Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study

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Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling : a UK Biobank study. / Winther-Sørensen, Marie; Garcia, Sara L; Bartholdy, Andreas; Ottenheijm, Maud E; Banasik, Karina; Brunak, Søren; Sørensen, Charlotte M; Gluud, Lise Lotte; Knop, Filip K; Holst, Jens J; Rosenkilde, Mette M; Jensen, Majken K; Wewer Albrechtsen, Nicolai J.

In: Diabetologia, 06.05.2024.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Winther-Sørensen, M, Garcia, SL, Bartholdy, A, Ottenheijm, ME, Banasik, K, Brunak, S, Sørensen, CM, Gluud, LL, Knop, FK, Holst, JJ, Rosenkilde, MM, Jensen, MK & Wewer Albrechtsen, NJ 2024, 'Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study', Diabetologia. https://doi.org/10.1007/s00125-024-06160-1

APA

Winther-Sørensen, M., Garcia, S. L., Bartholdy, A., Ottenheijm, M. E., Banasik, K., Brunak, S., Sørensen, C. M., Gluud, L. L., Knop, F. K., Holst, J. J., Rosenkilde, M. M., Jensen, M. K., & Wewer Albrechtsen, N. J. (2024). Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study. Diabetologia. https://doi.org/10.1007/s00125-024-06160-1

Vancouver

Winther-Sørensen M, Garcia SL, Bartholdy A, Ottenheijm ME, Banasik K, Brunak S et al. Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study. Diabetologia. 2024 May 6. https://doi.org/10.1007/s00125-024-06160-1

Author

Winther-Sørensen, Marie ; Garcia, Sara L ; Bartholdy, Andreas ; Ottenheijm, Maud E ; Banasik, Karina ; Brunak, Søren ; Sørensen, Charlotte M ; Gluud, Lise Lotte ; Knop, Filip K ; Holst, Jens J ; Rosenkilde, Mette M ; Jensen, Majken K ; Wewer Albrechtsen, Nicolai J. / Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling : a UK Biobank study. In: Diabetologia. 2024.

Bibtex

@article{6978bddfb31940e4bb6afd98c6f1b00d,
title = "Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study",
abstract = "AIMS/HYPOTHESES: Glucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, and dual agonists of their receptors are currently being explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals with type 2 diabetes but are also observed in individuals with obesity and MASLD. GLP-1 levels have been reported to be largely unaffected or even reduced in similar conditions. We investigated potential determinants of plasma proglucagon and associations of glucagon receptor signalling with metabolic diseases based on data from the UK Biobank.METHODS: We used exome sequencing data from the UK Biobank for ~410,000 white participants to identify glucagon receptor variants and grouped them based on their known or predicted signalling. Data on plasma levels of proglucagon estimated using Olink technology were available for a subset of the cohort (~40,000). We determined associations of glucagon receptor variants and proglucagon with BMI, type 2 diabetes and liver fat (quantified by liver MRI) and performed survival analyses to investigate if elevated proglucagon predicts type 2 diabetes development.RESULTS: Obesity, MASLD and type 2 diabetes were associated with elevated plasma levels of proglucagon independently of each other. Baseline proglucagon levels were associated with the risk of type 2 diabetes development over a 14 year follow-up period (HR 1.13; 95% CI 1.09, 1.17; n=1562; p=1.3×10 -12). This association was of the same magnitude across strata of BMI. Carriers of glucagon receptor variants with reduced cAMP signalling had elevated levels of proglucagon (β 0.847; 95% CI 0.04, 1.66; n=17; p=0.04), and carriers of variants with a predicted frameshift mutation had higher levels of liver fat compared with the wild-type reference group (β 0.504; 95% CI 0.03, 0.98; n=11; p=0.04). CONCLUSIONS/INTERPRETATION: Our findings support the suggestion that glucagon receptor signalling is involved in MASLD, that plasma levels of proglucagon are linked to the risk of type 2 diabetes development, and that proglucagon levels are influenced by genetic variation in the glucagon receptor, obesity, type 2 diabetes and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits.DATA AVAILABILITY: All coding is available through https://github.com/nicwin98/UK-Biobank-GCG.",
author = "Marie Winther-S{\o}rensen and Garcia, {Sara L} and Andreas Bartholdy and Ottenheijm, {Maud E} and Karina Banasik and S{\o}ren Brunak and S{\o}rensen, {Charlotte M} and Gluud, {Lise Lotte} and Knop, {Filip K} and Holst, {Jens J} and Rosenkilde, {Mette M} and Jensen, {Majken K} and {Wewer Albrechtsen}, {Nicolai J}",
note = "{\textcopyright} 2024. The Author(s).",
year = "2024",
month = may,
day = "6",
doi = "10.1007/s00125-024-06160-1",
language = "English",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer",

}

RIS

TY - JOUR

T1 - Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling

T2 - a UK Biobank study

AU - Winther-Sørensen, Marie

AU - Garcia, Sara L

AU - Bartholdy, Andreas

AU - Ottenheijm, Maud E

AU - Banasik, Karina

AU - Brunak, Søren

AU - Sørensen, Charlotte M

AU - Gluud, Lise Lotte

AU - Knop, Filip K

AU - Holst, Jens J

AU - Rosenkilde, Mette M

AU - Jensen, Majken K

AU - Wewer Albrechtsen, Nicolai J

N1 - © 2024. The Author(s).

PY - 2024/5/6

Y1 - 2024/5/6

N2 - AIMS/HYPOTHESES: Glucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, and dual agonists of their receptors are currently being explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals with type 2 diabetes but are also observed in individuals with obesity and MASLD. GLP-1 levels have been reported to be largely unaffected or even reduced in similar conditions. We investigated potential determinants of plasma proglucagon and associations of glucagon receptor signalling with metabolic diseases based on data from the UK Biobank.METHODS: We used exome sequencing data from the UK Biobank for ~410,000 white participants to identify glucagon receptor variants and grouped them based on their known or predicted signalling. Data on plasma levels of proglucagon estimated using Olink technology were available for a subset of the cohort (~40,000). We determined associations of glucagon receptor variants and proglucagon with BMI, type 2 diabetes and liver fat (quantified by liver MRI) and performed survival analyses to investigate if elevated proglucagon predicts type 2 diabetes development.RESULTS: Obesity, MASLD and type 2 diabetes were associated with elevated plasma levels of proglucagon independently of each other. Baseline proglucagon levels were associated with the risk of type 2 diabetes development over a 14 year follow-up period (HR 1.13; 95% CI 1.09, 1.17; n=1562; p=1.3×10 -12). This association was of the same magnitude across strata of BMI. Carriers of glucagon receptor variants with reduced cAMP signalling had elevated levels of proglucagon (β 0.847; 95% CI 0.04, 1.66; n=17; p=0.04), and carriers of variants with a predicted frameshift mutation had higher levels of liver fat compared with the wild-type reference group (β 0.504; 95% CI 0.03, 0.98; n=11; p=0.04). CONCLUSIONS/INTERPRETATION: Our findings support the suggestion that glucagon receptor signalling is involved in MASLD, that plasma levels of proglucagon are linked to the risk of type 2 diabetes development, and that proglucagon levels are influenced by genetic variation in the glucagon receptor, obesity, type 2 diabetes and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits.DATA AVAILABILITY: All coding is available through https://github.com/nicwin98/UK-Biobank-GCG.

AB - AIMS/HYPOTHESES: Glucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, and dual agonists of their receptors are currently being explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals with type 2 diabetes but are also observed in individuals with obesity and MASLD. GLP-1 levels have been reported to be largely unaffected or even reduced in similar conditions. We investigated potential determinants of plasma proglucagon and associations of glucagon receptor signalling with metabolic diseases based on data from the UK Biobank.METHODS: We used exome sequencing data from the UK Biobank for ~410,000 white participants to identify glucagon receptor variants and grouped them based on their known or predicted signalling. Data on plasma levels of proglucagon estimated using Olink technology were available for a subset of the cohort (~40,000). We determined associations of glucagon receptor variants and proglucagon with BMI, type 2 diabetes and liver fat (quantified by liver MRI) and performed survival analyses to investigate if elevated proglucagon predicts type 2 diabetes development.RESULTS: Obesity, MASLD and type 2 diabetes were associated with elevated plasma levels of proglucagon independently of each other. Baseline proglucagon levels were associated with the risk of type 2 diabetes development over a 14 year follow-up period (HR 1.13; 95% CI 1.09, 1.17; n=1562; p=1.3×10 -12). This association was of the same magnitude across strata of BMI. Carriers of glucagon receptor variants with reduced cAMP signalling had elevated levels of proglucagon (β 0.847; 95% CI 0.04, 1.66; n=17; p=0.04), and carriers of variants with a predicted frameshift mutation had higher levels of liver fat compared with the wild-type reference group (β 0.504; 95% CI 0.03, 0.98; n=11; p=0.04). CONCLUSIONS/INTERPRETATION: Our findings support the suggestion that glucagon receptor signalling is involved in MASLD, that plasma levels of proglucagon are linked to the risk of type 2 diabetes development, and that proglucagon levels are influenced by genetic variation in the glucagon receptor, obesity, type 2 diabetes and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits.DATA AVAILABILITY: All coding is available through https://github.com/nicwin98/UK-Biobank-GCG.

U2 - 10.1007/s00125-024-06160-1

DO - 10.1007/s00125-024-06160-1

M3 - Journal article

C2 - 38705923

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

ER -

ID: 391205109