Degradation and glycemic effects of His(7)-glucitol glucagon-like peptide-1(7-36)amide in obese diabetic ob/ob mice

Glucagon-like peptide-1(7-36)amide (tGLP-1) has attracted considerable pote ntial as a possible therapeutic agent for type 2 diabetes. However, tGLP-1 is rapidly inactivated in vivo by the exopeptidase dipeptidyl peptidase IV (DPP IV), thereby terminating its insulin releasing activity. The present s tudy has examined the ability of a novel analogue, His(7)-glucitol tGLP-1 t o resist plasma degradation and enhance the insulin-releasing and antihyper glycemic activity of the peptide in 20-25-week-old obese diabetic ob/ob mic e. Degradation of native tGLP-1 by incubation at 37 degreesC with obese mou se plasma was clearly evident after 3 h (35% intact). After 6 h, more than 87% of tGLP-1 was converted to GLP-1(9-36)amide and two further N-terminal fragments, GLP-1(7-28) and GLP-1(9-28). In contrast, His7-glucitol tGLP-1 w as completely resistant to N-terminal degradation. The formation of GLP-1(9 -36)amide from native tGLP-1 was almost totally abolished by addition of di protin A, a specific inhibitor of DPP IV. Effects of tGLP-1 and His7-glucit ol tGLP-1 were examined in overnight fasted obese mice following i.p. injec tion of either peptide (30 nmol/kg) together with glucose (18 mmol/kg) or i n association with feeding. Plasma glucose was significantly lower and insu lin response greater following administration of His7-glucitol tGLP-1 as co mpared to glucose alone. Native tGLP-1 lacked antidiabetic effects under th e conditions employed, and neither peptide influenced the glucose-lowering action of exogenous insulin (50 units/kg). Twice daily s.c. injection of ob /ob mice with His(7)-glucitol tGLP-1 (10 nmol/kg) for 7 days reduced fastin g hyperglycemia and greatly augmented the plasma insulin response to the pe ptides given in association with feeding. These data demonstrate that His(7 )-glucitol tGLP-1 displays resistance to plasma DPP IV degradation and exhi bits antihyperglycemic activity and substantially enhanced insulin-releasin g action in a commonly used animal model of type 2 diabetes. (C) 2001 Elsev ier Science B.V. All rights reserved.