Glucagon Resistance in Patients With NAFLD

Non-Alcoholic Fatty Liver Disease Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04042142
• Other study ID #: 230279
• Status: Completed
• Phase: N/A
• Start date: October 5, 2019
• Est. completion date: August 18, 2022

Study information

• Verified date: November 2020
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: August 18, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 38 Years to 68 Years

Eligibility

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)

Related Conditions & MeSH terms

• Fatty Liver
• Glucose Metabolism Disorders
• Liver Diseases
• Metabolic Diseases
• Non-Alcoholic Fatty Liver Disease
• Non-alcoholic Steatohepatitis

Intervention

Other:
• glucagon
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.

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital	Aarhus	Danmark

Sponsors (2)

Lead Sponsor	Collaborator
University of Aarhus	Danish Council for Independent Research

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Endogen glucose production (mmol/kg/min)	3-3H glucose tracer technique	30 minutes at steady-state
Secondary	LPL-activity (lipoprotein lipase, µmol/h)	Measured by the 'glycerol-stabilized substrate' method	30 minutes at steady-state
Secondary	VLDL-triglyceride-fatty acid uptake in muscle and fatty tissue (%)	Measurement of fatty acid concentration and specific activity in muscle- and adipose tissue biopsies	30 minutes at steady-state
Secondary	Expression of relevant genes in tissues	PCR in muscle- and adipose tissue biopsies	30 minutes at steady-state
Secondary	Fatty acid turnover (µmol/min)	Infusion af [9,10-3H] palmitate and measurement of specific activity in muscle and adipose tissue	30 minutesat steady-state