Comparing the Fasting and Random-Fed Metabolome Response to an Oral Glucose Tolerance Test in Children and Adolescents: Implications of Sex, Obesity, and Insulin Resistance

Abstract

As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state. Participants were recruited as lean (n = 55, aged 8–17 years, BMI percentile 5–85%) and overweight and obese (OVOB, n = 228, aged 8–17 years, BMI percentile ≥ 85%). Untargeted metabolomics profiled 246 annotated metabolites in plasma at t0 and t60 min during the OGTT. Our results suggest that obesity and IR influence the switch from fatty acid (FA) to glucose oxidation in response to the OGTT. Obesity was associated with a blunted decline of acylcarnitines and fatty acid oxidation intermediates. In females, metabolites from the Fasted and Random-Fed OGTT were associated with HOMA-IR, including diacylglycerols, leucine/isoleucine, acylcarnitines, and phosphocholines. Our results indicate that at an early age, obesity and IR may influence the metabolome dynamics in response to a glucose challenge.

Characterizing human postprandial metabolic response using multiway data analysis

“…The predominant way to analyze labelled data is to use univariate statistical methods in which the metabolites are analyzed separately. Depending on the exact background of the study design, such methods can be t -tests (14, 16) or analysis of variance (ANOVA) models (4, 12, 14, 17, 18) to study group differences. More advanced methods consider explicitly the temporal aspect of the data and/or unbalanced designs, e.g., by using linear mixed models (19), extensions of the analysis of variance-simultaneous component analysis (ASCA) (20).…”

Investigating the Postprandial Metabolome after Challenge Tests to Assess Metabolic Flexibility and Dysregulations Associated with Cardiometabolic Diseases

“…Some studies also attempted to compare plasma and serum metabolomes following glucose ingestion in lean and overweight or obese populations [ 37 , 40 , 41 , 42 , 43 , 44 ] ( Table 1 ). Interestingly, they reported alterations in metabolite postprandial trajectories similar to those observed in IR subjects with noticeably blunted decreases of circulating AA and lipids.…”

“…In addition, both studies reported a blunted FFA response in obese subjects. Labarre et al also reported a blunted decrease in FFA but also in acylcarnitine and FA oxidation product levels in obese compared to lean adolescents [ 44 ]. In addition, in obese or overweight females, but not in males, this blunted acylcarnitine decrease (represented by a postprandial fold change) was positively associated with HOMA-IR.…”

Dynamic patterns of postprandial metabolic responses to three dietary challenges

“…The oral glucose tolerance test (OGTT) is the most widely used standardized challenge (15,16). Initially, the OGTT was designed for the diagnosis of diabetes, but recently, it has become the main tool in human nutritional studies to assess individual systemic metabolic responses to glucose intake through metabolomics (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Within the OGTT, participants are given an oral bolus of 75 g of glucose after overnight fasting.…”