Abstract
Background & AimsThe incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.MethodsN = 52 patients (n = 16 NAFLD and n = 36 Non-alcoholic steatohepatitis (NASH) patients) and n = 50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.ResultsGlucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.ConclusionsGlucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) has become the most frequent chronic liver disease in Western countries
There was no difference in glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) secretion between NAFLD and Non-alcoholic steatohepatitis (NASH) subgroups
Fasting and glucoseinduced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished
Summary
Non-alcoholic fatty liver disease (NAFLD) has become the most frequent chronic liver disease in Western countries. Non-alcoholic steatohepatitis (NASH) is regarded as a subgroup of NAFLD defined by histological coexistence of hepatic steatosis and inflammation. Some authors postulate different conditions of diseases for NAFLD and NASH [1,2]. NASH, but not NAFLD, carries the risk of disease progression and complications such as cirrhosis, liver failure or hepatocellular carcinoma (HCC). NAFLD and NASH are associated with obesity, insulin resistance (IR) and type 2 diabetes mellitus (T2DM). GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients
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