Comparative effects of GLP-1 and GIP on cAMP production, insulin secretion, and in vivo antidiabetic actions following substitution of Ala8/Ala2 with 2-aminobutyric acid

Archives of Biochemistry and Biophysics
Brian D GreenFinbarr P M O'Harte

Abstract

The two major incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), are currently being considered as prospective drug candidates for treatment of type 2 diabetes. Interest in these gut hormones was initially spurred by their potent insulinotropic activities, but a number of other antihyperglycaemic actions are now established. One of the foremost barriers in progressing GLP-1 and GIP to the clinic concerns their rapid degradation and inactivation by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV). Here, we compare the DPP IV resistance and biological properties of Abu8/Abu2 (2-aminobutyric acid) substituted analogues of GLP-1 and GIP engineered to impart DPP IV resistance. Whereas (Abu8)GLP-1 was completely stable to human plasma (half-life >12 h), GLP-1, GIP, and (Abu2)GIP were rapidly degraded (half-lives: 6.2, 6.0, and 7.1 h, respectively). Native GIP, GLP-1, and particularly (Abu8)GLP-1 elicited significant adenylate cyclase and insulinotropic activity, while (Abu2)GIP was less effective. Similarly, in obese diabetic (ob/ob) mice, GIP, GLP-1, and (Abu8)GLP-1 displayed substantial glucose-lowering and insulin-releasing activities, whereas (Abu2)GIP was only weakl...Continue Reading

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Citations

Jan 13, 2011·Current Medical Research and Opinion·Jens Juul HolstEsther Nathanson
Sep 10, 2013·Endocrinology and Metabolism Clinics of North America·Efrat KravitzMichal Schnaider Beeri
Dec 29, 2009·European Journal of Pharmacology·Paula L McCleanChristian Hölscher
May 10, 2008·European Journal of Pharmacology·Victor A Gault, Christian Hölscher
Oct 9, 2007·Brain Research Reviews·Lin Li, Christian Hölscher
Nov 17, 2015·The Journal of Clinical Investigation·Makoto ShigetoPatrik Rorsman
Apr 3, 2010·Neurobiology of Aging·Simon GenglerChristian Hölscher
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Nov 26, 2011·European Journal of Pharmacology·Emilie FaivreChristian Hölscher
Jan 18, 2017·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Makoto ShigetoKohei Kaku
Aug 29, 2017·International Journal of Molecular Sciences·Jenq-Lin YangShang-Der Chen
Jun 8, 2021·Frontiers in Endocrinology·Ryan A LaffertyPeter R Flatt

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