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

<div><p>Background & Aims</p><p>The 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.</p><p>Methods</p><p>N = 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.</p><p>Results</p><p>Glucose 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.</p><p>Conclusions</p><p>Glucose-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.</p></div

Glucose-dependent insulinotropic polypeptide (GIP) secretion in response to oGTT.

<p><b>(A)</b> GIP secretion in response to oGTT is not different in patients vs. controls. Patients n = 52; controls n = 28. <b>(B)</b> GIP secretion in NAFLD and NASH vs. controls. NAFLD n = 16; NASH n = 36; controls n = 28. GIP (pg/ml) is expressed as mean±SEM.</p

Glucagon-like peptide 1 (GLP-1) secretion in response to oral glucose tolerance test (oGTT).

<p><b>(A)</b> GLP-1 secretion in response to oGTT is significantly decreased in patients vs. controls (p<0.001). Patients n = 52; controls n = 50. <b>(B)</b> GLP-1 secretion in NAFLD and NASH vs. controls. NAFLD n = 16; NASH n = 36; controls n = 50. GLP-1 (pmol/ml) is expressed as mean±SEM.</p

Secretion of Glucagon-like peptide-1 (GLP-1), Glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon and glucose disposal in NAFLD and NASH subgroups vs. controls in response to oral glucose tolerance test.

<p>NAFLD n = 16; NASH n = 36; controls n = 50. Data are expressed as mean±SEM. AUC, area under the curve; c_max, maximum plasma concentration. Multiple Mann-Whitney tests with Bonferroni-Holm adjustment of p-values for multiplicity of testing. P≤0.05, statistically significant difference; ns, not significant.</p

Baseline characteristics of Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) patients and controls.

<p>Data are expressed as mean±SEM. n = 52 patients (NAFLD n = 16 (30.8%), NASH n = 36 (69.2%)); n = 50 controls. Differences in baseline characteristics of patients vs. controls and NAFLD vs. NASH are expressed as p-values (Mann-Whitney U test). P≤0.05, statistically significant difference; ns, not significant.</p

Glucose, insulin and glucagon concentrations in response to oGTT.

<p>Plasma glucose <b>(A, B)</b>, insulin <b>(C, D)</b> and glucagon <b>(E, F)</b> concentration curves are shown for patients vs. controls <b>(A, C, E)</b> and NAFLD and NASH vs. controls <b>(B, D, F)</b>. Patients n = 52 (NAFLD n = 16; NASH n = 36); controls n = 50. Glucose (mmol/l), insulin (µU/ml) and glucagon (pg/ml) are expressed as mean±SEM.</p