BACKGROUND: @entity68965 is a K-cell derived gut peptide with insulin-releasing activity which is rapidly degraded following release into the circulation. We hypothesized that substitution of all naturally-occurring Lys and @entity534 residues with @entity7647 would lead to prolonged enzyme resistance and enhanced biological efficacy. METHODS: Peptide stability was assessed using @entity19 plasma, in vitro insulin-releasing actions evaluated in BRIN-BD11 cells and acute @entity413 -lowering and insulin-releasing actions examined in high fat fed @entity19 . For sub-chronic studies, a range of metabolic parameters and pancreatic histology were assessed in high fat fed @entity19 which had received saline vehicle or @entity68965 ( @entity7647 ) twice-daily for 21days. RESULTS: In contrast to native @entity68965 , @entity68965 ( @entity7647 ) was resistant to plasma-mediated degradation and significantly stimulated insulin secretion in BRIN-BD11 cells. Acute administration of @entity68965 ( @entity7647 ) in high fat fed @entity19 significantly reduced blood @entity413 and increased plasma insulin concentrations. Twice-daily administration of @entity68965 ( @entity7647 ) in high fat fed @entity19 did not affect food intake, body weight or circulating insulin concentrations but significantly decreased blood @entity413 from day 9 onwards. Furthermore, @entity413 tolerance, @entity413 -mediated insulin secretion, insulin sensitivity and GIP-stimulated insulin-release were significantly enhanced in @entity68965 ( @entity7647 )-treated @entity19 . Pancreatic immunohistochemistry revealed decreased alpha cell area with increased beta cell area and beta-to-alpha cell ratio in @entity68965 ( @entity7647 )-treated @entity19 . In addition, @entity68965 ( @entity7647 ) exerted similar beneficial actions in ob/ob @entity19 as demonstrated by reduced blood @entity413 , superior glycaemic response and @entity413 -mediated insulin release. CONCLUSIONS: @entity68965 ( @entity7647 ) is resistant to plasma-mediated degradation and exerts sustained and beneficial metabolic actions in high fat fed and ob/ob @entity19 . GENERAL SIGNIFICANCE: @entity3264 ( @entity7647 )-modified analogues of xenin may represent an attractive therapeutic approach for type 2 @entity6 .

A novel chemically modified analogue of @entity68965 exhibits improved XXXX -lowering and insulin-releasing properties.

@entity3264 :: ('D018698', 'Chemical') :: ['Glutamine'] @entity6 :: ('MESH:D003920', 'Disease') :: ['diabetes'] @entity19 :: ('10090', 'Species') :: ['mice', 'murine'] @entity534 :: ('CHEBI:16467', 'Chemical') :: ['Arg'] @entity7647 :: ('CHEBI:32668', 'Chemical') :: ['Gln', 'gln'] @entity68965 :: ('MESH:C077659', 'Chemical') :: ['xenin-25', 'Xenin-25'] @entity413 :: ('MESH:D005947', 'Chemical') :: ['glucose']
@entity413 :: (MESH:D005947,Chemical) :: ['glucose']
