How the Body Processes Sugar After Eating, in People With Different Body Weights

The Metabolic Effects of a Hyperglycaemic Meal in Lean and Obese Individuals Using a [14C]-Glucose Microtracer Approach

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.

Study Overview

• Status: Recruiting
• Conditions: Obesity & Overweight
• Intervention / Treatment: Dietary supplement: Low-glycemic breakfast (randomized vs high glycemic); Dietary supplement: High-glycaemic breakfast (randomized vs low glycemic); Dietary supplement: High-glycaemic breakfast

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marlou Dirks, PhD; Phone Number: +31 317-484 136; Email: Marlou.Dirks@wur.nl
• Study Contact Backup: Name: Ayesha Heinis, PhD; Phone Number: +31 6-21578392; Email: ayesha.heinis@wur.nl

Study Locations

• Netherlands
  • Wageningen, Netherlands, 6708 WD
    • Recruiting
    • Wageningen University and Research
    • Contact: Ayesha Heinis, PhD; Phone Number: 0621578392; Email: ayesha.heinis@wur.nl
    • Contact: Marlou Dirks, PhD; Phone Number: 0031317-484 136; Email: marlou.dirks@wur.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy males and females using contraception during and for 3 months after the study.
• Aged from 18-65 years at the time of signing informed consent
• 18.5 < BMI < 25 kg·m2 or 30< BMI <35 kg·m2
• Must be willing and able to communicate and participate in the whole study, including consumption of 14C-glucose and meals offered during study conduct
• Must have regular bowel movements (i.e. average stool production of ≥1 and ≤3 stools per day)
• Must usually eat 3 meals per day (i.e. breakfast, lunch and dinner)

Exclusion Criteria:

• Diabetes (Type 1, Type 2, or genetic form of diabetes)
• Any diagnosed cardiovascular (heart) disease or high blood pressure (≥140 mmHg systolic and/or ≥90 mmHg diastolic)
• HbA1c higher than 53 mmol/mol
• History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastro-intestinal disease, immunodeficiency, endocrine, neurological, or psychiatric disorders
• Any diagnosed respiratory disease, such as COPD or asthma
• Any previous motor disorders or disorders in muscle and/or lipid metabolism
• Known severe kidney problems
• Presence of an ulcer in the stomach or gut and/or strong history of indigestion
• Recent or chronic history of diarrhoea
• Known anaemia
• A personal or family history of thrombosis (clots), epilepsy, seizures, or schizophrenia.
• Regular use of dietary supplements (>3 times per week)
• Chronic use of any prescribed or over the counter pharmaceuticals (excluding oral contraceptives and contraceptive devices)
• History of any drug or alcohol abuse in the past two years
• A confirmed positive alcohol breath test at screening or admission
• Drug use
• Claustrophobia
• Subjects who are on a weight loss diet or following a high calorific/high protein diet to gain weight
• Subjects with functional constipation
• Any known food allergies or intolerances to the 14 major food allergens (celery, cereals containing gluten, crustaceans, eggs, fish, lupin, milk, molluscs, mustard, tree nuts, peanuts, sesame seeds, soybeans, sulphur dioxide and sulphites) or history of a malabsorption syndrome including coeliac disease
• Subjects who have regular gastrointestinal complaints including abdominal pain, stomach upsets and borborygmi or known or suspected irritable bowel syndrome
• Currently taking part in another scientific research
• Having received a product with 14C in the past 12 months
• Pregnant or breastfeeding
• Smoking or having used nicotine-containing products in the 6 months prior to the study.
• Subjects who have taken antibiotics within the 60 days prior to the adaptation period.
• Currently involved in a structured progressive resistance training programme (>3 times per week)
• Sedentary lifestyle as assessed using the International Physical Activity Questionnaire [IPAQ].
• Unable to give consent
• Employed or undertaking a thesis or internship at the department of Human and Animal Physiology

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A - Lean individuals (Low-glycemic breakfast); 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); 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.
Experimental: B - Lean individuals (High-glycemic breakfast); 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 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.
Experimental: C - Individuals with obesity (High-glycemic breakfast); 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 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to 72 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Polyol pathway activity (fructose-to-glucose ratio)	Ratio of 14C-fructose to 14C-glucose concentrations	Baseline to 72 hours post 14C ingestion
Polyol pathway activity (sorbitol-to-glucose ratio)	Ratio of 14C-sorbitol to 14C-glucose concentrations	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	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	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	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	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.	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.	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.	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.	Baseline to 72 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Polyol Pathway Activity Markers	Plasma and erythrocyte sorbitol concentrations	Baseline and up to 8 hours after 14C-glucose ingestion
Plasma glucose	Plasma glucose concentration	Baseline and up to 8 hours after 14C-glucose ingestion
Insulin	Serum insulin concentration	Baseline and up to 8 hours after 14C-glucose ingestion
Exploratory Metabolic Phenotyping	Metabolomic, proteomic, and/or transcriptomic profiles in plasma and erythrocytes	Baseline and up to 8 hours after 14C-glucose ingestion
Body Weight	Body weight measured in kilograms	Baseline (pre-intervention)
Height	Height measured in meters	Baseline (pre-intervention)
Body mass index (BMI)	Body mass index calculated as weight in kilograms divided by height in meters squared (kg/m²)	Baseline (pre-intervention)
Blood pressure	Systolic and diastolic blood pressure measured in mmHg	Baseline (pre-intervention)
Glycated haemoglobin (HbA1c)	HbA1c concentration in blood	Baseline

Collaborators and Investigators

• Sponsor: Wageningen University
• Collaborators: TNO; Bonumose, Inc.
• Investigators: Principal Investigator: Marlou Dirks, PhD, Wageningen University

Publications and helpful links

General Publications

• Kruszynska YT, Mulford MI, Yu JG, Armstrong DA, Olefsky JM. Effects of nonesterified fatty acids on glucose metabolism after glucose ingestion. Diabetes. 1997 Oct;46(10):1586-93. doi: 10.2337/diacare.46.10.1586.
• Fery F, d'Attellis NP, Balasse EO. Mechanisms of starvation diabetes: a study with double tracer and indirect calorimetry. Am J Physiol. 1990 Dec;259(6 Pt 1):E770-7. doi: 10.1152/ajpendo.1990.259.6.E770.
• Moseley L, Jentjens RL, Waring RH, Harris RM, Harding LK, Jeukendrup AE. Measurement of exogenous carbohydrate oxidation: a comparison of [U-14C]glucose and [U-13C]glucose tracers. Am J Physiol Endocrinol Metab. 2005 Aug;289(2):E206-11. doi: 10.1152/ajpendo.00423.2004. Epub 2005 Feb 22.
• Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Craig JC. Dual carbon-labeled isotope experiments using D-[6-14C] glucose and L-[1,2,3-13C3] lactate: a new approach for investigating human myocardial metabolism during ischemia. J Am Coll Cardiol. 1985 May;5(5):1138-46. doi: 10.1016/s0735-1097(85)80016-4.
• Virkamaki A, Puhakainen I, Nurjhan N, Gerich JE, Yki-Jarvinen H. Measurement of lactate formation from glucose using [6-3H]- and [6-14C]glucose in humans. Am J Physiol. 1990 Sep;259(3 Pt 1):E397-404. doi: 10.1152/ajpendo.1990.259.3.E397.
• Bell PM, Firth RG, Rizza RA. Assessment of insulin action in insulin-dependent diabetes mellitus using [6(14)C]glucose, [3(3)H]glucose, and [2(3)H]glucose. Differences in the apparent pattern of insulin resistance depending on the isotope used. J Clin Invest. 1986 Dec;78(6):1479-86. doi: 10.1172/JCI112739.
• McMahon MM, Schwenk WF, Haymond MW, Rizza RA. Underestimation of glucose turnover measured with [6-3H]- and [6,6-2H]- but not [6-14C]glucose during hyperinsulinemia in humans. Diabetes. 1989 Jan;38(1):97-107. doi: 10.2337/diab.38.1.97.
• Katz H, Homan M, Butler P, Rizza R. Use of [3-3H]glucose and [6-14C]glucose to measure glucose turnover and glucose metabolism in humans. Am J Physiol. 1992 Jul;263(1 Pt 1):E17-22. doi: 10.1152/ajpendo.1992.263.1.E17.
• Ferrannini E, Bjorkman O, Reichard GA Jr, Pilo A, Olsson M, Wahren J, DeFronzo RA. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes. 1985 Jun;34(6):580-8. doi: 10.2337/diab.34.6.580.
• Gallen IW, Macdonald IA. Effect of two methods of hand heating on body temperature, forearm blood flow, and deep venous oxygen saturation. Am J Physiol. 1990 Nov;259(5 Pt 1):E639-43. doi: 10.1152/ajpendo.1990.259.5.E639.
• ANDRES R, ZIERLER KL, ANDERSON HM, STAINSBY WN, CADER G, GHRAYYIB AS, LILIENTHAL JL Jr. Measurement of blood flow and volume in the forearm of man; with notes on the theory of indicator-dilution and on production of turbulence, hemolysis, and vasodilatation by intra-vascular injection. J Clin Invest. 1954 Apr;33(4):482-504. doi: 10.1172/JCI102919. No abstract available.
• Dirks ML, Wall BT, Otten B, Cruz AM, Dunlop MV, Barker AR, Stephens FB. High-fat Overfeeding Does Not Exacerbate Rapid Changes in Forearm Glucose and Fatty Acid Balance During Immobilization. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz049. doi: 10.1210/clinem/dgz049.
• Batchuluun B, Pinkosky SL, Steinberg GR. Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat Rev Drug Discov. 2022 Apr;21(4):283-305. doi: 10.1038/s41573-021-00367-2. Epub 2022 Jan 14.
• Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014 Mar;146(3):726-35. doi: 10.1053/j.gastro.2013.11.049. Epub 2013 Dec 4.
• Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005 May;115(5):1343-51. doi: 10.1172/JCI23621.
• Johnson RJ, Lanaspa MA, Sanchez-Lozada LG, Tolan D, Nakagawa T, Ishimoto T, Andres-Hernando A, Rodriguez-Iturbe B, Stenvinkel P. The fructose survival hypothesis for obesity. Philos Trans R Soc Lond B Biol Sci. 2023 Sep 11;378(1885):20220230. doi: 10.1098/rstb.2022.0230. Epub 2023 Jul 24.
• Tang WH, Martin KA, Hwa J. Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol. 2012 May 9;3:87. doi: 10.3389/fphar.2012.00087. eCollection 2012.
• Kivimaki M, Strandberg T, Pentti J, Nyberg ST, Frank P, Jokela M, Ervasti J, Suominen SB, Vahtera J, Sipila PN, Lindbohm JV, Ferrie JE. Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study. Lancet Diabetes Endocrinol. 2022 Apr;10(4):253-263. doi: 10.1016/S2213-8587(22)00033-X. Epub 2022 Mar 4.

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2026
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): July 30, 2026

Study Registration Dates

• First Submitted: April 17, 2026
• First Submitted That Met QC Criteria: July 1, 2026
• First Posted (Actual): July 8, 2026

Study Record Updates

• Last Update Posted (Actual): July 8, 2026
• Last Update Submitted That Met QC Criteria: July 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: de novo lipogenesis; accelerator mass spectrometry; microtracer; Hyperglycaemic meal; 14C-glucose; polyol pathway; arteriovenous forearm balance
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity
• Other Study ID Numbers: NL85522.028.24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared outside the study team.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No