Development and Evaluation of a Glucagon Sensitivity Test in Individuals With and Without Hepatic Steatosis

Summary

Glucagon is secreted from pancreatic alpha-cells in response to protein-rich meals and during hypoglycemia. A physiological feedback system exists between the liver and the pancreatic alpha cells termed the liver-alpha cell axis and signifies the role between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid metabolism.

Individuals with non-alcoholic fatty liver disease have increased levels of glucagon (hyperglucagonemia) and amino acids (hyperaminoacidemia), which suggests that hepatic steatosis may uncouple glucagon's effect on amino acid metabolism (i.e. reduced glucagon sensitivity). Since hyperglucagonemia contributes to diabetes progression - due to its potentiating effects on hepatic glucose production - hepatic steatosis may create a diabetogenic circle. This study aims to develop and evaluate a test for measuring glucagon sensitivity in humans.

The investigators (Associate Prof. Nicolai J Wewer Albrechtsen and Prof. Jørgen Rungby) will investigate whether amino acid metabolism is attenuated in individuals with hepatic steatosis (assessed by magnetic resonance imaging) due to impaired hepatic glucagon sensitivity and if glucagon's effect on hepatic glucose production is intact compared to individuals without hepatic steatosis suggestive of biased signaling.

Conditions

• Non-Alcoholic Fatty Liver Disease
• Glucagon Resistance
• Type 1 Diabetes
• Obesity

Interventions

DIAGNOSTIC_TEST

Glucagon Sensitivity test consisting of an amino acid tolerance test and a bolus infusion of glucagon

The test consists of two experimental study days: Day 1: intravenous bolus-injection of glucagon (0.2 mg at time 0 minutes) evaluating the effect of exogenous glucagon on amino acid disappearance. Blood samples will be obtained from time -10 to 120 minutes. Day 2: 45-minute intravenous infusion of mixed amino acids (331 mg/min/kg body weight from time 0-45 minutes) to evaluate the effect of endogenous glucagon on amino acid metabolism. Blood samples will be obtained from time -10 to 180 minutes. All participants will be subjected to a magnetic resonance imaging scan to assess whole-liver steatosis, and a bioelectrical impedance analysis to assess body composition. Following study inclusion and the magnetic resonance imaging scan, participants will be stratified into groups based on hepatic steatosis. Individuals with \<5.6 % hepatic steatosis will be classified as controls and individuals with ≥5.6 % hepatic steatosis will be classified as MASLD.

Sponsors & Collaborators

• Bispebjerg Hospital

  collaborator OTHER

• Rigshospitalet, Denmark

  collaborator OTHER

• University of Copenhagen

  lead OTHER

Study Design

Allocation

NA

Purpose

BASIC_SCIENCE

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

25 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2021-05-27

Primary Completion

2023-10-21

Completion

2023-10-21

Countries

• Denmark

Study Locations