Postprandial dysfunction in fatty liver disease.

Fatty liver disease has mainly been characterized under fasting conditions. However, as the liver is essential for postprandial homeostasis, identifying postprandial disturbances may be important. Here, we investigated postprandial changes in markers of metabolic dysfunction between healthy individuals, obese individuals with non-alcoholic fatty liver disease (NAFLD) and patients with cirrhosis. We included individuals with biopsy-proven NAFLD (n = 9, mean age 50 years, mean BMI 35 kg/m2 , no/mild fibrosis), cirrhosis with hepatic steatosis (n = 10, age 62 years, BMI 32 kg/m2 , CHILD A/B) and healthy controls (n = 10, age 23, BMI 25 kg/m2 ), randomized 1:1 to fasting or standardized mixed meal test (postprandial). None of the patients randomized to mixed meal test had type 2 diabetes (T2D). Peripheral blood was collected for 120 min. After 60 min, a transjugular liver biopsy and liver vein blood was taken. Plasma levels of glucose, insulin, C-peptide, glucagon, and fibroblast growth factor 21 (FGF21) were measured. Postprandial peak glucose and C-peptide were significantly increased in NAFLD, and cirrhosis compared with healthy. Patients with NAFLD and cirrhosis had hyperglucagonemia as a potential sign of glucagon resistance. FGF21 was increased in NAFLD and cirrhosis independent of sampling from the liver vein versus peripheral blood. Glucagon levels were higher in the liver vein compared with peripheral blood. Patients with NAFLD and cirrhosis without T2D showed impaired glucose tolerance, hyperinsulinemia, and hyperglucagonemia after a meal compared to healthy individual. Postprandial characterization of patients with NAFLD may be important to capture their metabolic health.

Opposing effects of chronic glucagon receptor agonism and antagonism on amino acids, hepatic gene expression, and alpha cells.

The pancreatic hormone, glucagon, is known to regulate hepatic glucose production, but recent studies suggest that its regulation of hepatic amino metabolism is equally important. Here, we show that chronic glucagon receptor activation with a long-acting glucagon analog increases amino acid catabolism and ureagenesis and causes alpha cell hypoplasia in female mice. Conversely, chronic glucagon receptor inhibition with a glucagon receptor antibody decreases amino acid catabolism and ureagenesis and causes alpha cell hyperplasia and beta cell loss. These effects were associated with the transcriptional regulation of hepatic genes related to amino acid uptake and catabolism and by the non-transcriptional modulation of the rate-limiting ureagenesis enzyme, carbamoyl phosphate synthetase-1. Our results support the importance of glucagon receptor signaling for amino acid homeostasis and pancreatic islet integrity in mice and provide knowledge regarding the long-term consequences of chronic glucagon receptor agonism and antagonism.

Glucagon receptor antagonism impairs and glucagon receptor agonism enhances triglycerides metabolism in mice.

OBJECTIVE: Treatment with glucagon receptor antagonists (GRAs) reduces blood glucose but causes dyslipidemia and accumulation of fat in the liver. We investigated the acute and chronic effects of glucagon on lipid metabolism in mice. METHODS: Chronic effects of glucagon receptor signaling on lipid metabolism were studied using oral lipid tolerance tests (OLTTs) in overnight fasted glucagon receptor knockout (Gcgr-/-) mice, and in C57Bl/6JRj mice treated with a glucagon receptor antibody (GCGR Ab) or a long-acting glucagon analogue (GCGA) for eight weeks. Following treatment, liver tissue was harvested for RNA-sequencing and triglyceride measurements. Acute effects were studied in C57Bl/6JRj mice treated with a GRA or GCGA 1 h or immediately before OLTTs, respectively. Direct effects of glucagon on hepatic lipolysis were studied using isolated perfused mouse liver preparations. To investigate potential effects of GCGA and GRA on gastric emptying, paracetamol was, in separate experiments, administered immediately before OLTTs. RESULTS: Plasma triglyceride concentrations increased 2-fold in Gcgr-/- mice compared to their wild-type littermates during the OLTT (P = 0.001). Chronic treatment with GCGR Ab increased, whereas GCGA treatment decreased, plasma triglyceride concentrations during OLTTs (P < 0.05). Genes involved in lipid metabolism were upregulated upon GCGR Ab treatment while GCGA treatment had opposite effects. Acute GRA and GCGA treatment, respectively, increased (P = 0.02) and decreased (P = 0.003) plasma triglyceride concentrations during OLTTs. Glucagon stimulated hepatic lipolysis, evident by an increase in free fatty acid concentrations in the effluent from perfused mouse livers. In line with this, GCGR Ab treatment increased, while GCGA treatment decreased, liver triglyceride concentrations. The effects of glucagon appeared independent of changes in gastric emptying of paracetamol. CONCLUSIONS: Glucagon receptor signaling regulates triglyceride metabolism, both chronically and acutely, in mice. These data expand glucagon´s biological role and implicate that intact glucagon signaling is important for lipid metabolism. Glucagon agonism may have beneficial effects on hepatic and peripheral triglyceride metabolism.