Glucagon-like peptide 1 receptor

The glucagon-like peptide 1 receptor (GLP1R) is a human is_associated_with::gene which resides on is_associated_with::chromosome 6. The protein encoded by this gene is a member of the is_associated_with::glucagon receptor family of is_associated_with::G protein-coupled receptors.

Ligand specificity
GLP1R binds specifically the is_associated_with::glucagon-like peptide-1 (GLP1) and has much lower affinity for related peptides such as the is_associated_with::gastric inhibitory polypeptide and is_associated_with::glucagon.

Function and therapeutic potential
GLP1R is known to be expressed in pancreatic is_associated_with::beta cells. Activated GLP1R stimulates the is_associated_with::adenylyl cyclase pathway which results in increased is_associated_with::insulin synthesis and release of insulin. Consequently GLP1R has been suggested as a potential target for the treatment of is_associated_with::diabetes.

GLP1R is also expressed in the brain where it is involved in the control of is_associated_with::appetite. Furthermore, mice which over express GLP1R display improved memory and learning.

Huntington's disease
The diabetic, pancreatic, and neuroprotection implications of GLP1R are also thought to be potential therapies for treating the diabetes and energy metabolism abnormalities associated with is_associated_with::Huntington's disease affecting the brain and periphery. is_associated_with::Exendin-4, an FDA-approved antidiabetic glucagon-like peptide 1 (GLP-1) receptor agonist, has been tested in mice with the mutated human huntingtin protein showing neurodegenerative changes, motor dysfunction, poor energy metabolism, and high blood glucose levels. Exendin-4 (Ex-4) treatment reduced the accumulation of mhtt protein aggregates, improved motor function, extended the survival time, improved glucose regulation, and decreased brain and pancreas pathology.

Exendin-4 increases beta cell mass in the pancreatic islets to improve the release of insulin to ultimately increase glucose uptake. The mechanism regarding this insulin increase involves Ex-4 and GLP-1. When the islets in the pancreas are exposed to GLP-1, there is an increased expression of the anti-apoptotic gene is_associated_with::bcl-2 and decreased expression of pro-apoptotic genes bax and is_associated_with::caspase-3, which leads to greater cell survival. GLP-1 binding to its is_associated_with::G protein-coupled receptor activates various different pathways including the growth factor receptor and is coupled to pathways stimulating is_associated_with::mitogenesis. Some of these pathways include Rap, Erk1/2, is_associated_with::MAPK, is_associated_with::B-RAF, is_associated_with::PI3-K, cAMP, PKA, and TORC2 that are activated to initiate is_associated_with::exocytosis, proinsulin gene expression and translation, increase insulin biosynthesis, and genetically increase beta cell proliferation and neogenesis. The GLP-1R is a G protein-coupled receptor that is dependent on glucose and GLP-1 is a peptide hormone that acts directly on the beta cell to stimulate insulin secretion by activating signal transduction when glucose is present. When glucose is not present, this receptor no longer couples to stimulate insulin secretion in order to prevent hypoglycemia.

Relating glucose metabolism and insulin sensitivity back to Huntington's disease, increased insulin release and beta cell proliferation by a GLP-1 agonist, Ex-4, helps combat the damage done by mutant htt in peripheral tissues. Htt aggregation decreases beta cell mass and thus impairs insulin release and increases blood glucose levels. Disruption of glycemic homeostasis then affects nutrient availability to neurons and alters neuron function contributing to neurodegeneration and motor problems seen in Huntington's disease. The health of the nervous system is related to metabolic health, thus a diabetes medication as a Huntington's disease treatment is a potential treatment. Ex-4 easily crosses the blood-brain barrier and GLP-1 and Ex-4 have been shown to act on neurons in the brain by exerting neuroprotective actions.

In studies with Huntington's disease mice, daily treatments of Ex-4 significantly reduced glucose levels compared to those mice treated with saline. It also increased insulin sensitivity by about 50%, improved insulin-stimulated glucose uptake, and protect pancreatic beta cell function. Huntington's disease has also been linked to imbalances in is_associated_with::leptin and is_associated_with::ghrelin levels. Ex-4 restored ghrelin levels and also lowered leptin levels allowing Huntington's disease mice to eat more and counteract symptomatic weight loss. This treatment restored beta cell cells and islet structure, reduce mhtt aggregates in the brain and pancreas, and also improve motor function seen by the increased activity level of the mice. Improvements were found in the areas of the body that expressed GLP-1R. In addition to its other effects on the Huntington's disease mouse model, daily treatment of Ex-4, the GLP-1R agonist, significantly delayed the onset of mortality and extended the lifespan by approximately one month.