oxyntomodulin and Liver-Diseases

Topics: Biomarkers; Diabetes Mellitus; Diagnostic Techniques, Endocrine; Dumping Syndrome; Glucagon; Glucagon-Like Peptides; Glucagonoma; Humans; Liver Diseases; Pancreatic Diseases; Pancreatic Neoplasms; Radioimmunoassay; Reference Values; Specimen Handling

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Liver Diseases; Peptide Fragments; Receptor, Insulin

Semaglutide is a human glucagon-like peptide-1 analog that has been co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child-Pugh criteria, and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post-last dose. Area under the semaglutide plasma concentration-time curve from 0-24 hours after the 10th dose (primary end point) and maximum semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum semaglutide concentration (median range 1.0-1.5 hours) or half-life (geometric mean range 142-156 hours). No safety concerns were identified in subjects with hepatic impairment receiving semaglutide. Reported adverse events were in line with those observed for other glucagon-like peptide-1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral semaglutide. The results of this trial suggest that dose adjustment of oral semaglutide is not warranted in subjects with hepatic impairment.

Topics: Administration, Oral; Adult; Area Under Curve; Blood Glucose; Female; Glucagon-Like Peptides; Half-Life; Humans; Hypoglycemic Agents; Liver Diseases; Male; Middle Aged

Total parenteral nutrition (TPN) is essential for patients with impaired gut function but leads to parenteral nutrition-associated liver disease (PNALD). TPN disrupts the normal enterohepatic circulation of bile acids, and we hypothesized that it would decrease intestinal expression of the newly described metabolic hormone fibroblast growth factor-19 (FGF19) and also glucagon-like peptides-1 and -2 (GLP-1 and GLP-2). We tested the effects of restoring bile acids by treating a neonatal piglet PNALD model with chenodeoxycholic acid (CDCA). Neonatal pigs received enteral feeding (EN), TPN, or TPN + CDCA for 14 days, and responses were assessed by serum markers, histology, and levels of key regulatory peptides. Cholestasis and steatosis were demonstrated in the TPN group relative to EN controls by elevated levels of serum total and direct bilirubin and also bile acids and liver triglyceride (TG) content. CDCA treatment improved direct bilirubin levels by almost fourfold compared with the TPN group and also normalized serum bile acids and liver TG. FGF19, GLP-1, and GLP-2 were decreased in plasma of the TPN group compared with the EN group but were all induced by CDCA treatment. Intestinal mucosal growth marked by weight and villus/crypt ratio was significantly reduced in the TPN group compared with the EN group, and CDCA treatment increased both parameters. These results suggest that decreased circulating FGF19 during TPN may contribute to PNALD. Moreover, we show that enteral CDCA not only resolves PNALD but acts as a potent intestinal trophic agent and secretagogue for GLP-2.

Topics: Animals; Animals, Newborn; Atrophy; Chenodeoxycholic Acid; Cholestasis; Disease Models, Animal; Fibroblast Growth Factors; Glucagon-Like Peptides; Intestinal Mucosa; Liver Diseases; Parenteral Nutrition, Total; Swine; Treatment Outcome

Topics: Animals; Diabetes Mellitus, Type 2; Gastroenterology; Gastrointestinal Diseases; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; History, 20th Century; History, 21st Century; Humans; Liver Diseases; Pancreatic Diseases; Peptide Fragments; Peptides; Protein Precursors

Topics: Acute Disease; Animals; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptides; Liver Diseases; Pancreatic Polypeptide; Swine; Vasoactive Intestinal Peptide