Glucagon Resistance in Patients With NAFLD

Not Applicable

Completed

• Conditions: Non-alcoholic Steatohepatitis; Glucose Metabolism Disorders; Non-Alcoholic Fatty Liver Disease
• Interventions: Other: glucagon

• Registration Number: NCT04042142
• Lead Sponsor: University of Aarhus

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2019-05-23
• Study First Submitted QC: 2019-07-31
• Study First Posted: 2019-08-01
• Study Start: 2019-10-05
• Status Verified: 2020-11
• Primary Completion: 2022-06-30
• Study Completion: 2022-08-18
• Last Update Submitted: 2022-11-03
• Last Update Posted: 2022-11-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Healthy overweight subjects	glucagon	MR spectroscopy verified no steatosis
Subjects with non-alcoholic fatty liver disease	glucagon	MR spectroscopy verified steatosis, no steatohepatitis on liver biopsy
Subjects with non-alcoholic steatohepatitis	glucagon	MR spectroscopy verified steatosis, steatohepatitis on liver biopsy

Primary Outcome Measures

Name	Time	Method
Endogen glucose production (mmol/kg/min)	30 minutes at steady-state	3-3H glucose tracer technique
VLDL-triglyceride kinetics (appearance rate (µmol/min) and oxidation (µmol/min))	30 minutes at steady-state	Ex vivo labeled VLDL \[14C\]-triolein tracer technique. Oxidation is measured by specific activity in exhaled air.

Secondary Outcome Measures

Name	Time	Method
LPL-activity (lipoprotein lipase, µmol/h)	30 minutes at steady-state	Measured by the 'glycerol-stabilized substrate' method
VLDL-triglyceride-fatty acid uptake in muscle and fatty tissue (%)	30 minutes at steady-state	Measurement of fatty acid concentration and specific activity in muscle- and adipose tissue biopsies
Expression of relevant genes in tissues	30 minutes at steady-state	PCR in muscle- and adipose tissue biopsies
Fatty acid turnover (µmol/min)	30 minutesat steady-state	Infusion af \[9,10-3H\] palmitate and measurement of specific activity in muscle and adipose tissue

Trial Locations

Locations (1)

Aarhus University Hospital; 🇩🇰 Aarhus, Danmark, Denmark