GLP1 Agonists and DPP4 Inhibitors How do they

GLP-1 Agonists and DPP-4 Inhibitors How do they work? Part 1

Overview • Discuss normal GLP-1 physiology • Examine the actions of DPP-4 inhibitors and GLP-1 R agonists • Review the tissue-specific differences in the mechanisms of action of GLP-1 analogs, DPP-4 inhibitors, and GLP 1 R agonists

GLP-1 • GLP-1 (1 -37) is synthesized as a 37 amino-acid peptide • Predominant circulating bioactive form of GLP-1 is GLP-1 (7 -36)amide, but GLP-1 (7 -37) is equipotent • Native peptide undergoes rapid cleavage by DPP-4 and inactivation within minutes in vivo, thus limiting the effectiveness of the native peptide for the treatment of

Pleiotropic Actions of GLP-1 Heart Brain Neuroprotection Appetite Stomach Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver GI Tract Insulin Secretion β-Cell Neogenesis Glucose Production Drucker DJ. Cell Metab. 2006; 3: 153 -165. Muscle + β-Cell Apoptosis Glucose Uptake Glucagon Secretion

Incretins • In response to equivalent hyperglycemic stimuli, oral glucose elicits a greater insulin response than intravenus glucose • The term “incretin” was introduced by La Barre to describe gut humoral activity that stimulated pancreatic endocrine secretion La Barre J, et al. Am J. Physiol. 1930; 91: 649 -653.

GLP-1 and Glucose-Dependent Insulinotropic Polypeptide (GIP) Account for ~90% of the Incretin Effect

Native GLP-1 Is Rapidly and Constantly Degraded and Cleared by the Kidney