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.

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.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Non-Alcoholic Fatty Liver Disease; Non-alcoholic Steatohepatitis
• Intervention / Treatment: Other: glucagon

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Danmark
    • Aarhus, Danmark, Denmark, 8200
      • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Healthy overweight subjects; MR spectroscopy verified no steatosis	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.
Active Comparator: Subjects with non-alcoholic fatty liver disease; MR spectroscopy verified steatosis, no steatohepatitis on liver biopsy	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.
Active Comparator: Subjects with non-alcoholic steatohepatitis; MR spectroscopy verified steatosis, steatohepatitis on liver biopsy	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
LPL-activity (lipoprotein lipase, µmol/h)	Measured by the 'glycerol-stabilized substrate' method	30 minutes at steady-state
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
Expression of relevant genes in tissues	PCR in muscle- and adipose tissue biopsies	30 minutes at steady-state
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

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Danish Council for Independent Research
• Investigators: Principal Investigator: Sara Heebøll, Aarhus University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2019
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): August 18, 2022

Study Registration Dates

• First Submitted: May 23, 2019
• First Submitted That Met QC Criteria: July 31, 2019
• First Posted (Actual): August 1, 2019

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 3, 2022
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Metabolic Diseases; Glucose Metabolism Disorders; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: 230279

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No