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Therapeutic strategies based on glucagon-like peptide 1 Deacon CFDiabetes 2004[Sep]; 53 (9): 2181-9Glucagon-like peptide (GLP)-1 is an incretin hormone with potent glucose-dependent insulinotropic and glucagonostatic actions, trophic effects on the pancreatic beta-cells, and inhibitory effects on gastrointestinal secretion and motility, which combine to lower plasma glucose and reduce glycemic excursions. Furthermore, via its ability to enhance satiety, GLP-1 reduces food intake, thereby limiting weight gain, and may even cause weight loss. Taken together, these actions give GLP-1 a unique profile, considered highly desirable for an antidiabetic agent, particularly since the glucose dependency of its antihyperglycemic effects should minimize any risk of severe hypoglycemia. However, its pharmacokinetic/pharmacodynamic profile is such that native GLP-1 is not therapeutically useful. Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short-lasting effects. GLP-1 is highly susceptible to enzymatic degradation in vivo, and cleavage by dipeptidyl peptidase IV (DPP-IV) is probably the most relevant, since this occurs rapidly and generates a noninsulinotropic metabolite. Strategies for harnessing GLP-1's therapeutic potential, based on an understanding of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation of the peptide.|Amino Acid Sequence[MESH]|Diabetes Mellitus, Type 2/*drug therapy[MESH]|Dipeptidyl Peptidase 4/*metabolism[MESH]|Glucagon-Like Peptide 1[MESH]|Glucagon/*administration & dosage/chemistry/*pharmacokinetics[MESH]|Humans[MESH]|Molecular Sequence Data[MESH]|Peptide Fragments/*administration & dosage/chemistry/*pharmacokinetics[MESH]|Protein Precursors/*administration & dosage/chemistry/*pharmacokinetics[MESH] |
