| Autor: |
Kjeldsen SAS; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark., Werge MP; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Grandt J; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Richter MM; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Thing M; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Hetland LE; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Rashu EB; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Jensen AH; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark.; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Winther-Sørensen M; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark., Kellemann JS; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark., Holst JJ; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Junker AE; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Serizawa RR; Department of Pathology, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark., Vyberg M; Department of Pathology, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark.; Department of Clinical Medicine, Center for RNA Medicine, Aalborg University, Copenhagen, Denmark., Gluud LL; Gastro Unit, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Wewer Albrechtsen NJ; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. |
| Abstrakt: |
Increased plasma concentrations of glucagon (hyperglucagonemia) are reported in patients with type 2 diabetes (T2D) and are considered a diabetogenic risk factor. Emerging evidence suggests that hepatic steatosis in obesity is causing a condition of resistance toward glucagon's effects on amino acid metabolism, resulting in an amino acid-induced hyperglucagonemia. We investigated the presence of hyperglucagonemia in individuals with biopsy-verified metabolic dysfunction-associated steatotic liver disease (MASLD), and whether body mass index (BMI), T2D, hepatic steatosis, and/or fibrosis contribute to this relationship. To dissect potential mechanisms, we also determined hepatic gene expression related to amino acid transport and catabolism. Individuals with MASLD had hyperglucagonemia {controls ( n = 74) vs. MASLD ( n = 106); median [Q1, Q3]; 4 [3, 7] vs. 8 [6, 13] pM), P < 0.0001} and were glucagon resistant (assessed by the glucagon-alanine index) {1.3 [0.9, 2.1] vs. 3.3 [2.1, 5.3] pM·mM, P < 0.0001}. These changes were associated with hepatic steatosis ( P < 0.001, R 2 > 0.25) independently of BMI, sex, age, and T2D. Plasma levels of glucagon were similar in individuals with MASLD when stratified on T2D status {MASLD-T2D ( n = 52) vs. MASLD + T2D ( n = 54); 8 [6, 11] vs. 8 [6, 13] pM, P = 0.34} and hepatic fibrosis {MASLD + F0 ( n = 25) vs. MASLD + F1-F3 ( n = 67); 8.4 [7.0, 13.3] vs. 7.9 [5.2, 11.6] pM, P = 0.43}. Obesity (BMI = 30 kg/m 2 ) did not alter glucagon levels ( P = 0.65) within groups (control/MASLD). The mRNA expression of proteins involved in amino acid transport and catabolism was downregulated in MASLD. Thus, relative hyperglucagonemia is present in individuals with biopsy-verified MASLD, and hepatic steatosis partially drives hyperglucagonemia and glucagon resistance, irrespective of T2D, BMI, and hepatic fibrosis. NEW & NOTEWORTHY Individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) present with increased plasma levels of glucagon (hyperglucagonemia), irrespective of body mass index (BMI) and type 2 diabetes. Therefore, MASLD and the resultant hyperglucagonemia may act as a diabetogenic risk factor. Notably, hepatic steatosis was a significant contributor to the hyperglucagonemia in MASLD, potentially unveiling a pathway for the hyperglucagonemia in some patients with type 2 diabetes. |
