Glucose-Induced Glucagon-Like Peptide 1 Secretion Is Deficient in Patients with Non-Alcoholic Fatty Liver Disease

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.

Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia

“…This finding is consistent with patients with type 2 diabetes having reduced beta cell sensitivity to the incretin hormones . Previous studies found blunted GLP‐1 secretion in obese patients with NAFLD compared to controls . The discrepancy may partly reflect differences in the selection of the control group and the fact that we included obese individuals as controls.…”

Impaired Secretion of Glucagon-Like Peptide 1 in Patients with Colorectal Adenoma after an Oral Glucose Load

“…However, it was observed that low GLP-1 levels were associated with a delayed glucose-lowering effect but increased and prolonged insulin secretion in patients with CRA. Similar trends have been reported in patients with non-alcoholic fatty liver disease [31], which is known to be related to insulin resistance and obesity. This observation suggests that hyperinsulinemia is caused by factors other than GLP-1 stimulation in these patients with adenoma.…”

Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model

“…3D), observations which agree well with those in a previous report (4). GLP-1 secretion is decreased in NASH patients (6) and GLP-1 reportedly attenuates NASH development (38). In addition, a GLP-1 receptor agonist reportedly suppressed SREBP1c expressions in the liver (32), and GLP-1 treatment decreased liver inflammation (40).…”