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Current Pharmaceutical Design

Eiditor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Development of Glucagon-Like Peptide-1-Based Pharmaceuticals as Therapeutic Agents for the Treatment of Diabetes

Author(s): Daniel J. Drucker

Volume 7 , Issue 14 , 2001

Page: [1399 - 1412] Pages: 14

DOI: 10.2174/1381612013397401

Price: $58

Abstract

Glucagon-like peptide-1 (GLP-1) is released from gut endocrine cells following nutrient ingestion and acts to regulate nutrient assimilation via effects on gastrointestinal motility, islet hormone secretion, and islet cell proliferation. Exogenous administration of GLP-1 lowers blood glucose in normal rodents and in multiple experimental models of diabetes mellitus. Similarly, GLP-1 lowers blood glucose in normal subjects and in patients with type 2 diabetes. The therapeutic utility of the native GLP-1 molecule is limited by its rapid enzymatic degradation by the serine protease dipeptidyl peptidase IV. This review highlights recent advances in our understanding of GLP-1 physiology and GLP-1 receptor signaling, and summarizes current pharmaceutical strategies directed at sustained activation of GLP-1 receptor-dependent actions for glucoregulation in vivo. Given the nutrient-dependent control of GLP-1 release, neutraceuticals or modified diets that enhance GLP-1 release from the enteroendocrine cell may exhibit glucose-lowering properties in human subjects. The utility of GLP-1 derivatives engineered for sustained action and/or DP IV-resistance, and the biological activity of naturally occurring GLP-1-related molecules such as exendin-4 is reviewed. Circumventing DP IV-mediated incretin degradation via inhibitors that target the DP IV enzyme represents a complementary strategy for enhancing GLP-1-mediated actions in vivo. Finally, the current status of alternative GLP-1-delivery systems via the buccal and enteral mucosa is briefly summarized. The findings that the potent glucose-lowering properties of GLP-1 are preserved in diabetic subjects, taken together with the potential for GLP-1 therapy to preserve or augment b cell mass, provides a powerful impetus for development of GLP-1-based human pharmaceuticals.

Keywords: glucagon like peptide, therapeutic agents, diabetes, glucagon-like peptide glp, glp synthesis, dipeptidyl peptidase IV, glucagon-Like Peptode receptor, glp-analogues, exendin


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