Clinical trial NCT04042142: Glucagon Resistance in Patients With NAFLD
Official title: In-depth Studies of Glucagon Resistance on Hepatic Glucose, Fatty Acid and Triglyceride Kinetics and Generation of Toxic Lipid Intermediates in NAFLD and NASH.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Non-Alcoholic Fatty Liver Disease
Non-alcoholic Steatohepatitis
Glucose Metabolism Disorders
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Danish Council for Independent Research
First posted: 2019-08-01
Enrollment: 28
Sex: ALL
Minimum age (years): 38
Maximum age (years): 68
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

* BMI \> 28 kg/m2
* steatosis FF% \> 5,6% on MR spectroscopy for NAFLD and NASH groups

Exclusion Criteria:

* 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)

Primary outcomes:
measure: VLDL-triglyceride kinetics (appearance rate (µmol/min) and oxidation (µmol/min))
timeFrame: 30 minutes at steady-state
measure: Endogen glucose production (mmol/kg/min)
timeFrame: 30 minutes at steady-state
Secondary outcomes:
measure: LPL-activity (lipoprotein lipase, µmol/h)
timeFrame: 30 minutes at steady-state
measure: VLDL-triglyceride-fatty acid uptake in muscle and fatty tissue (%)
timeFrame: 30 minutes at steady-state
measure: Expression of relevant genes in tissues
timeFrame: 30 minutes at steady-state
measure: Fatty acid turnover (µmol/min)
timeFrame: 30 minutesat steady-state
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
state: Danmark
Study officials:
affiliation: Aarhus University Hospital
name: Sara Heebøll
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heeboll 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.