An interventional study of Low-glycemic breakfast (randomized vs high glycemic) and High-glycaemic breakfast (randomized vs low glycemic) in Obesity & Overweight, sponsored by Wageningen University. Recruiting at 1 site in Netherlands. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-07-08.
Sponsored by Wageningen University · Not applicable, Interventional, and Basic science
The goal of this clinical trial is to learn how a high-glycaemic meal affects the way the body processes glucose in healthy adults who are either lean or have obesity. The main questions it aims to answer are: Is the polyol pathway (conversion of glucose into sorbitol and fructose) more active after a hyperglycaemic meal? Is this pathway more active in individuals with obesity compared with lean individuals? We will compare people who eat a high-glycaemic meal with those who eat a low-glycaemic meal to see whether meal type changes how glucose is metabolized in the body. Participants will drink a small amount of 14C-labelled glucose so researchers can trace how the body uses glucose, spend one long study day (about 12 hours in the lab) plus short morning visits on days 2 to 4, and undergo repeated measurements, including blood sampling, breath sampling, indirect calorimetry, and complete urine and stool collection for 72 hours. This information will help us understand how glucose is processed in the body and whether people with obesity handle glucose differently than lean individuals.
Obesity is associated with substantial metabolic dysregulation, including impaired glucose handling, increased oxidative stress, and altered nutrient partitioning. A metabolic pathway of particular interest in this context is the polyol pathway, in which glucose is converted to sorbitol by aldose reductase and subsequently to fructose. Preclinical studies suggest that flux through this pathway increases when intracellular glucose concentrations rise, such as during hyperglycaemia or insulin resistance. Greater activity of this pathway has been linked to the formation of advanced glycation end products, oxidative stress, and stimulation of de novo lipogenesis. These mechanisms have been proposed as contributors to metabolic complications commonly observed in individuals with obesity. Despite these findings from animal and in vitro studies, polyol pathway activity and its regulation by dietary glycaemic load have not been systematically quantified in humans. This clinical trial addresses this gap by applying a highly sensitive [14C]-glucose microtracer approach to measure the metabolic fate of glucose following ingestion of meals with differing glycaemic properties in lean individuals and individuals with obesity.
The study makes use of uniformly labelled [14C]-glucose, which allows tracing of glucose-derived carbon into metabolic intermediates, expired CO₂, urine, faeces, and lipids using Accelerator Mass Spectrometry. This technology enables quantification of metabolic products with extremely small isotope doses, resulting in radiation exposure far below natural background levels. Through this approach, the study can directly assess the extent to which ingested glucose is oxidized, converted into polyol pathway intermediates, incorporated into lipids, or excreted. The microtracer method provides a level of mechanistic resolution that cannot be achieved with stable isotopes or traditional metabolic tests.
The study design includes a single 72-hour metabolic test period during which participants consume either a high- or low-glycaemic breakfast depending on group allocation. The subsequent ingestion of [14C]-glucose allows tracking of postprandial metabolic routing under these two dietary conditions. Lean participants are randomized to either glycaemic condition, whereas individuals with obesity receive the high-glycaemic meal to address the study's main objective of comparing pathway activity between lean and obese phenotypes under hyperglycaemic challenge. Although the protocol includes multiple laboratory measurements, the aim of this Detailed Description is not to reproduce the procedure schedule, but to summarize the scientific characteristics of the design. In general terms, the study integrates whole-body, biochemical, and tissue-level metabolic assessments to characterize glucose metabolism in vivo.
Whole-body energy expenditure and substrate oxidation are measured repeatedly through indirect calorimetry to determine the proportion of glucose that is oxidized versus stored or redirected into other metabolic pathways. Breath samples are collected to quantify 14CO₂ production, which provides a sensitive measure of glucose oxidation and contributes to mass balance calculations. Serial blood sampling enables the measurement of plasma glucose, insulin, and the appearance of 14C-labelled metabolites, providing insight into the dynamics of glucose disposal and conversion to sorbitol, fructose, and downstream metabolites.
A distinctive feature of this study is the assessment of forearm arteriovenous metabolite balance, obtained from arterialized and deep-venous blood sampling combined with Doppler ultrasound measurement of forearm blood flow. This technique allows calculation of tissue-specific uptake and release of glucose and glucose-derived metabolites across skeletal muscle, a major site of postprandial glucose disposal. These measurements offer a physiologically meaningful index of muscle insulin sensitivity and provide additional perspective on how glycaemic load and obesity influence metabolic flux at the tissue level.
Collection of urine and faeces for 72 hours enables full recovery of the administered tracer, allowing detailed mass balance calculations. This information reveals how much of the ingested glucose is oxidized, excreted, or directed into biosynthetic pathways. By integrating data from breath, blood, urine, and faeces, the study can comprehensively map the metabolic fate of glucose and determine how this differs across physiological states.
The primary scientific questions addressed by this study are whether polyol pathway activity increases under hyperglycaemic conditions in humans and whether individuals with obesity demonstrate greater pathway activation than lean individuals. The study further explores the relationship between polyol pathway activation and de novo lipogenesis and evaluates whether the glycaemic load of a meal modulates these pathways. By combining microtracer-based flux analysis with whole-body and tissue-specific measurements, the study aims to provide mechanistic insight into early metabolic disturbances associated with obesity.
Overall, this trial will generate foundational human data on endogenous fructose production and glucose routing in response to dietary glycaemic load. These findings may contribute to improved understanding of how carbohydrate metabolism becomes dysregulated in obesity and may support the development of nutritional or therapeutic strategies targeting glucose-handling pathways. The study also demonstrates the potential of Accelerator Mass Spectrometry as a powerful tool for investigating nutrient metabolism in vivo with minimal participant burden and extremely low radiation exposure.
Exclusion Criteria:
Lean participants randomized to consume a low-glycemic breakfast prior to administration of an oral \[¹⁴C\]-glucose microtracer to assess postprandial glucose metabolism.
Dietary Supplement: Low-glycemic breakfast (randomized vs high glycemic)
Lean participants randomized to consume a high-glycemic breakfast prior to administration of an oral \[¹⁴C\]-glucose microtracer to assess postprandial glucose metabolism.
Dietary Supplement: High-glycaemic breakfast (randomized vs low glycemic)
Participants with obesity consume a high-glycemic breakfast prior to administration of an oral \[¹⁴C\]-glucose microtracer to assess postprandial glucose metabolism.
Dietary Supplement: High-glycaemic breakfast
Participants receive a single oral microtracer dose of \[14C\] glucose (≤10 kBq / 270 nCi) mixed with 1 g unlabeled glucose, administered immediately after a low glycemic breakfast. The dose is prepared fresh on the morning of administration and consumed as a liquid drink. This approach enables tracing of glucose metabolism using Accelerator Mass Spectrometry (AMS) at extremely low radiation exposure (\~0.006 mSv). The intervention is combined with indirect calorimetry, serial blood sampling (including arterialized and deep-venous lines), expired air collection for 14CO₂ recovery, and pooled urine/feces collection over 72 hours to quantify metabolic fate and pathway activity.
Participants receive a single oral microtracer dose of \[14C\] glucose (≤10 kBq / 270 nCi) mixed with 1 g unlabeled glucose, administered immediately after a high glycemic breakfast. The dose is prepared fresh on the morning of administration and consumed as a liquid drink. This approach enables tracing of glucose metabolism using Accelerator Mass Spectrometry (AMS) at extremely low radiation exposure (\~0.006 mSv). The intervention is combined with indirect calorimetry, serial blood sampling (including arterialized and deep-venous lines), expired air collection for 14CO₂ recovery, and pooled urine/feces collection over 72 hours to quantify metabolic fate and pathway activity.
Participants receive a single oral microtracer dose of \[14C\] glucose (≤10 kBq / 270 nCi) mixed with 1 g unlabeled glucose, administered immediately after a high glycemic breakfast. The dose is prepared fresh on the morning of administration and consumed as a liquid drink. This approach enables tracing of glucose metabolism using Accelerator Mass Spectrometry (AMS) at extremely low radiation exposure (\~0.006 mSv). The intervention is combined with indirect calorimetry, serial blood sampling (including arterialized and deep-venous lines), expired air collection for 14CO₂ recovery, and pooled urine/feces collection over 72 hours to quantify metabolic fate and pathway activity.
Total mass balance (cumulative recovery of 14C)
Cumulative recovery of total radioactivity across all excreta (urine, faeces, and expired CO₂) expressed as percentage of the administered dose.
Time frame: Baseline to 72 hours post dose
Polyol pathway activity (fructose-to-glucose ratio)
Ratio of 14C-fructose to 14C-glucose concentrations
Time frame: Baseline to 72 hours post 14C ingestion
Polyol pathway activity (sorbitol-to-glucose ratio)
Ratio of 14C-sorbitol to 14C-glucose concentrations
Time frame: Baseline to 72 hours post 14C ingestion
Polyol pathway activity (AUC-based ratio)
Ratio of area under the curve (AUC) for 14C-fructose to AUC for 14C-glucose
Time frame: Baseline to 72 hours post 14C ingestion
De novo lipogenesis from glucose
Incorporation of 14C label into plasma lipids as a measure of fatty acid synthesis from glucose
Time frame: Baseline to 72 hours
Caloric value of glucose
Recovery of 14C label in expired CO2 and excreta, expressed as a measure of energy yield of ingested glucose
Time frame: Baseline to 72 hours
Forearm arteriovenous balance of 14C-glucose and metabolites
Arteriovenous concentration differences of 14C-glucose and metabolites across the forearm, combined with blood flow measurements
Time frame: 0-240 minutes post dose
14C-labelled metabolites in carbohydrate metabolism pathways
Concentrations and 14C-enrichment of glucose, fructose, and related metabolites in plasma and erythrocytes.
Time frame: Baseline to 72 hours post 14C ingestion
Carbohydrate oxidation
Carbohydrate oxidation rate measured using indirect calorimetry and calculated according to standard equations under fasted and postprandial conditions following ingestion of a high- or low-glycaemic meal.
Time frame: Baseline to 72 hours
Lipid oxidation
Lipid oxidation rate measured using indirect calorimetry and calculated according to standard equations under fasted and postprandial conditions following ingestion of a high- or low-glycaemic meal.
Time frame: Baseline to 72 hours
Energy expenditure
Total energy expenditure measured using indirect calorimetry and calculated according to standard equations under fasted and postprandial conditions following ingestion of a high- or low-glycaemic meal.
Time frame: Baseline to 72 hours
Polyol Pathway Activity Markers
Plasma and erythrocyte sorbitol concentrations
Time frame: Baseline and up to 8 hours after 14C-glucose ingestion
Plasma glucose
Plasma glucose concentration
Time frame: Baseline and up to 8 hours after 14C-glucose ingestion
Insulin
Serum insulin concentration
Time frame: Baseline and up to 8 hours after 14C-glucose ingestion
Exploratory Metabolic Phenotyping
Metabolomic, proteomic, and/or transcriptomic profiles in plasma and erythrocytes
Time frame: Baseline and up to 8 hours after 14C-glucose ingestion
Body Weight
Body weight measured in kilograms
Time frame: Baseline (pre-intervention)
Height
Height measured in meters
Time frame: Baseline (pre-intervention)
Body mass index (BMI)
Body mass index calculated as weight in kilograms divided by height in meters squared (kg/m²)
Time frame: Baseline (pre-intervention)
Blood pressure
Systolic and diastolic blood pressure measured in mmHg
Time frame: Baseline (pre-intervention)
Glycated haemoglobin (HbA1c)
HbA1c concentration in blood
Time frame: Baseline
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