Metabolic Flux Analysis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Metabolic Flux Analysis in MASLD
研究概览
地位
详细说明
MASLD and its progressive form MASH are associated with obesity, insulin resistance, altered hepatic substrate delivery, and changes in mitochondrial metabolism. However, the direction and significance of hepatic citric acid cycle flux changes in human MASLD remain unresolved. This study will apply in vivo metabolic flux analysis using non-radioactive stable isotope tracers to quantify hepatic and extrahepatic metabolic pathway activity in bariatric surgery participants before and after surgery.
Participants will complete three study timepoints. Approximately one week before surgery, participants will undergo fasting physical measurements, questionnaires, research blood collection, and abdominal MRI/MRE to quantify liver fat and stiffness. On the day of surgery, participants will receive intravenous infusions of [¹³C₃]lactate, [6,6-²H₂]-D-glucose, and [9,9-²H₂]palmitate for approximately 120 minutes with serial blood collection. During the clinically planned bariatric surgery, research tissue specimens may be collected from liver, omentum, subcutaneous adipose tissue, and skeletal muscle only if the surgeon determines collection can be performed safely without interfering with clinical care. Approximately 6 months after surgery, participants will repeat fasting physical measurements, questionnaires, MRI/MRE, stable isotope tracer infusion, and blood collection; no follow-up tissue biopsies will be collected.
Isotope enrichment patterns in plasma metabolites and tissue metabolites will be analyzed by mass spectrometry and modeled using metabolic flux analysis software to estimate hepatic citric acid cycle flux, gluconeogenesis, glucose turnover, free fatty acid turnover, lactate turnover, and selected extrahepatic metabolic fluxes. Liver fat and stiffness will be assessed by MRI/MRE, and intraoperative liver tissue will be scored for MASLD/MASH features using established histologic criteria.
研究类型
注册 (估计的)
阶段
- 不适用
联系人和位置
学习联系方式
- 姓名：Charles R Flynn, PhD
- 电话号码：615-343-8329
- 邮箱：MASLD.research@vumc.org
参与标准
资格标准
适合学习的年龄
- 成人
- 年长者
接受健康志愿者
描述
Inclusion Criteria:
- Scheduled and clinically cleared for protocol-eligible bariatric surgery at Vanderbilt University Medical Center.
- BMI ≥40 kg/m², or BMI >35 kg/m² with at least one obesity-associated comorbidity, such as type 2 diabetes, cardiovascular disease, hypertension, hyperlipidemia, obstructive sleep apnea, MASLD, osteoarthritis, or polycystic ovarian syndrome.
- Able and willing to complete study procedures, including informed consent, questionnaires, blood draws, MRI/MRE imaging, stable isotope tracer infusion, and research tissue collection during planned bariatric surgery.
- Able to provide informed consent in English.
Exclusion Criteria:
- Contraindication to MRI/MRE, including implanted cardiac defibrillator, pacemaker, or other MRI-incompatible implanted device.
- Prior gastric or intestinal surgery, pancreatic surgery, or other prior surgery that, in the judgment of the study team or bariatric surgeon, would interfere with study procedures or outcome interpretation.
- Active cancer or ongoing cancer treatment.
- Presence or history of HIV infection.
- Alcohol use above study-defined limits: more than 14 alcoholic drinks per week for men or more than 7 alcoholic drinks per week for women, or illicit drug use that would interfere with safe participation or interpretation of study results.
- Anemia or other hematologic condition that would increase risk from study blood collection.
- Abnormal ECG or clinically significant cardiovascular finding that would increase risk from study procedures.
- Impaired renal function or other clinically significant condition that would increase risk from study participation.
- Known Wilson's disease, alpha-1 antitrypsin deficiency, hemochromatosis, or other non-MASLD chronic liver disease that would confound interpretation of study outcomes.
- Any medical, surgical, or safety condition that, in the judgment of the PI, clinical co-investigator, CRC staff, anesthesia team, or bariatric surgeon, would make participation unsafe or interfere with completion of study procedures.
学习计划
研究是如何设计的？
设计细节
- 主要用途：基础科学
- 分配：不适用
- 介入模型：单组作业
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
|
实验性的：Bariatric Surgery Participants Undergoing Metabolic Flux Assessment
Adults scheduled and clinically cleared for protocol-eligible bariatric surgery at VUMC will undergo research MRI/MRE, blood collection, non-radioactive stable isotope tracer infusions, and intraoperative research tissue collection during planned bariatric surgery, followed by repeat noninvasive metabolic assessment approximately 6 months after surgery.
|
Clinically indicated bariatric surgery, such as Roux-en-Y gastric bypass or sleeve gastrectomy, performed as part of standard clinical care.
其他名称：
Intravenous non-radioactive stable isotope tracers administered for research measurement of metabolic flux: [¹³C₃]lactate, [6,6-²H₂]-D-glucose, and [9,9-²H₂]palmitate.
Abdominal MRI proton density fat fraction and magnetic resonance elastography to assess hepatic fat and stiffness before surgery and approximately 6 months after surgery.
其他名称：
Liver, omentum, subcutaneous adipose tissue, and skeletal muscle specimens collected only during clinically planned bariatric surgery and only if safe in the surgeon's judgment.
|
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Change in hepatic citric acid cycle flux after bariatric surgery
大体时间：Baseline/day of surgery to approximately 6 months post-surgery
|
Change in hepatic citric acid cycle flux estimated from stable isotope enrichment patterns, including [¹³C₃]lactate-based measurements, before bariatric surgery and approximately 6 months after surgery.
|
Baseline/day of surgery to approximately 6 months post-surgery
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Change in hepatic gluconeogenic flux
大体时间：Baseline/day of surgery to ~6 months
|
Estimated from plasma glucose isotope enrichment and metabolic flux modeling
|
Baseline/day of surgery to ~6 months
|
|
Change in endogenous glucose production
大体时间：Baseline/day of surgery to ~6 months
|
Estimated using [6,6-²H₂]-D-glucose tracer dilution
|
Baseline/day of surgery to ~6 months
|
|
Change in free fatty acid turnover
大体时间：Baseline/day of surgery to ~6 months
|
Estimated using [9,9-²H₂]palmitate tracer dilution
|
Baseline/day of surgery to ~6 months
|
|
Change in lactate turnover / lactate-related flux
大体时间：Baseline/day of surgery to ~6 months
|
Estimated using stable isotope enrichment patterns
|
Baseline/day of surgery to ~6 months
|
|
Liver fat by MRI-PDFF
大体时间：Baseline to ~6 months
|
Hepatic fat fraction quantified by MRI-PDFF
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Baseline to ~6 months
|
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Liver stiffness by MRE
大体时间：Baseline to ~6 months
|
Liver stiffness quantified by magnetic resonance elastography
|
Baseline to ~6 months
|
|
Histologic MASLD/MASH severity
大体时间：Intraoperative baseline only
|
Liver biopsy scored for steatosis, inflammation, ballooning, fibrosis, and MASLD activity score
|
Intraoperative baseline only
|
|
Extrahepatic metabolic fluxes
大体时间：Intraoperative baseline only
|
Metabolic fluxes in skeletal muscle, omentum, and subcutaneous adipose tissue estimated from intraoperative tissue specimens
|
Intraoperative baseline only
|
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Serum inflammatory markers
大体时间：Baseline/day of surgery; possibly ~6 months if collected
|
Research measurement of inflammatory markers including CRP, cytokines, adhesion molecules, and related biomarkers
|
Baseline/day of surgery; possibly ~6 months if collected
|
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Metabolic hormone profile
大体时间：Baseline/day of surgery; possibly ~6 months if collected
|
Insulin, leptin, C-peptide, GLP-1, GIP, PYY, ghrelin
|
Baseline/day of surgery; possibly ~6 months if collected
|
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Bile acid profile
大体时间：Baseline/day of surgery; possibly ~6 months if collected
|
Bile acids measured by LC-IM-MS
|
Baseline/day of surgery; possibly ~6 months if collected
|
合作者和调查者
调查人员
- 首席研究员：Charles R Flynn, PhD、Vanderbilt University Medical Center
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
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关键字
其他相关的 MeSH 术语
其他研究编号
- 260832
计划个人参与者数据 (IPD)
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IPD 计划说明
IPD 共享时间框架
IPD 共享支持信息类型
- 研究方案
- 树液
- 国际碳纤维联合会
- 企业社会责任
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