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Glucagon Resistance in Patients With NAFLD

Primary Purpose

Non-Alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis, Glucose Metabolism Disorders

Status
Completed
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
glucagon
Sponsored by
University of Aarhus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Non-Alcoholic Fatty Liver Disease

Eligibility Criteria

38 Years - 68 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

  • Aarhus University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Healthy overweight subjects

Subjects with non-alcoholic fatty liver disease

Subjects with non-alcoholic steatohepatitis

Arm Description

MR spectroscopy verified no steatosis

MR spectroscopy verified steatosis, no steatohepatitis on liver biopsy

MR spectroscopy verified steatosis, steatohepatitis on liver biopsy

Outcomes

Primary Outcome Measures

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.
Endogen glucose production (mmol/kg/min)
3-3H glucose tracer technique

Secondary Outcome Measures

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

Full Information

First Posted
May 23, 2019
Last Updated
November 3, 2022
Sponsor
University of Aarhus
Collaborators
Danish Council for Independent Research
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1. Study Identification

Unique Protocol Identification Number
NCT04042142
Brief Title
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

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
October 5, 2019 (Actual)
Primary Completion Date
June 30, 2022 (Actual)
Study Completion Date
August 18, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aarhus
Collaborators
Danish Council for Independent Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis, Glucose Metabolism Disorders

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Healthy overweight subjects
Arm Type
Active Comparator
Arm Description
MR spectroscopy verified no steatosis
Arm Title
Subjects with non-alcoholic fatty liver disease
Arm Type
Active Comparator
Arm Description
MR spectroscopy verified steatosis, no steatohepatitis on liver biopsy
Arm Title
Subjects with non-alcoholic steatohepatitis
Arm Type
Active Comparator
Arm Description
MR spectroscopy verified steatosis, steatohepatitis on liver biopsy
Intervention Type
Other
Intervention Name(s)
glucagon
Intervention Description
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.
Primary Outcome Measure Information:
Title
VLDL-triglyceride kinetics (appearance rate (µmol/min) and oxidation (µmol/min))
Description
Ex vivo labeled VLDL [14C]-triolein tracer technique. Oxidation is measured by specific activity in exhaled air.
Time Frame
30 minutes at steady-state
Title
Endogen glucose production (mmol/kg/min)
Description
3-3H glucose tracer technique
Time Frame
30 minutes at steady-state
Secondary Outcome Measure Information:
Title
LPL-activity (lipoprotein lipase, µmol/h)
Description
Measured by the 'glycerol-stabilized substrate' method
Time Frame
30 minutes at steady-state
Title
VLDL-triglyceride-fatty acid uptake in muscle and fatty tissue (%)
Description
Measurement of fatty acid concentration and specific activity in muscle- and adipose tissue biopsies
Time Frame
30 minutes at steady-state
Title
Expression of relevant genes in tissues
Description
PCR in muscle- and adipose tissue biopsies
Time Frame
30 minutes at steady-state
Title
Fatty acid turnover (µmol/min)
Description
Infusion af [9,10-3H] palmitate and measurement of specific activity in muscle and adipose tissue
Time Frame
30 minutesat steady-state

10. Eligibility

Sex
All
Minimum Age & Unit of Time
38 Years
Maximum Age & Unit of Time
68 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sara Heebøll
Organizational Affiliation
Aarhus University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Aarhus University Hospital
City
Aarhus
State/Province
Danmark
ZIP/Postal Code
8200
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
36001750
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.
Results Reference
derived

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Glucagon Resistance in Patients With NAFLD

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