Glucagon Resistance in Patients With NAFLD
In-depth Studies of Glucagon Resistance on Hepatic Glucose, Fatty Acid and Triglyceride Kinetics and Generation of Toxic Lipid Intermediates in NAFLD and NASH.
1 other identifier
interventional
28
1 country
1
Brief Summary
The investigators propose that the sensitivity to glucagon in hepatic lipid metabolism is impaired in subjects with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Moreover, they propose a dys-coordinated, reduced glucagon sensitivity in hepatic lipid metabolism and endogen glucose production in patients with NAFLD and NASH compared with healthy subjects and patients with simple steatosis. This reduced sensitivity may be the basis of a more severe dyslipidemia and the production of increased concentrations of toxic lipid intermediates in plasma and muscle tissue. The study will include healthy subjects with obesity and subjects with simple steatosis and NASH, tested at basal glucagonemia and moderate hyperglucagonemia to mimic insulin resistant levels during simultaneous somatostatin infusion and replacement doses of insulin and growth hormone. Infusion of palmitate, VLDL-triglyceride and glucose tracers in combination with indirect calorimetry as well as skeletal and adipose tissue biopsies will be employed to assess free fatty acid and VLDL-triglyceride kinetics (turnover, and oxidation) and hepatic fatty acid-esterification.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for not_applicable
Started Oct 2019
Typical duration for not_applicable
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 23, 2019
CompletedFirst Posted
Study publicly available on registry
August 1, 2019
CompletedStudy Start
First participant enrolled
October 5, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 30, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
August 18, 2022
CompletedNovember 4, 2022
November 1, 2020
2.7 years
May 23, 2019
November 3, 2022
Conditions
Outcome Measures
Primary Outcomes (2)
VLDL-triglyceride kinetics (appearance rate (µmol/min) and oxidation (µmol/min))
Ex vivo labeled VLDL \[14C\]-triolein tracer technique. Oxidation is measured by specific activity in exhaled air.
30 minutes at steady-state
Endogen glucose production (mmol/kg/min)
3-3H glucose tracer technique
30 minutes at steady-state
Secondary Outcomes (4)
LPL-activity (lipoprotein lipase, µmol/h)
30 minutes at steady-state
VLDL-triglyceride-fatty acid uptake in muscle and fatty tissue (%)
30 minutes at steady-state
Expression of relevant genes in tissues
30 minutes at steady-state
Fatty acid turnover (µmol/min)
30 minutesat steady-state
Study Arms (3)
Healthy overweight subjects
ACTIVE COMPARATORMR spectroscopy verified no steatosis
Subjects with non-alcoholic fatty liver disease
ACTIVE COMPARATORMR spectroscopy verified steatosis, no steatohepatitis on liver biopsy
Subjects with non-alcoholic steatohepatitis
ACTIVE COMPARATORMR spectroscopy verified steatosis, steatohepatitis on liver biopsy
Interventions
Infusion of low dose glucagon and high dose glucagon during simultaneous somatostatin infusion and replacement doses of insulin and growth hormone. Infusion of palmitate, VLDL-triglyceride and glucose tracers.
Eligibility Criteria
You may qualify if:
- BMI \> 28 kg/m2
- steatosis FF% \> 5,6% on MR spectroscopy for NAFLD and NASH groups
You may not qualify if:
- active smoking
- pregnancy
- comorbidity other than hypertension and hyperlipidemia
- participation in other radioactive isotope studies within the past 3-5 months (depending on radiation dose)
- blood donation (within 3 months)
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- University of Aarhuslead
- Danish Council for Independent Researchcollaborator
Study Sites (1)
Aarhus University Hospital
Aarhus, Danmark, 8200, Denmark
Related Publications (2)
Heeboll S, Wegener G, Gronbaek H, Nielsen S. Comparable glucagon-stimulated amino acid suppression in individuals with and without hepatic steatosis or steatohepatitis. Am J Physiol Endocrinol Metab. 2024 Dec 1;327(6):E679-E685. doi: 10.1152/ajpendo.00187.2024. Epub 2024 Sep 18.
PMID: 39291967DERIVEDHeeboll S, Risikesan J, Ringgaard S, Kumarathas I, Sandahl TD, Gronbaek H, Sondergaard E, Nielsen S. Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Diabetes. 2022 Nov 1;71(11):2402-2411. doi: 10.2337/db22-0313.
PMID: 36001750DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Sara Heebøll
Aarhus University Hospital
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- BASIC SCIENCE
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 23, 2019
First Posted
August 1, 2019
Study Start
October 5, 2019
Primary Completion
June 30, 2022
Study Completion
August 18, 2022
Last Updated
November 4, 2022
Record last verified: 2020-11