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The Effect of Lifestyle-induced Hepatic Steatosis on Glucagon-stimulated Amino Acid Turnover

Primary Purpose

Non-Alcoholic Fatty Liver Disease, Glucagon Resistance

Status
Completed
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
Glucagon
Sponsored by
Malte Palm Suppli, MD
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

20 Years - 65 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Normal fasting plasma glucose and glycated haemoglobin (HbA1c) <42 mmol/mol
  • Body mass index (BMI) between 18.5 and 25 kg/m2
  • Haemoglobin >8.3 mmol/l
  • Habitual diet in accordance with the Nordic Nutrition Recommendations
  • Age between 20 and 65 years
  • Oral and written informed consent

Exclusion Criteria:

  • Diabetes
  • First-degree relatives with diabetes
  • Fasting plasma triacylglycerol indicating dyslipidemia (≥2 mmol/l)
  • Nephropathy (estimated glomerular filtration rate (eGFR) <60 ml/min and/or microalbuminuria with an albumin to creatinine ratio of 30-300 μg/mg)
  • Known liver disease and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 × normal values
  • Signs of liver fibrosis and/or steatosis evaluated by FibroScan (CAP value >2380 dB/m and/or kPa >65.0) and/or FIB-4 score (>1.45)
  • >5% steatosis evaluated by MRI carried out before experimental Day A (see Methods)
  • Use of medication
  • Use of dietary protein supplementation or any other dietary supplements that cannot be paused during participation
  • Excessive training habits, defined as >2 weekly strength and/or aerobic training sessions
  • Pregnancy and/or breastfeeding
  • Implanted metal objects incompatible with magnetic resonance imaging (MRI)
  • Any condition that the investigator feels would interfere with trial completion

Sites / Locations

  • Center for Clinical Metabolic Research

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Healthy Participants

Arm Description

20 healthy participants included in the arm for 3 experimental days each. On each experimental day infusions of stable isotope glucose (0,6 micromol/kg/min), glucagon (1 hour low; 0,6 ng/kg/min, 2 hours high; 4,0 ng/kg/min), somatostatin (450 micrograms/hour) and insulin (0,1 mU/kg/min) will be administered. Between the first two experimental days the participants will follow a sedentary lifestyle combined with a high-calorie diet intervention

Outcomes

Primary Outcome Measures

Nadir of the total amino acid concentration during a two-hour high physiological glucagon infusion during a pancreatic clamp with somatostatin
micromol/liter

Secondary Outcome Measures

average slope of the curve describing the change in the total amino acid concentration during 'supraphysiological' glucagon infusion
micromol/liter/minute
the incremental area under the curve (iAUC) for total amino acid concentrations during 'supraphysiological' glucagon infusion
micromol/liter
the percentage change in amino acid concentration during the last hour of the 'supraphysiological' glucagon infusion as assessed by baseline subtracted AUC
micromol/liter

Full Information

First Posted
April 21, 2021
Last Updated
May 10, 2023
Sponsor
Malte Palm Suppli, MD
Collaborators
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark, Clinical Metabolomics Core Facility, Department of Clinical, Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, Department of Biomedical Sciences & NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health, and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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1. Study Identification

Unique Protocol Identification Number
NCT04859322
Brief Title
The Effect of Lifestyle-induced Hepatic Steatosis on Glucagon-stimulated Amino Acid Turnover
Official Title
The Effect of Lifestyle-induced Hepatic Steatosis on Glucagon-stimulated Amino Acid Turnover
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
February 8, 2021 (Actual)
Primary Completion Date
December 9, 2021 (Actual)
Study Completion Date
December 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Malte Palm Suppli, MD
Collaborators
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark, Clinical Metabolomics Core Facility, Department of Clinical, Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, Department of Biomedical Sciences & NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health, and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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
Many patients with type 2 diabetes exhibit elevated plasma concentrations of the glucose-mobilising pancreatic hormone glucagon; i.e. hyperglucagonaemia. This contributes to the hyperglycaemic state of the patients and is considered an important component in the pathophysiology of type 2 diabetes; but the mechanisms underlying this phenomenon remain unclear. The liver constitutes the main target organ of glucagon, and studies have shown that hyperglucagonaemia goes hand in hand with hyperaminoacidaemia and that both are associated with non-alcoholic fatty liver disease (NAFLD), independently of the presence of type 2 diabetes. In line with this, several recent studies support the existence of a feedback-cycle between the liver and the pancreatic alpha cells, governed by circulating glucagon and amino acids. The investigators hypothesise that the presence of hepatic steatosis results in hepatic glucagon resistance at the level of amino acid turnover, i.e. impaired glucagon-induced suppression of circulating amino acid concentrations. If this hypothesis proves correct, it would establish build-up of fat in the liver as a core mechanism underlying hyperglucagonaemia and, since the hyperglucagonemia is at least partly responsible for the fasting hyperglycaemia, as an important contributor to the hyperglycaemia of type 2 diabetes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Alcoholic Fatty Liver Disease, Glucagon Resistance

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Healthy Participants
Arm Type
Experimental
Arm Description
20 healthy participants included in the arm for 3 experimental days each. On each experimental day infusions of stable isotope glucose (0,6 micromol/kg/min), glucagon (1 hour low; 0,6 ng/kg/min, 2 hours high; 4,0 ng/kg/min), somatostatin (450 micrograms/hour) and insulin (0,1 mU/kg/min) will be administered. Between the first two experimental days the participants will follow a sedentary lifestyle combined with a high-calorie diet intervention
Intervention Type
Drug
Intervention Name(s)
Glucagon
Other Intervention Name(s)
Insulin, Somatostatin, 6,6 H2-glucose
Intervention Description
Pancreatic clamp
Primary Outcome Measure Information:
Title
Nadir of the total amino acid concentration during a two-hour high physiological glucagon infusion during a pancreatic clamp with somatostatin
Description
micromol/liter
Time Frame
depending on the nadir between time 60 minutes and time 180 minutes
Secondary Outcome Measure Information:
Title
average slope of the curve describing the change in the total amino acid concentration during 'supraphysiological' glucagon infusion
Description
micromol/liter/minute
Time Frame
between time 60 minutes and time 180 minutes
Title
the incremental area under the curve (iAUC) for total amino acid concentrations during 'supraphysiological' glucagon infusion
Description
micromol/liter
Time Frame
between time 60 minutes and time 180 minutes
Title
the percentage change in amino acid concentration during the last hour of the 'supraphysiological' glucagon infusion as assessed by baseline subtracted AUC
Description
micromol/liter
Time Frame
between time 60 minutes and time 180 minutes

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Normal fasting plasma glucose and glycated haemoglobin (HbA1c) <42 mmol/mol Body mass index (BMI) between 18.5 and 25 kg/m2 Haemoglobin >8.3 mmol/l Habitual diet in accordance with the Nordic Nutrition Recommendations Age between 20 and 65 years Oral and written informed consent Exclusion Criteria: Diabetes First-degree relatives with diabetes Fasting plasma triacylglycerol indicating dyslipidemia (≥2 mmol/l) Nephropathy (estimated glomerular filtration rate (eGFR) <60 ml/min and/or microalbuminuria with an albumin to creatinine ratio of 30-300 μg/mg) Known liver disease and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 × normal values Signs of liver fibrosis and/or steatosis evaluated by FibroScan (CAP value >2380 dB/m and/or kPa >65.0) and/or FIB-4 score (>1.45) >5% steatosis evaluated by MRI carried out before experimental Day A (see Methods) Use of medication Use of dietary protein supplementation or any other dietary supplements that cannot be paused during participation Excessive training habits, defined as >2 weekly strength and/or aerobic training sessions Pregnancy and/or breastfeeding Implanted metal objects incompatible with magnetic resonance imaging (MRI) Any condition that the investigator feels would interfere with trial completion
Facility Information:
Facility Name
Center for Clinical Metabolic Research
City
Hellerup
State/Province
Copenhagen
ZIP/Postal Code
2900
Country
Denmark

12. IPD Sharing Statement

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The Effect of Lifestyle-induced Hepatic Steatosis on Glucagon-stimulated Amino Acid Turnover

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