Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1
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B. D. Green
Abstract
Glucagon-like peptide-1(7 36)amide (GLP-1) is an incretin hormone with therapeutic potential for type 2 diabetes. Rapid removal of the N-terminal dipeptide, His7-Ala8, by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) curtails the biological activity of GLP-1. Chemical modifications or substitutions of GLP-1 at His7 or Ala8 improve resistance to DPPIV action, but this often reduces potency. Little attention has focused on the metabolic stability and functional activity of GLP-1 analogues with amino acid substitution at Glu9, adjacent to the DPP IV cleavage site. We generated three novel Glu9-substituted GLP-1 analogues, (Pro9)GLP-1, (Phe9)GLP-1 and (Tyr9)GLP-1 and show for the first time that Glu9 of GLP-1 is important in DPP IV degradation, since replacing this amino acid, particularly with proline, substantially reduced susceptibility to degradation. All three novel GLP-1 analogues showed similar or slightly enhanced insulinotropic activity compared with native GLP-1 despite a moderate 4–10-fold reduction in receptor binding and cAMP generation. In addition, (Pro9)GLP 1 showed significant ability to moderate the plasma glucose excursion and increase circulating insulin concentrations in severely insulin resistant obese diabetic (ob/ob) mice. These observations indicate the importance of Glu9 for the biological activity of GLP-1 and susceptibility to DPP IV-mediated degradation.
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
Artikel in diesem Heft
- Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1
- Characterisation of Human Dipeptidyl Peptidase IV Expressed in Pichia pastoris. A Structural and Mechanistic Comparison between the Recombinant Human and the Purified Porcine Enzyme
- Effects of Iron Limitation on the Respiratory Chain and the Membrane Cytochrome Pattern of the Euryarchaeon Halobacterium salinarum
- Anti-Mouse GPI-PLD Antisera Highlight Structural Differences between Murine and Bovine GPI-PLDs
- Substrate Specificity of Glutaminyl Cyclases from Plants and Animals
- The Binding of Haptoglobin to Apolipoprotein AI: Influence of Hemoglobin and Concanavalin A
- A Novel Water-Soluble and Cell-Permeable Calpain Inhibitor Protects Myocardial and Mitochondrial Function in Postischemic Reperfusion
- Potent Bivalent Inhibition of Human Tryptase-? by a Synthetic Inhibitor
- Aza-Peptide Epoxides: Potent and Selective Inhibitors of Schistosoma mansoni and Pig Kidney Legumains (Asparaginyl Endopeptidases)
- Semisynthesis and Application of Carboxyfluorescein-Labelled Biologically Active Human Interleukin-8
- Acknowledgment
- Content Index
- Author Index
- Subject Index
Artikel in diesem Heft
- Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1
- Characterisation of Human Dipeptidyl Peptidase IV Expressed in Pichia pastoris. A Structural and Mechanistic Comparison between the Recombinant Human and the Purified Porcine Enzyme
- Effects of Iron Limitation on the Respiratory Chain and the Membrane Cytochrome Pattern of the Euryarchaeon Halobacterium salinarum
- Anti-Mouse GPI-PLD Antisera Highlight Structural Differences between Murine and Bovine GPI-PLDs
- Substrate Specificity of Glutaminyl Cyclases from Plants and Animals
- The Binding of Haptoglobin to Apolipoprotein AI: Influence of Hemoglobin and Concanavalin A
- A Novel Water-Soluble and Cell-Permeable Calpain Inhibitor Protects Myocardial and Mitochondrial Function in Postischemic Reperfusion
- Potent Bivalent Inhibition of Human Tryptase-? by a Synthetic Inhibitor
- Aza-Peptide Epoxides: Potent and Selective Inhibitors of Schistosoma mansoni and Pig Kidney Legumains (Asparaginyl Endopeptidases)
- Semisynthesis and Application of Carboxyfluorescein-Labelled Biologically Active Human Interleukin-8
- Acknowledgment
- Content Index
- Author Index
- Subject Index
