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

NCT ID: NCT04859322

Last Updated: 2023-05-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-08
• Study Completion Date: 2021-12-09

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Healthy Participants

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

Group Type: EXPERIMENTAL

Glucagon

Intervention Type: DRUG

Pancreatic clamp

Interventions

Glucagon

Pancreatic clamp

Intervention Type: DRUG

Other Intervention Names

Insulin; Somatostatin; 6,6 H2-glucose

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

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

UNKNOWN

Sponsor Role: collaborator

Clinical Metabolomics Core Facility, Department of Clinical, Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

UNKNOWN

Sponsor Role: collaborator

Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

UNKNOWN

Sponsor Role: collaborator

Department of Biomedical Sciences & NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

UNKNOWN

Sponsor Role: collaborator

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health, and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

UNKNOWN

Sponsor Role: collaborator

Malte Palm Suppli, MD

OTHER

Sponsor Role: lead

Responsible Party

Malte Palm Suppli, MD

MD

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Center for Clinical Metabolic Research

Hellerup, Copenhagen, Denmark

Countries

Denmark

Other Identifiers

SIRG-2

Identifier Type: -

Identifier Source: org_study_id