Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index

Sasha A S Kjeldsen; Michael M Richter; Nicole J Jensen; Malin S D Nilsson; Niklas Heinz; Janus D Nybing; Frederik H Linden; Erik Høgh-Schmidt; Mikael P Boesen; Thomas L Andersen; Helle H Johannesen; Samuel A J Trammell; Trisha J Grevengoed; Sten Madsbad; Hendrik Vilstrup; Frank Vinholt Schiødt; Andreas Møller; Elias B Rashu; Kirsten Nørgaard; Signe Schmidt; Lise L Gluud; Steen B Haugaard; Jens J Holst; Jørgen Rungby; Nicolai J Wewer Albrechtsen

doi:10.2337/db23-0858

Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index

Sasha A S Kjeldsen, Michael M Richter, Nicole J Jensen, Malin S D Nilsson, Niklas Heinz, Janus D Nybing, Frederik H Linden, Erik Høgh-Schmidt, Mikael P Boesen, Thomas L Andersen, Helle H Johannesen, Samuel A J Trammell, Trisha J Grevengoed, Sten Madsbad, Hendrik Vilstrup, Frank Vinholt Schiødt, Andreas Møller, Elias B Rashu, Kirsten Nørgaard, Signe SchmidtLise L Gluud, Steen B Haugaard, Jens J Holst, Jørgen Rungby, Nicolai J Wewer Albrechtsen^*

^*Corresponding author for this work

3 Citations (Scopus)

Abstract

Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, which consists of 2 study days: a glucagon injection and measurements of plasma amino acids and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The δ-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (P = 0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (P < 0.0001) but not T1D (P > 0.99). In contrast, glucagon-induced glucose increments were similar in control participants and participants with MASLD (P = 0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.

Original language	English
Journal	Diabetes
Volume	73
Issue number	10
Pages (from-to)	1716-1727
Number of pages	12
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db23-0858
Publication status	Published - 1 Oct 2024

Keywords

Adult
Amino Acids/blood
Blood Glucose/metabolism
Diabetes Mellitus, Type 1/metabolism
Fatty Liver/metabolism
Female
Glucagon/blood
Humans
Male
Middle Aged
Obesity/metabolism

Access to Document

10.2337/db23-0858

Cite this

Kjeldsen, S. A. S., Richter, M. M., Jensen, N. J., Nilsson, M. S. D., Heinz, N., Nybing, J. D., Linden, F. H., Høgh-Schmidt, E., Boesen, M. P., Andersen, T. L., Johannesen, H. H., Trammell, S. A. J., Grevengoed, T. J., Madsbad, S., Vilstrup, H., Vinholt Schiødt, F., Møller, A., Rashu, E. B., Nørgaard, K., ... Wewer Albrechtsen, N. J. (2024). Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index. Diabetes, 73(10), 1716-1727. https://doi.org/10.2337/db23-0858

Kjeldsen, SAS , Richter, MM , Jensen, NJ , Nilsson, MSD, Heinz, N, Nybing, JD , Linden, FH , Høgh-Schmidt, E , Boesen, MP , Andersen, TL , Johannesen, HH, Trammell, SAJ, Grevengoed, TJ, Madsbad, S, Vilstrup, H, Vinholt Schiødt, F, Møller, A, Rashu, EB , Nørgaard, K , Schmidt, S , Gluud, LL , Haugaard, SB, Holst, JJ, Rungby, J & Wewer Albrechtsen, NJ 2024, 'Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index', Diabetes, vol. 73, no. 10, pp. 1716-1727. https://doi.org/10.2337/db23-0858

@article{3e7190a9cc534302859de2be3647189e,

title = "Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index",

abstract = "Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, which consists of 2 study days: a glucagon injection and measurements of plasma amino acids and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The δ-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (P = 0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (P < 0.0001) but not T1D (P > 0.99). In contrast, glucagon-induced glucose increments were similar in control participants and participants with MASLD (P = 0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.",

keywords = "Adult, Amino Acids/blood, Blood Glucose/metabolism, Diabetes Mellitus, Type 1/metabolism, Fatty Liver/metabolism, Female, Glucagon/blood, Humans, Male, Middle Aged, Obesity/metabolism",

author = "Kjeldsen, {Sasha A S} and Richter, {Michael M} and Jensen, {Nicole J} and Nilsson, {Malin S D} and Niklas Heinz and Nybing, {Janus D} and Linden, {Frederik H} and Erik H{\o}gh-Schmidt and Boesen, {Mikael P} and Andersen, {Thomas L} and Johannesen, {Helle H} and Trammell, {Samuel A J} and Grevengoed, {Trisha J} and Sten Madsbad and Hendrik Vilstrup and {Vinholt Schi{\o}dt}, Frank and Andreas M{\o}ller and Rashu, {Elias B} and Kirsten N{\o}rgaard and Signe Schmidt and Gluud, {Lise L} and Haugaard, {Steen B} and Holst, {Jens J} and J{\o}rgen Rungby and {Wewer Albrechtsen}, {Nicolai J}",

note = "{\textcopyright} 2024 by the American Diabetes Association.",

year = "2024",

month = oct,

day = "1",

doi = "10.2337/db23-0858",

language = "English",

volume = "73",

pages = "1716--1727",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "10",

}

TY - JOUR

T1 - Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index

AU - Kjeldsen, Sasha A S

AU - Richter, Michael M

AU - Jensen, Nicole J

AU - Nilsson, Malin S D

AU - Heinz, Niklas

AU - Nybing, Janus D

AU - Linden, Frederik H

AU - Høgh-Schmidt, Erik

AU - Boesen, Mikael P

AU - Andersen, Thomas L

AU - Johannesen, Helle H

AU - Trammell, Samuel A J

AU - Grevengoed, Trisha J

AU - Madsbad, Sten

AU - Vilstrup, Hendrik

AU - Vinholt Schiødt, Frank

AU - Møller, Andreas

AU - Rashu, Elias B

AU - Nørgaard, Kirsten

AU - Schmidt, Signe

AU - Gluud, Lise L

AU - Haugaard, Steen B

AU - Holst, Jens J

AU - Rungby, Jørgen

AU - Wewer Albrechtsen, Nicolai J

PY - 2024/10/1

Y1 - 2024/10/1

N2 - Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, which consists of 2 study days: a glucagon injection and measurements of plasma amino acids and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The δ-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (P = 0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (P < 0.0001) but not T1D (P > 0.99). In contrast, glucagon-induced glucose increments were similar in control participants and participants with MASLD (P = 0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.

AB - Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, which consists of 2 study days: a glucagon injection and measurements of plasma amino acids and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The δ-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (P = 0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (P < 0.0001) but not T1D (P > 0.99). In contrast, glucagon-induced glucose increments were similar in control participants and participants with MASLD (P = 0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.

KW - Adult

KW - Amino Acids/blood

KW - Blood Glucose/metabolism

KW - Diabetes Mellitus, Type 1/metabolism

KW - Fatty Liver/metabolism

KW - Female

KW - Glucagon/blood

KW - Humans

KW - Male

KW - Middle Aged

KW - Obesity/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85204745648&partnerID=8YFLogxK

U2 - 10.2337/db23-0858

DO - 10.2337/db23-0858

M3 - Journal article

C2 - 38976454

SN - 0012-1797

VL - 73

SP - 1716

EP - 1727

JO - Diabetes

JF - Diabetes

IS - 10

ER -

Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this