Structure
Bound to the GLP-1 receptor, GLP-1 has an alpha-helical structure that is near glycine 22 in some complexes. In solution, GLP-1 is according to NMR data when in the presence of helix-stabilizers, and fairly unstructured otherwise[2]. Looking at the helix-propensity of the peptide sequence, the N-terminal part of Glp-1 (7-37) is less likely to be alpha-helical than the C-terminal half.
Synthesis through proglucagon processing
is a prohormone made of 177 amino acids (in humans). In the polypeptide form, it is inactive until processed to yield mature hormones. Proglucagon is found in the human body, specifically in L-cells (within the gut) and 𝜶-cells (within the pancreas).
It is broken down using specific enzymes called prohormone convertases (PCs). These convertases are endopeptidases (they can act in the middle of an extended peptide), different from exopeptidases DPP-4 and CPE, which also play a role in GLP-1 synthesis and degradation.
In healthy individuals, PCs produce GLP-1 precursors in L-cells and glucagon precursors in 𝜶-cells. These then are trimmed on the C-terminal side by carboxypeptidase E (CPE), and sometimes the C-terminus is amidated[3]. Other pathways of proglucagon yield other products such as GRPP, and IP-1 in the pancreas and Glicentin, GRRP, Oxyntomodulin, and GLP-2 in the intestines [4].
Glucagon and GLP-1 work to balance the levels of sugar in the blood. However, when a person has type 2 diabetes, they struggle to lower blood sugar on their own, due to a resistance to insulin. As a result of diabetes, proglucagon processes differently in order to adapt. For people with type 2 diabetes, proglucagon may yield GLP-1 in 𝜶-cells rather than glucagon[5].
Degradation
GLP-1 (7-39) is initially by dipeptidyl peptidase IV to yield GLP-1 (9-37) (). For a discussion how this affects the half-life of GLP-1 and synthetic analogs, see the semaglutide article.
Binding to receptor
GLP-1 binds to the extracellular side of its receptor. By to the receptor, GLP-1 acts as agonist, leading to conformational change and intracellular consequences. For more information about the receptor, see GLP-1R.
Consequences of receptor binding
In the pancreas, GLP-1 plays a critical role in glucose regulation through its glucose-dependent insulin secretion. It stimulates insulin release only when blood glucose levels are elevated, preventing hypoglycemia. In the brain, GLP-1 receptor agonists play a significant role in regulating feeding behaviors and appetite[6]. In the heart, GLP-1 receptor activation has several cardio-protective effects. It reduces oxidative stress (unstable molecules with not enough antioxidants to neutralize) and improves cardiac function during low blood flow events. These and other actions make GLP-1 beneficial for patients with type 2 diabetes or cardiovascular disease[7].
Student contributors
This page was created as a two-week project of an undergraduate biochemistry course. Karsten Theis would like to acknowledge contributors Jamie, Trey, Spencer, Pam, Summer, and Hyancinth Osei.
