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

NCT04859322 | Completed DMC

• 1 other identifier: SIRG-2
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Non-Alcoholic Fatty Liver Disease; Glucagon Resistance

Outcome Measures

Primary Outcomes (1)

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

  micromol/liter

  depending on the nadir between time 60 minutes and time 180 minutes

Secondary Outcomes (3)

• average slope of the curve describing the change in the total amino acid concentration during 'supraphysiological' glucagon infusion

  between time 60 minutes and time 180 minutes

• the incremental area under the curve (iAUC) for total amino acid concentrations during 'supraphysiological' glucagon infusion

  between time 60 minutes and time 180 minutes

• the percentage change in amino acid concentration during the last hour of the 'supraphysiological' glucagon infusion as assessed by baseline subtracted AUC

  between time 60 minutes and time 180 minutes

Study Arms (1)

Healthy Participants

EXPERIMENTAL

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

Drug: Glucagon

Interventions

Glucagon DRUG

Pancreatic clamp

Also known as: Insulin, Somatostatin, 6,6 H2-glucose

Healthy Participants

Eligibility Criteria

• Age: 20 Years - 65 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Malte Palm Suppli, MD: lead
• Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark: collaborator
• Rigshospitalet, Denmark: collaborator
• Department of Biomedical Sciences & NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark: collaborator
• Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health, and Medical Sciences, University of Copenhagen, Copenhagen, Denmark: collaborator

Study Sites (1)

Center for Clinical Metabolic Research

Hellerup, Copenhagen, 2900, Denmark

Location

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Glucagon; Insulin; Somatostatin

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Proglucagon; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Proinsulin; Insulins; Pituitary Hormone Release Inhibiting Hormones; Hypothalamic Hormones; Neuropeptides; Nerve Tissue Proteins; Proteins

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: April 21, 2021
• First Posted: April 26, 2021
• Study Start: February 8, 2021
• Primary Completion: December 9, 2021
• Study Completion: December 9, 2021
• Last Updated: May 11, 2023

Record last verified: 2023-05

Locations

DK (1)