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

  • STATUS
    Recruiting
  • days left to enroll
    55
  • participants needed
    65
  • sponsor
    University of Copenhagen
Updated on 25 May 2022
diabetes
insulin
fatty liver
glucagon
immune tolerance
hypoglycemia
c-peptide
Accepts healthy volunteers

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

Description

Amino acids administered orally or intravenously stimulate glucagon secretion from the pancreas and in turn, glucagon is a powerful stimulus for hepatic amino acid turnover through transcriptional (long-term) and non- transcriptional (acute) mechanisms. Several groups including the investigators have linked glucagon secretion to hepatic amino acid metabolism suggesting a mutual feedback cycle, termed the liver-alpha cell axis. A disruption of this axis, which has been shown both pharmacologically using glucagon receptor antagonists and genetically in glucagon receptor knockout mouse models, leads to increased glucagon (hyperglucagonemia) and amino acid (hyperaminoacidemia) concentrations. This phenotype is also evident in subjects with biopsy-verified non-alcoholic fatty liver disease (NAFLD) independent of type 2 diabetes suggesting reduced hepatic glucagon sensitivity in the presence of hepatic steatosis. Glucagon increases amino acid catabolism by potentiating ureagenesis, a pathway exclusive to the liver, and hepatic accumulation of triglycerides may reduce glucagon's ability to augment amino acid turnover. Some amino acids are more potent in stimulating glucagon secretion (glucagonotropic amino acids), including alanine, and the glucagon-alanine index is currently used as a surrogate marker for the hepatic actions of glucagon on ureagenesis. The fate of amino acid turnover depends on both glucagon and insulin dynamics by stimulating amino acid catabolism and synthesis, respectively. Studying the effects of glucagon in individuals with type 1 diabetes will allow one to differentiate between the combined effects of glucagon and insulin compared to the effects of glucagon alone.

This study aims to explore hepatic glucagon sensitivity towards amino acid metabolism in individuals with and without hepatic steatosis (based on magnetic resonance imaging (MRI)).

The investigators hypothesize that the effect of endogenous and exogenous glucagon on plasma amino acid levels are impaired in individuals with NAFLD (based on hepatic steatosis measured by MRI) compared to controls.

Details
Condition Non-Alcoholic Fatty Liver Disease, Glucagon Resistance, Type 1 Diabetes, Obesity
Treatment Glucagon Sensitivity test consisting of an amino acid tolerance test and a bolus infusion of glucagon
Clinical Study IdentifierNCT04907721
SponsorUniversity of Copenhagen
Last Modified on25 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

BMI = 18.6-40 kg/m2
Male or female
C-peptide negative
Insulin pump user

Exclusion Criteria

Type 2 diabetes
Closed loop user
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
Abdominal diameter >70 cm
Fib4 score > 3.25
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