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.
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
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.
Factorial
[6,6-D2]-labeled glucose (intravenous)
Other interventionParticipants 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.
Saline (0.9% sodium chloride infusion)
Other interventionParticipants 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.
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.
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.
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.
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.
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).
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Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Lead sponsor
Spaarne Gasthuis
Collaborator
