Physiological Effects Of Glp And

GLP-1 enhances glucose-induced insulin secretion and contributes to the incretin effect. Plasma concentrations of GLP-1 increase after a carbohydrate-rich meal three- to eightfold (12). The contribution of GIP to the incretin effect exceeds that of GLP-1 at typical postprandial plasma concentrations in healthy subjects (14).

Since GLP-1 lowers postprandial glycemia not only by its effect on endocrine pancreatic secretion, but also by a significant deceleration of gastric emptying (15-18), the physiological contribution of both hormones to the maintenance of normoglycemia after meal ingestion may be considered to be similar (19). GLP-1, but not GIP action is essential for the control of fasting glycemia, as acute antagonism (studies with the GLP-1-antagonist exendin(9-39)) or genetic disruption of GLP-1 action (studies in GLP-1 receptor knockout mice) leads to increased levels of fasting glucose in rodents (20). Additionally, GLP-1 is essential for glucose homeostasis also in humans, as studies with GLP-7 antagonist exendin (9-39) demonstrate impaired glucose-stimulated insulin secretion, reduced glucose clearance, increased levels of glucagon and more rapid gastric emptying (21). The actions of GLP-1 and GIP on the control of blood glucose have lead to considerable interest in the use of these agents for the treatment of type 2 diabetes.

However, GIP has lost most of its insulinotropic potency in type 2 diabetes (22,23). The majority of pharmaceutical efforts directed at potentiation of incretin action for the treatment of type 2 diabetes have focused on GLP-1 for this reason.

The GLP-1 receptor is expressed in the islet alpha and beta cells and in peripheral tissues including the central and peripheral nervous system, heart, lung and gastrointestinal tract (24). Activation of GLP-1 and GIP receptors leads to increases of cyclic AMP and intracellular calcium, followed by insulin exocytosis, in a glucose-dependent manner (25). More sustained incretin receptor signaling is associated with protein kinase A activation, induction of gene transcription, enhanced levels of insulin biosynthesis, and stimulation of p-cell proliferation (26).

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