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NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

O'Harte, Finbarr, Mooney, MH and Flatt, Peter (1999) NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity. DIABETES, 48 (4). pp. 758-765. [Journal article]

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Abstract

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis that, like glucagon-like peptide 1(7-36) amide (tGLP-I), has a functional profile of possible therapeutic value for type 2 diabetes, Both incretin hormones are rapidly inactivated in plasma by the exopeptidase dipeptidyl peptidase (DPP) IV, The present study examined the ability of NH2-terminal modification of human GIP to protect Born plasma degradation and enhance insulin-releasing and antihyperglycemic activity Degradation of GIP by incubation at 37 degrees C with purified DPP IV was clearly evident after 4 h (54% intact). After 12 h, >60% of GIP was converted to GIP(3-42), whereas >99% of NH2-terminally modified Tyr(1)-glucitol GIP remained intact. Tyr(1)-glucitol GIP was similarly resistant to serum degradation. The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A, Effects of GIP and Tyr(1)-glucitol GIP were examined in Wistar rats after intraperitoneal injection of either peptide (10 nmol/kg) together with glucose (18 mmol/kg), Plasma glucose concentrations were significantly lower and insulin concentrations higher after both peptides compared with glucose alone. More importantly, individual glucose values at 15 and 30 min together with the areas under the curve (AUCs) for glucose were significantly lower after administration of Tyr(1)-glucitol GIP compared with GIP (AUC 255 +/- 33 vs. 368 +/- 8 mmol.l(-1).min(-1), respectively; P < 0.01), This was associated with a significantly greater and more protracted insulin response after Tyr(1)-glucitol GIP than GIP (AUC 773 +/- 41 vs. 639 +/- 39 ng.ml(-1).min(-1) P < 0.05). These data demonstrate that Tyr(1)-glucitol GIP displays resistance to plasma DPP IV degradation and exhibits enhanced antihyperglycemic activity and insulin-releasing action in vivo.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:3115
Deposited By:Professor Peter Flatt
Deposited On:08 Jan 2010 15:23
Last Modified:11 Jun 2010 12:48

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