Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas

Diabetologia. 2010 Jan;53(1):153-9. doi: 10.1007/s00125-009-1515-4. Epub 2009 Sep 13.

Abstract

Aims/hypothesis: Exendin-4 is a 39 amino acid agonist of the glucagon-like peptide receptor and has been approved for treatment of type 2 diabetes. Many reports describe an increased incidence of acute pancreatitis in humans treated with exendin-4 (exenatide). Previous studies have evaluated the effect of exendin-4 on beta cells and beta cell function. We evaluated the histological and biochemical effects of exendin-4 on the pancreas in rats.

Methods: We studied 20 Sprague-Dawley male rats, ten of which were treated with exendin-4 and ten of which were used as controls. The study period was 75 days. Serum and pancreatic tissue were removed for biochemical and histological study. Blood glucose, amylase, lipase, insulin and adipocytokines were compared between the two groups.

Results: Animals treated with exendin-4 had more pancreatic acinar inflammation, more pyknotic nuclei and weighed significantly less than control rats. They also had higher serum lipase than control animals. Exendin-4 treatment was associated with lower insulin and leptin levels as well as lower HOMA values than in the untreated control group.

Conclusions/interpretation: Although the use of exendin-4 in rats is associated with decreased weight gain, lower insulin resistance and lower leptin levels than in control animals, extended use of exendin-4 in rats leads to pancreatic acinar inflammation and pyknosis. This raises important concerns about the likelihood of inducing acute pancreatitis in humans receiving incretin mimetic therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / blood
  • Alanine Transaminase / blood
  • Amylases / blood
  • Amylases / drug effects
  • Animals
  • Aspartate Aminotransferases / blood
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Exenatide
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin / blood
  • Lipase / blood
  • Lipase / drug effects
  • Male
  • Pancreas / cytology
  • Pancreas / drug effects
  • Pancreas / metabolism*
  • Pancreas / pathology
  • Pancreatitis / chemically induced
  • Pancreatitis / pathology
  • Peptides / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Venoms / pharmacology*

Substances

  • Adipokines
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • Venoms
  • Exenatide
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Lipase
  • Amylases