GSK716155

GSK716155 (Albugon) is a recombinant Human Glucagon-like Peptide (GLP)-1-Albumin Protein created using Human Genome Sciences’ proprietary albumin fusion technology, which involves fusing the gene that expresses human albumin to the gene that expresses a therapeutically active protein (GLP-1) ^[1] . It is an agonist of the Glucagon-like Peptide-1 Receptor (GLP1R) and is currently undergoing clinical drug trials for treatment of Type 2 Diabetes Mellitus. The fusing of therapeutic proteins to human albumin decreases clearance and prolongs the half-life of therapeutically active proteins in the body ^[1] .

GSK716155 and other GLP-1 Agonists Effects

GSK716155 mimics the effects of GLP-1 which activates GLP-1 receptors on beta cells in the pancreas ^[2] . GLP-1 is a 30 amino acid peptide hormone (from a family called incretins) secreted from gut endocrine cells that acts throughout the body to help maintain healthy blood sugar levels and to control appetite. Type 2 diabetes is a metabolic disorder characterized by insulin resistance, relative insulin deficiency and hyperglycemia.

Normally GLP-1 levels rise during a meal to help the body utilize and control the elevation in blood sugar levels but this response is hindered in Type 2 diabetics ^[3] . If injected to treat hyperglycemia it stimulates insulin production and inhibits glucagon secretion in the pancreas. GLP-1 itself can be used to treat diabetes but it only has a half life of around 5 minutes, by attaching the albumin this half life is significantly increase so that there are detectable level 11-15 hours after administration ^[2] .GLP-1 also contributes to the health and survival of the insulin producing cells in the body. Studies in rodents and humans illustrate that the incretin hormones play a central role in the homeostasis of pancreatic β cell mass as well as function. Chronic treatment of both normal and diabetic rodents with GLP-1R agonists can result in an increase in β cell mass due to increases in β cell 1) proliferation, 2) neogenesis and/or, 3) decreases in β cell apoptosis ^[3] .

GLP-1 is also shown to inhibit food intake, presumably via activation of central hypothalamic centers regulating satiety, but GSK716155 cannot cross the blood brain barrier since it is a large peptide ^[2] . However, GSK716155 rapidly reduces food intake and inhibits gastric emptying in preclinical studies within minutes of administration, suggesting that direct central nervous system penetration of GLP-1R agonists may not be required for GLP-1R dependent actions in the brain. The anorectic properties of GLP-1 and its peptide analogs are thought to be due in part to both inhibition of gastric emptying and deactivation of central satiety centers coupled with reduction of energy intake. GSK716155 may not be as potent at reducing these effects, but other GLP-1 receptor agonists must be injected once or twice daily and GSK716155 is a step towards developing longer circulating half-lives ^[2] .

Effect on Insulin Transcription

Activation of the GLP-1 receptor, which is a 7TM G- protein coupled receptor, stimulates adenylyl cyclase and phospholipase. Adenylyl cyclase produces cAMP, which activates Protein Kinase A (PKA), EPAC and Protein Kinase C. These are the starting points to cascades that lead to the activation of different transcription factors for insulin. The receptor activates insulin gene expression by activation of MAPK through a mechanism dependent on MEK but independent of both Raf and Ras ^[3] . These pathways lead to a direct increases insulin gene transcription. Insulin then instructs the body’s cells to take in glucose from the blood in times of satiation. Activation of the GLP-1 receptor will also cause a decrease in glucagon which is produced by the pancreas when the blood glucose level is low, causing the liver to convert stored glycogen into glucose and release it into the blood stream ^[3] .

References

#Citation| last = Baggio| first = Laurie L.| author-link = Laurie L. Baggio| last2 = Huang| first2 = Qingling| author2-link = Qingling Huang| last3 = Brown| first3 = Theodore J.| author3-link = Theodore J. Brown| last4 = Drucker| first4 = Daniel J.| author4-link = Daniel J. Drucker| title = A Recombinant Human Glucagon-Like Peptide (GLP)-1-Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor-Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis| journal = DIABETES| volume = 53| pages = 2492-2500| date = Septemer 2004.
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