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Completed

NCT Number: NCT04859322

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

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.

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Key information

Conditions

Non-Alcoholic Fatty Liver Disease Digestive System Diseases Fatty Liver Glucagon Resistance Liver Diseases

Age range

20 year–65 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Center for Clinical Metabolic Research

Hellerup, Copenhagen, 2900, Denmark

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

glucagon

Drug

Pancreatic clamp

Other names: Insulin, Somatostatin, 6,6 H2-glucose

Primary outcomes

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

    Time frame: depending on the nadir between time 60 minutes and time 180 minutes

    micromol/liter

Secondary outcomes

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

    Time frame: between time 60 minutes and time 180 minutes

    micromol/liter/minute

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

    Time frame: between time 60 minutes and time 180 minutes

    micromol/liter

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

    Time frame: between time 60 minutes and time 180 minutes

    micromol/liter

Sponsors and collaborators

Lead sponsor

Malte Palm Suppli, MD

Other

Collaborators

  • 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
  • Rigshospitalet, Denmark
  • Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark

Registry information

Important dates

Study start
2021
Primary completion
2021
Study completion
2021
First posted
Apr 26, 2021
Registry last updated
May 11, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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