Hepatic Gene Response to Intravenous Glucose in Obese Patients With and Without MASLD Undergoing Bariatric Surgery (GHAST)

Glucose IV and Its Hepatic Outcomes After a Metabolic Stress Test During Bariatric Surgery in Obese Patients With and Without MASLD

The goal of this clinical trial is to learn how the liver responds to sugar in people with obesity who are having bariatric surgery. Researchers want to understand differences between people with and without metabolic associated steatotic liver disease (MASLD).

The main question is:

Does giving sugar directly into the vein change how liver genes work in people with and without MASLD?

Researchers will compare:

• People with MASLD who receive sugar
• People with MASLD who receive saline (salt water)
• People without MASLD who receive sugar
• People without MASLD who receive saline

During surgery, participants will:

• Receive either a sugar solution (35 grams of glucose in 150 mL fluid) or saline
• Have small samples (biopsies) taken from the liver and fat tissue before and 45 minutes after the infusion
• Provide blood samples to measure sugar, insulin, and other metabolites
• Provide a one-time sample of intestinal tissue that is normally removed during surgery

This study may help explain why MASLD develops and how the liver reacts to sugar. The results could lead to new ways to understand and treat liver disease in people with obesity.

Study Overview

• Status: Recruiting
• Conditions: MASLD
• Intervention / Treatment: Other: [6,6-D2]-labeled glucose (intravenous); Other: Saline (0.9% sodium chloride infusion)

Detailed Description

Metabolic Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease worldwide and a major cause of liver-related illness and death. Current knowledge is largely based on fasting-state liver biopsies, which do not capture the transcriptional changes triggered by nutrient intake. Postprandial dysfunction is a hallmark of MASLD, yet the molecular mechanisms in human liver tissue under metabolic stress remain poorly understood.

This study uses bariatric surgery as a unique opportunity to obtain paired liver and adipose tissue biopsies before and after an intravenous glucose challenge. By administering a 35-gram bolus of [6,6-D2]-labeled glucose during surgery, researchers can mimic the caloric load of a high-sugar meal while controlling for confounding factors such as anesthesia and surgical stress through saline control groups.

The design is a single-center, interventional, 2 × 2 factorial trial with 40 obese participants (20 with MASLD, 20 without MASLD). Participants are randomized to receive either labeled glucose or saline. Biopsies of liver, subcutaneous, omental, and visceral adipose tissue are collected at baseline and 45 minutes after infusion. Jejunal tissue routinely removed during Roux-en-Y gastric bypass is also analyzed for transcriptomic and microbiome profiling.

Primary analyses focus on single-cell RNA sequencing of liver biopsies to identify transcriptional changes induced by glucose infusion and to compare responses between MASLD and non-MASLD participants. Secondary analyses include transcriptomic profiling of adipose depots (subcutaneous, visceral and omental), jejunal tissue, and untargeted metabolomics/proteomics of plasma samples. The use of stable isotope-labeled glucose allows tracing of metabolic pathways, including erythritol synthesis via the pentose phosphate pathway.

This approach builds on prior work done using the BARIA cohort (DOI: 10.1111/joim.13157), which demonstrated that postprandial states reveal clinically relevant differences in metabolic health not apparent in fasting conditions. By integrating tissue transcriptomics, plasma metabolomics, and microbiome data, the GHAST study aims to uncover mechanisms of metabolic dysregulation in MASLD and identify novel therapeutic targets.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Daniël P Baars, MD; Phone Number: 0650063930; Email: d.p.baars@amsterdamumc.nl

Study Locations

• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1105AZ
      • Recruiting
      • AMC
      • Contact: Daniël P Baars; Phone Number: 0650063930; Email: d.p.baars@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

To be eligible to participate in this study, a subject must meet all of the following criteria:

Adult individuals, age >35 < 65 years old. Stable weight (no more than 3% TWL of initial body weight from screening to surgery) Subjects should be able to give informed consent Subjects agree to have tissue biopsies performed during surgery, that is 2 liver, subcutaneous, visceral and omental biopsies plus a one-time jejunal biopsy.

For obese non-MASLD patients:

• Adult individuals, age >35 < 65 years old.
• BMI ≥ 40 kg/m², or a BMI ≥ 35 kg/m² with an obesity-related comorbidity
• No MASLD based on Fibroscan
• Estimated glomerular filtration rate (eGFR) > 60mL/min/1.73m2

For obese MASLD patients:

• MASLD diagnosis according to Fibroscan

• Compensated liver disease with the following hematologic and biochemical criteria on entry into study:

  • ALAT <10x ULN
  • Hemoglobin > 11g/dL for females and 12 g/dL for males
  • White blood cell (WBC) > 2.5 K/ μL
  • Neutrophil count > 1.5 K μL
  • Platelets > 100 K/μL
  • Total bilirubin <35 μmol/L
  • Albumin >30 g/L
  • TP >80% or INR <1.4
  • Serum creatinine <1.3 mg/dL (men) or <1.1 mg/dL (women) or
• Estimated glomerular filtration rate (eGFR) > 60mL/min/1.73m2

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

• Use of metformin and SGLT2/ exogenous insulin/GLP-1 RA
• Primary lipid disorder
• Known genetic basis for insulin resistance or glucose intolerance
• All medical and psychiatric conditions except for obesity related diseases.
• Uncontrolled hypertension (RR > 150/95 mmHg)
• Chronic kidney disease (creatinine > 150 umol/L)
• Pregnancy, females who are breastfeeding
• Evidence of another form of liver disease
• History of sustained excess alcohol ingestion: daily consumption >30g/day (3 drinks per day) for males and >20 g/day (2 drinks per day) for females
• Significant systemic or major illnesses other than liver disease, including congestive heart failure (class C and D of the AHA), unstable coronary artery disease, cerebrovascular disease, pulmonary disease, kidney failure, organ transplantation, serious psychiatric disease, active malignancy, compromised immunity
• Body mass index (BMI) >45 kg/m2
• Type 1 or type 2 diabetes
• Hemostasis disorders or current treatment with anticoagulants
• Known heart failure
• Contra-indication for liver biopsy History of/or current cardiac dysrhythmias and/or a history of cardiovascular events including myocardial infarction, except patients with only well-controlled hypertension

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MASLD + Glucose; Participants with metabolic associated steatotic liver disease (MASLD) undergoing bariatric surgery receive a 35-gram intravenous bolus of [6,6-D2]-labeled glucose in 150 mL solution.	Other: [6,6-D2]-labeled glucose (intravenous); Participants receive a 35-gram intravenous bolus of [6,6-D2]-labeled glucose dissolved in 150 mL solution. The infusion is administered at the start of bariatric surgery over 3-5 minutes via an indwelling catheter. Liver and adipose tissue biopsies are collected before infusion and 45 minutes after infusion to assess transcriptomic changes. Blood samples are taken at multiple timepoints to measure glucose, insulin, and plasma metabolites, metabolites can be traced using the labeled glucose.
Placebo Comparator: MASLD + Saline; Participants with MASLD undergoing bariatric surgery receive an intravenous infusion of 150 mL saline (0.9% sodium chloride)	Other: Saline (0.9% sodium chloride infusion); Participants receive an intravenous infusion of 150 mL saline (0.9% sodium chloride) at the start of bariatric surgery. The infusion is administered over 3-5 minutes via an indwelling catheter. Liver and adipose tissue biopsies are collected before infusion and 45 minutes after infusion to serve as controls for transcriptomic and metabolic changes.; Other Names: Intravenous saline
Experimental: Non-MASLD + Glucose; Participants without MASLD undergoing bariatric surgery receive a 35-gram intravenous bolus of [6,6-D2]-labeled glucose in 150 mL solution.	Other: [6,6-D2]-labeled glucose (intravenous); Participants receive a 35-gram intravenous bolus of [6,6-D2]-labeled glucose dissolved in 150 mL solution. The infusion is administered at the start of bariatric surgery over 3-5 minutes via an indwelling catheter. Liver and adipose tissue biopsies are collected before infusion and 45 minutes after infusion to assess transcriptomic changes. Blood samples are taken at multiple timepoints to measure glucose, insulin, and plasma metabolites, metabolites can be traced using the labeled glucose.
Placebo Comparator: Non-MASLD + Saline; Participants without MASLD undergoing bariatric surgery receive an intravenous infusion of 150 mL saline (0.9% sodium chloride).	Other: Saline (0.9% sodium chloride infusion); Participants receive an intravenous infusion of 150 mL saline (0.9% sodium chloride) at the start of bariatric surgery. The infusion is administered over 3-5 minutes via an indwelling catheter. Liver and adipose tissue biopsies are collected before infusion and 45 minutes after infusion to serve as controls for transcriptomic and metabolic changes.; Other Names: Intravenous saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in hepatic gene expression at 45 minutes after intravenous glucose bolus compared to saline infusion	Liver biopsies are collected at two timepoints: (1) baseline, immediately after anesthesia induction and before infusion, and (2) 45 minutes after infusion of either [6,6-D2]-labeled glucose or saline. Single-cell RNA sequencing (scRNA-seq) is performed on these paired samples to measure changes in hepatic gene expression. The primary comparison is the difference in transcriptomic profiles between baseline and 45 minutes post-infusion, stratified by MASLD status (confirmed by Fibroscan and histology). Gene expression changes are quantified as fold-change in transcript abundance, normalized to baseline values.	Baseline (pre-infusion, at start of surgery) to 45 minutes after infusion during bariatric surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in gene expression in subcutaneous, omental, and visceral adipose tissue	Biopsies of subcutaneous, omental, and visceral adipose tissue are collected at two timepoints: (1) baseline, immediately after anesthesia induction and before infusion, and (2) 45 minutes after infusion of either [6,6-D2]-labeled glucose or saline. Single-cell RNA sequencing is performed to assess transcriptomic changes in each adipose depot. Gene expression changes are reported as fold-change relative to baseline values, stratified by MASLD status and intervention group.	Baseline (pre-infusion) to 45 minutes post-infusion during bariatric surgery
Jejunal tissue gene expression profile	Jejunal tissue routinely removed during Roux-en-Y gastric bypass surgery will be collected once during surgery. Transcriptomic profiling (bulk RNA sequencing) will be performed to characterize jejunal gene expression.	One-time collection during bariatric surgery
Plasma metabolite changes following labeled glucose infusion	Plasma samples collected at baseline and post-infusion will be analyzed using metabolomics to quantify changes in metabolites related to glucose catabolism, including isotope-labeled metabolites.	Baseline (pre-infusion) to 45 minutes post-infusion during bariatric surgery
Insulin sensitivity index derived from IVGTT	Plasma glucose and insulin concentrations measured during the IVGTT will be used to calculate a prespecified insulin sensitivity index (reported as a single derived value per participant per timepoint).	Baseline (pre-infusion) to 45 minutes post-infusion during bariatric surgery
Intra-jejunal microbiota composition	Intra-jejunal contents collected once during bariatric surgery will be analyzed to characterize microbiota composition.	One-time collection during bariatric surgery.
Plasma protein changes following labeled glucose infusion	Plasma samples collected at baseline and post-infusion will be analyzed using proteomic profiling to quantify changes in circulating proteins related to metabolic pathways.	Baseline (pre-infusion) to 45 minutes post-infusion during bariatric surgery.

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Spaarne Gasthuis
• Investigators: Principal Investigator: Max Nieuwdorp, Prof. Dr., Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: December 3, 2025
• First Submitted That Met QC Criteria: December 25, 2025
• First Posted (Actual): January 8, 2026

Study Record Updates

• Last Update Posted (Actual): January 8, 2026
• Last Update Submitted That Met QC Criteria: December 25, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Obesity; Metabolomics; Bariatric surgery; RNA sequencing; Roux-en-Y gastric bypass (RYGB); Postprandial metabolism; MASLD (Metabolic Associated Steatotic Liver Disease); [6,6-D2]-labeled glucose; Hepatic gene expression; Adipose tissue transcriptomics
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Inorganic Chemicals; Chlorine Compounds; Sodium Compounds; Chlorides; Hydrochloric Acid; Sodium Chloride
• Other Study ID Numbers: 2025.0097

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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