The glucagon-like peptide-1 (GLP1) is a crucial regulatory peptide, released predominantly in the intestines and plays a significant role in glucose homeostasis.
Background information on GLP1
GLP1 was identified initially in the 1980s by a team of scientists examining the sequences of the proglucagon gene, first sequenced in hamsters by Bell and colleagues in 1983. Structurally, the GLP1 is a potent 30 amino acid peptide hormone that derives from the proteolytic cleavage of the 160 amino acid preproglucagon molecule.
The GLP1 gene, also known as the GCG gene, is located on chromosome 2 in humans. Specifically, the locus of the gene is reportedly 2q36.3, and it encompasses a total of six exons. This gene codes for the proglucagon protein which, in turn, generates several glucagon-like peptides including not just GLP1, but also GLP2, glucagon, and the major proglucagon fragment.
GLP1 function
The primary role of GLP1, basically functioning as an incretin hormone, entails enhancing insulin's secretion in a glucose-dependent manner, thereby inhibiting glucagon's secretion, slowing gastric emptying, and promoting satiety.
GLP1 -related signaling pathways
Numerous signaling pathways are intimately related to the function of GLP1. Chief among them is the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. Activated by GLP1, this pathway subsequently enhances insulin gene transcription and exocytosis of insulin-containing granules.
Another associated pathway is the mitogen-activated protein kinases (MAPK) pathway, which GLP1 activates and plays a pivotal role in cell proliferation and apoptosis. Meanwhile, the Phosphoinositide 3-Kinase (PI3K)/protein kinase B (Akt) pathway, also modulated by GLP1, is crucial for regulating cellular metabolism and survival.
GLP1 related diseases and the role of GLP1 in diseases
GLP1 has been associated with several metabolic diseases, mainly type 2 diabetes (T2D) and obesity. In T2D, GLP1 deficiency is believed to cause impaired insulin secretion and aberrant blood glucose levels. In contrast, obesity links with GLP1 due to its role in appetite regulation and gastric motility.
In neurodegenerative disorders, GLP1 has shown potential neuroprotective effects, making it a prospective therapeutic target in Alzheimer's and Parkinson's diseases. In cardiovascular diseases, GLP1 receptor activation is thought to promote cardiac function and prevent apoptosis in cardiomyocytes, making it useful in heart failure management.
The application of GLP1 in medicine
The notable role of GLP1 in modulating glucose homeostasis has made it a promising therapeutic target in T2D management. Medications like exenatide and liraglutide, GLP1 receptor agonists, are now standard therapeutic agents in T2D management. Other pharmacological applications of GLP1 include obesity management and potential neuroprotective and cardioprotective roles.
List of drug candidates related to GLP1:
Several drug candidates related to GLP1 have been developed, including:
Exenatide: an injectable GLP1 receptor agonist used to treat type 2 diabetes.
Liraglutide: another injectable GLP1 receptor agonist with approval for treating both T2D and obesity.
Dulaglutide: an injectable, long-acting GLP1 receptor agonist used to manage T2D.
Semaglutide: available in injectable and oral formulations, this GLP1 receptor agonist is used for T2D and obesity management.
In conclusion, the discovery, complex structure, and biological functionalities of GLP1 have significantly broadened our understanding of metabolic regulation and disease pathophysiology. The subsequent development of GLP1- based therapeutics has further revolutionized disease management, demonstrating the power of translating basic research findings into viable healthcare solutions.
