Metabolite profiles during oral glucose challenge

Abstract

To identify distinct biological pathways of glucose metabolism, we conducted a systematic evaluation of biochemical changes after an oral glucose tolerance test (OGTT) in a community-based population. Metabolic profiling was performed on 377 nondiabetic Framingham Offspring cohort participants (mean age 57 years, 42% women, BMI 30 kg/m(2)) before and after OGTT. Changes in metabolite levels were evaluated with paired Student t tests, cluster-based analyses, and multivariable linear regression to examine differences associated with insulin resistance. Of 110 metabolites tested, 91 significantly changed with OGTT (P ≤ 0.0005 for all). Amino acids, β-hydroxybutyrate, and tricarboxylic acid cycle intermediates decreased after OGTT, and glycolysis products increased, consistent with physiological insulin actions. Other pathways affected by OGTT included decreases in serotonin derivatives, urea cycle metabolites, and B vitamins. We also observed an increase in conjugated, and a decrease in unconjugated, bile acids. Changes in β-hydroxybutyrate, isoleucine, lactate, and pyridoxate were blunted in those with insulin resistance. Our findings demonstrate changes in 91 metabolites representing distinct biological pathways that are perturbed in response to an OGTT. We also identify metabolite responses that distinguish individuals with and without insulin resistance. These findings suggest that unique metabolic phenotypes can be unmasked by OGTT in the prediabetic state.

FIG. 1.

Heat map of correlated metabolite changes with glucose challenge.

FIG. 2.

Metabolite excursions after glucose challenge in metabolic pathways that reflect the effects of insulin. Notable perturbations include decreased proteolysis (as evidenced by lower amino acids and amino acid metabolites), inhibition of ketogenesis (lower β-hydroxybutyrate), suppression of the TCA cycle, and activation of glycolysis. % change = 100 × (up-fold change – 1) or 100 × (1 − down-fold change).

FIG. 3.

Metabolite excursions after glucose challenge in pathways that are not previously established in relation to glucose or insulin metabolism. Notable perturbations include inhibition of the serotonin system, decrease in metabolites of the urea cycle, suppression of nucleic acids, decrease in all vitamins of the B superfamily, increase in all conjugated bile acids, and decrease in deconjugated bile acids. % change = 100 × (up-fold change – 1) or 100 × (1 − down-fold change).

FIG. 4.

Metabolite excursions after glucose challenge in participants with and without insulin resistance. Analyses are adjusted for age, sex, and BMI. Error bars represent 95% CIs. Changes for ketogenesis (β-hydroxybutyrate), proteolysis (isoleucine), and glycolysis (lactate) are all blunted in insulin-resistant individuals.