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.
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 ZDFrats. 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 ZDFrats with matched initial HbA1c values (n=7 rats/group). RESULTS: In contrast to the progressive 3.22+/-0.42% increase in HbA1c in control ZDFrats 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 ZDFrat model of type 2 diabetes suggests that tachyphylaxis is unlikely to be a feature of exenatide-LAR preparations, and supports further clinical exploration.
Authors: Bronislava R Gedulin; Svetlana E Nikoulina; Pamela A Smith; George Gedulin; Loretta L Nielsen; Alain D Baron; David G Parkes; Andrew A Young Journal: Endocrinology Date: 2004-12-23 Impact factor: 4.736
Authors: John B Buse; Robert R Henry; Jenny Han; Dennis D Kim; Mark S Fineman; Alain D Baron Journal: Diabetes Care Date: 2004-11 Impact factor: 19.112
Authors: Kristine B Degn; Birgitte Brock; Claus B Juhl; Christian B Djurhuus; Jaime Grubert; Dennis Kim; Jenny Han; Kristin Taylor; Mark Fineman; Ole Schmitz Journal: Diabetes Date: 2004-09 Impact factor: 9.461
Authors: R A Pittner; C X Moore; S P Bhavsar; B R Gedulin; P A Smith; C M Jodka; D G Parkes; J R Paterniti; V P Srivastava; A A Young Journal: Int J Obes Relat Metab Disord Date: 2004-08