(P16-026-23) Classifying the Acute Metabolic Response to a High-Fat Meal To Reveal Mechanisms of the Origins of Type 2 Diabetes in Adolescents

Objectives: The prevalence of youth-onset type 2 diabetes (T2D) continues to increase due to elevations in obesity in the pediatric population. Identifying early alterations in molecular markers associated with insulin resistance in adolescents is crucial, revealing mechanisms of the origins of T2D. Utilizing a high-fat meal, this pilot study was designed to stress the biological system and classify the physiological response to excess lipids.

Methods: Our protocol was piloted in adolescents with low-metabolic risk to demonstrate feasibility (NCT05230433). The high-fat meal was a mixture of BOOST Glucose Control® (Nestlé Products) supplemented with palm oil, containing approximately 15% calories from carbohydrates, 15% from protein, and 70% from fat. Blood was sampled at baseline and after consuming the challenge (30, 60, 120, and 180 minutes). Across the time course, metabolomics was used to profile intermediates of beta-oxidation (acylcarnitines [AC]), extra-mitochondrial fatty acid (FA) oxidation (dicarboxylic FA), and the global lipidome. Statistical analyses compared metabolic response by BMI percentile.

Results: Average age was 13.7 years (range 11-17 years, 7♀/4♂). On average, participants consumed 80% of the high-fat shake. Insulin AUC was trending towards significantly higher levels in overweight and obese (4067) vs. leans (2665) (p=0.14), with significant differences at 30 minutes post-challenge (p=0.01) (unpaired t-test). There was a decline in medium-chain (MC) ACs (0 to 60 minutes) followed by an increase in MC-ACs (60 to 180 minutes) with varying slopes. Positive associations were observed between BMI percentile and MC-AC fold changes from 60 to180 minutes, specifically AC 12:0 (r=0.72, p=0.04). This may suggest that obesity is associated with incomplete beta-oxidation of the high-fat meal.

Conclusions: Our pilot study tested our research protocol and demonstrated study feasibility, successful sample processing pipelines, and potential biological mechanisms warranting future studies. Evaluating the postprandial response to a dietary challenge containing all macronutrients—carbohydrates, lipids, and protein—may provide more robust insights into metabolic health than a fasted measurement.

Funding Sources: Geisel School of Medicine Department of Medicine Donor Funds
NIGMS COBRE Center of Molecular Epidemiology Pilot funds