Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats

Diabetologia. 2005 Jul;48(7):1380-5. doi: 10.1007/s00125-005-1795-2. Epub 2005 May 25.

Abstract

Aims/hypothesis: Exenatide (exendin-4) injected subcutaneously twice daily reduces glycaemic deterioration in diabetic fatty Zucker (ZDF) rats and reduces HbA1c in humans with type 2 diabetes. Because tachyphylaxis may develop with continuous peptide exposure, we examined the activity of a long-acting-release (LAR) formulation of exenatide on HbA1c, insulin sensitivity and beta cell secretion in ZDF rats.

Methods: Single subcutaneous injections of a poly-lactide-glycolide microsphere suspension (3% peptide) containing 0, 1, 10, 100, 1,000, 3,000 or 9,000 mug exenatide were administered to 9-week-old ZDF rats with matched initial HbA1c values (n=7 rats/group).

Results: In contrast to the progressive 3.22+/-0.42% increase in HbA1c in control ZDF rats observed over 28 days, single exenatide-LAR injections dose-proportionally prevented such glycaemic deterioration (median effective dose 74 microg+/-0.1 log per rat; median effective concentration 52 pmol/l+/-0.06 log). Hyperinsulinaemic-euglycaemic clamp procedures incorporating an intraclamp glucose challenge performed 28 days after treatment revealed increases in beta cell response to the glucose challenge at lower exenatide-LAR doses, and up to a 2.1-fold increase in insulin sensitivity at higher exenatide-LAR doses.

Conclusions/interpretation: The finding that a single dose of exenatide-LAR enhanced glucose control for 28 days in the ZDF rat model of type 2 diabetes suggests that tachyphylaxis is unlikely to be a feature of exenatide-LAR preparations, and supports further clinical exploration.

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / blood*
  • Disease Models, Animal
  • Exenatide
  • Glucose Clamp Technique
  • Glycated Hemoglobin A / drug effects
  • Glycated Hemoglobin A / metabolism
  • Hyperinsulinism
  • Infusions, Intravenous
  • Insulin / administration & dosage
  • Insulin / pharmacology
  • Male
  • Peptides / pharmacology*
  • Rats
  • Rats, Zucker
  • Venoms / pharmacology*

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Insulin
  • Peptides
  • Venoms
  • Exenatide