Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats.
OBJECTIVE
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
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.
Gedulin
B R
BR
Amylin Pharmaceuticals, 9360 Towne Centre Dr., Suite 110, San Diego, CA 92121, USA.
Smith
P
P
Prickett
K S
KS
Tryon
M
M
Barnhill
S
S
Reynolds
J
J
Nielsen
L L
LL
Parkes
D G
DG
Young
A A
AA
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004195:Disease Models, Animal; D000077270:Exenatide; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D006946:Hyperinsulinism; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D014688:Venoms / Q000494:pharmacology*
D001786:Blood Glucose; D000077270:Exenatide; D006442:Glycated Hemoglobin; D007328:Insulin; D010455:Peptides; D014688:Venoms