which half enrolled into a weight-loss program over a three-month period. A standard oral glucose tolerance test (OGTT) served as dietary challenge test to identify changes in postprandial metabolite profiles. Despite classified as healthy according to WHO criteria, two discrete clusters (A and B) were identified based on the postprandial glucose profiles with a balanced distribution of volunteers based on gender and other measures. Cluster A individuals displayed 26% higher postprandial glucose levels, delayed glucose clearance and increased fasting plasma concentrations of more than 20 known biomarkers of insulin resistance and diabetes previously identified in large cohort studies. The volunteers identified by canonical postprandial responses that form cluster A may be called pre-pre-diabetics and defined as “at risk” for development of insulin resistance. Moreover, postprandial changes in selected fatty acids and complex lipids, bile acids, amino acids, acylcarnitines and sugars like mannose revealed marked differences in the responses seen in cluster A and cluster B individuals that sustained over the entire challenge test period of 240 min. Almost all metabolites, including glucose and insulin, returned to baseline values at the end of the test (at 240 min), except a variety of amino acids and here those that have been linked to diabetes development. Analysis of the corresponding metabolite profile in a fasting blood sample may therefore allow for early identification of these subjects at risk for insulin resistance without the need to undergo an OGTT.

Diet-induced Weight Loss and Phenotypic Flexibility Among Healthy Overweight Adults: A Randomized Trial

“…Shah et al. [ 49 ] reported similar findings with a linear relationship between the level of plasma BCAA at baseline and improved insulin sensitivity induced by weight loss [ 50 ]. Moreover, a novel observation in our study was that plasma concentration of DCA was at least 100% higher throughout the OGTT and MMTT in participants with improved insulin sensitivity after weight loss.…”

Effects of genotype and food on naltrexone exposure in adolescents

“…39 Negative feedback of cholesterol metabolism leading to reduced bile acid metabolites in the liver upstream of LXRα may contribute to reduced AKR1C4 expression and altered NTX metabolism. Post-prandial changes in fatty acid concentrations may also contribute to altered AKR1C4 activity 11,14 and the food effect detected in this study. Sex-dependent effects on AKR1C4 activity as a function of testosterone and progesterone exposure are not expected due to the supraphysiologic concentrations required for inhibition.…”

“…AKR1C4 activity is inhibited by fatty acids at physiologically relevant plasma concentrations 11,12 . Both bile acid metabolites and fatty acid concentrations change in response to food intake 13–15 . Together, this suggests the possibility of acute dietary modulation of AKR1C4; however, the clinical relevance is unknown.…”

“…11,12 Both bile acid metabolites and fatty acid concentrations change in response to food intake. [13][14][15] Together, this suggests the possibility of acute dietary modulation of AKR1C4; however, the clinical relevance is unknown. There are little data regarding a food effect on NTX systemic exposure as no fed/fasted bioequivalence or wellcontrolled dietary studies are available.…”

Dynamics and determinants of human plasma bile acid profiles during dietary challenges

“…Metabolomics studies have identified BA as the most responsive group of plasma metabolites in healthy human volunteers when challenged with an oral glucose tolerance test (OGTT) ( 6 , 7 ). Although BA are efficiently extracted from the portal blood when passing the liver, a fraction of BA escapes this first-pass hepatic extraction and spills over to systemic circulation.…”