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

NCT04907721 | Completed

• 1 other identifier: GLUSENTIC
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

Brief 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

Outcome Measures

Primary Outcomes (1)

• Differences in the calculated GLUSENTIC index between individuals with or without MASLD without diabetes

  This index is conceptually be based on the Matsuda/composite index, and will factor in fasting and amino acid-stimulated levels of glucagon and total amino acids using the following formula: 100/(SQRT(Fasting plasma amino acids levels (mean at time -10 and 0 minutes) \* Fasting plasma glucagon levels (mean at time -10 and 0 minutes) \* Amino acid-stimulated amino acid levels (mean at time 40 and 45 minutes) \* Amino acid-stimulated glucagon levels (mean at time 40 and 45 minutes)).

  Time from the first blood sample (at time -10 minutes, following an overnight fast) until the amino acid infusion stops (45 minutes)

Secondary Outcomes (23)

• Simple linear regression between hepatic steatosis (%) and the GLUSENTIC index

  Time from the first blood sample (at time -10 minutes, following an overnight fast) until the amino acid infusion stops (45 minutes)

• ROC curve analysis to evaluate cut-off value for GLUSENTIC index

  Time from the first blood sample (at time -10 minutes, following an overnight fast) until the amino acid infusion stops (45 minutes)

• Differences in the glucagon-alanine index

  The index will be measured on samples collected after an overnight fast (12 hours)

• Differences in plasma levels of amino acids during the amino acid tolerance test (determined by baseline corrected AUC)

  Time from the start of infusion (0 minutes) until time 60 minutes.

• Glucagon's ability (exogenous glucagon) to increase amino acid disappearance (determined by baseline corrected AUC or delta) for total amino acid levels and the individual amino acids.

  Time from the glucagon injection (time 0 minutes) until time 20 minutes.

Other Outcomes (7)

• Differences in FGF-21

  From time -10 to 120 minutes on the day of the glucagon bolus infusion and from time -10 to 180 minuteson the day of the amino acid infusion.

• Differences in GLP-1

  From time -10 to 120 minutes on the day of the glucagon bolus infusion and from time -10 to 180 minutes on the day of the amino acid infusion.

• Differences in GIP

  From time -10 to 120 minutes on the day of the glucagon bolus infusion and from time -10 to 180 minutes on the day of the amino acid infusion.

Study Arms (1)

Measuring glucagon sensitivity in humans

EXPERIMENTAL

Participants will be subjected to two experimental days.

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

Interventions

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

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.

Measuring glucagon sensitivity in humans

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• BMI = 18.6-25 kg/m2
• Male or female
• years of age

You may not qualify if:

• Diabetes (ADA criteria)
• Significant alcohol/drug abuse as per investigators judgement
• Amino acid-related diseases such as phenylketonuria
• Kidney disease
• Cardiac problems
• Cancer within the past 1 year
• Severe claustrophobia
• Pacemaker or other non-MR-compatible devices
• Pregnancy or breastfeeding.
• Fib4 score \> 3.25.
• Any medicine, acute illness (within the last two weeks) or other circumstances that in the opinion of the investigator might endanger the participants' safety or compliance with the protocol
• Group 2 (overweight and obese individuals)
• BMI = 25-40 kg/m2
• Male or female
• years of age

Sponsors & Collaborators

• University of Copenhagen: lead
• Bispebjerg Hospital: collaborator
• Rigshospitalet, Denmark: collaborator

Study Sites (1)

Bispebjerg University Hospital

Copenhagen, Denmark

Location

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 1; Obesity

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

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

Study Record Dates

• First Submitted: May 17, 2021
• First Posted: June 1, 2021
• Study Start: May 27, 2021
• Primary Completion: October 21, 2023
• Study Completion: October 21, 2023
• Last Updated: October 24, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)