TY - JOUR
T1 - Hepatic steatosis and not type 2 diabetes, body mass index, or hepatic fibrosis associates with hyperglucagonemia in individuals with steatotic liver disease
AU - Kjeldsen, Sasha A. S.
AU - Werge, Mikkel P.
AU - Grandt, Josephine
AU - Richter, Michael M
AU - Thing, Mira
AU - Hetland, Liv E.
AU - Rashu, Elias B.
AU - Jensen, Anne-Sofie H.
AU - Winther-Sørensen, Marie
AU - Kellemann, Jesper Sloth
AU - Holst, Jens J.
AU - Junker, Anders E.
AU - Serizawa, Reza R.
AU - Vyberg, Mogens
AU - Gluud, Lise Lotte
AU - Wewer Albrechtsen, Nicolai J
PY - 2024
Y1 - 2024
N2 - 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, R2 > 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/m2) 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.
AB - 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, R2 > 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/m2) 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.
KW - Humans
KW - Diabetes Mellitus, Type 2/blood
KW - Glucagon/blood
KW - Male
KW - Body Mass Index
KW - Middle Aged
KW - Female
KW - Fatty Liver/blood
KW - Liver Cirrhosis/blood
KW - Obesity/complications
KW - Liver/metabolism
KW - Aged
KW - Adult
KW - Amino Acids/blood
U2 - 10.1152/ajpgi.00147.2024
DO - 10.1152/ajpgi.00147.2024
M3 - Journal article
C2 - 39104323
VL - 327
SP - G558-G570
JO - American Journal of Physiology: Gastrointestinal and Liver Physiology
JF - American Journal of Physiology: Gastrointestinal and Liver Physiology
SN - 0193-1857
IS - 4
ER -