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

Aims/hypothesis: Exenatide ( exendin-4) injected subcutaneously twice daily reduces glycaemic deterioration in diabetic fatty Zucker ( ZDF) rats and reduces HbA(1)c 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 mu g 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 mu g +/- 0.1 log per rat; median effective concentration 52 pmol/1 +/- 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.