Abstract
Although the insulinotropic actions of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been known for almost 2 decades, the incretin hormones have not yet become available for clinical application. This can be explained by their unfavourable pharmacological properties. Both hormones are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP IV), yielding biologically inactive fragments. There have been several attempts to make use of the antidiabetogenic potential of the incretin hormones. Various analogues of GLP-1 and GIP have been generated in order to achieve resistance to DPP IV degradation. The natural GLP-1 receptor agonist exendin-4, found in the saliva of the Gila monster, has a longer biological half-life after subcutaneous injection than GLP-1, and inhibition of DPP IV using, for example, pyrrolidine derivatives provides elevated concentrations of intact, biologically active GIP and GLP-1 endogenously released from the gut. A continuous intravenous infusion of native GLP-1 for a limited time may be suitable in certain clinical situations. Numerous clinical studies are currently underway to evaluate these approaches. Therefore, an anti-diabetic treatment based on incretin hormones may become available within the next 5 years.
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Acknowledgements
The authors gratefully acknowledge support of their work by the Deutsche Forschungsgemeinschaft (grant No 203/6-1), by the Deutsche Diabetes-Gesellschaft, and by the Ruhr-University Bochum (FoRUM programm). We also thank Professor W. Schmidt, Bochum and Professor J. Holst, Copenhagen, for critical and helpful discussion. Michael Nauck has received grant support for clinical research involving GLP-1 or derivatives from NovoNordisk, Copenhagen, Denmark, from Eli Lilly & Co., Indianapolis, Indiana, USA, from Novartis Pharma GmbH, Basel, Switzerland, from probiodrug GmbH, Halle, Germany, and from Restoragen Inc., Lincoln, Nebraska, USA. He has also received honoraria as a consultant or speaker from these companies as well as Amylin Pharmaceuticals, San Diego, California, USA.
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Meier, J.J., Gallwitz, B. & Nauck, M.A. Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide. BioDrugs 17, 93–102 (2003). https://doi.org/10.2165/00063030-200317020-00002
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DOI: https://doi.org/10.2165/00063030-200317020-00002