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

Overview

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.

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.