Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Hepatic steatosis-and not type 2 diabetes, body mass index or hepatic fibrosis-associates with hyperglucagonemia in individuals with steatotic liver disease.

Increased plasma concentrations of glucagon (hyperglucagonemia) are reported in patients with type 2 diabetes (T2D) and act as a prediabetogenic risk factor. Emerging evidence suggests that hepatic steatosis in obesity is causing a condition of glucagon resistance towards amino acid catabolism, resulting in a compensatory 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 determined hepatic gene expression related to amino acid transport and catabolism. Individuals with MASLD had hyperglucagonemia (controls (n=74) versus MASLD (n=106); median [Q1, Q3]; 4 [3, 7] versus 8 [6, 13] pM), p<.0001) and were glucagon resistant (assessed by the glucagon-alanine index) (1.3 [0.9, 2.1] versus 3.3 [2.1, 5.3] pM*mM, p<.0001). These changes associated with hepatic steatosis (p<.001, R2>.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) versus MASLD+T2D (n=54); 8 [6, 11] versus 8 [6, 13] pM, p=.34) and hepatic fibrosis (MASLD+F0 (n=25) versus MASLD+F1-F3 (n=67); 8.4 [7.0, 13.3] versus 7.9 [5.2, 11.6] pM, p=.43). Obesity (BMI=30kg/m2) did not alter glucagon levels (p=.65) within groups (control/MASLD). The mRNA expression of proteins involved in amino acid transport and catabolism were downregulated in MASLD. Thus, prediabetogenic 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.