Glucagon-like peptide-1, or GLP-1, is a peptide hormone naturally produced in the human body that plays a fundamental role in regulating metabolism. It belongs to a class of hormones known as incretins, which are released from the gut into the bloodstream in response to nutrient ingestion. The primary function of GLP-1 is to help manage blood glucose levels, a process that is activated immediately following a meal. Understanding this molecule’s native sequence and biological function provides the foundation for comprehending its widespread use in modern medicine. This naturally occurring peptide has become a significant focus in the treatment of metabolic disorders.
Biosynthesis and Origin of GLP-1
The genesis of glucagon-like peptide-1 begins with the proglucagon gene, which contains the genetic blueprint for a large precursor molecule called preproglucagon. This single gene is expressed in multiple tissues, but the final peptides produced vary significantly depending on the specific location. The creation of GLP-1 is a prime example of tissue-specific post-translational processing.
The primary site of GLP-1 production is the enteroendocrine L-cells, which are specialized hormone-secreting cells located predominantly in the lower small intestine and the colon. In these L-cells, the proglucagon precursor is cleaved by a specific enzyme called prohormone convertase 1 (PC1/3). This differential cleavage results in the liberation of several distinct peptides, including GLP-1.
In contrast, the same proglucagon molecule is processed differently in the alpha cells of the pancreas, where a different enzyme, prohormone convertase 2 (PC2), is active. This processing yields glucagon, a hormone with an opposite effect on blood sugar, instead of GLP-1. This regulatory mechanism ensures that the correct hormones are released from the correct tissues at the appropriate time to maintain metabolic balance. The release of GLP-1 from L-cells is rapidly stimulated by the presence of nutrients, such as carbohydrates and fats, in the gut lumen.
The Native GLP-1 Sequence and Structure
The biologically active forms of the native GLP-1 peptide are short chains of amino acids, primarily GLP-1(7-36)NH2 and a lesser amount of GLP-1(7-37). The numbers indicate that the active hormone starts at the seventh amino acid position of the larger proglucagon molecule. The most prevalent active form, GLP-1(7-36)NH2, is a 30-amino-acid peptide with an amide group attached to its C-terminus.
Despite its potent biological activity, the native sequence possesses a structural vulnerability that severely limits its time in the circulation. Specifically, the peptide is quickly targeted by an enzyme known as Dipeptidyl Peptidase-4 (DPP-4). This widespread enzyme rapidly cleaves the native peptide between the alanine residue at position 8 and the histidine residue at position 7.
This enzymatic cleavage renders the peptide inactive, resulting in an extremely short circulating half-life of only one to two minutes in the bloodstream. This rapid degradation means that only a small percentage of the GLP-1 released from the L-cells ever reaches its target organs. The inherent instability of the native sequence poses a significant challenge for its potential therapeutic use.
Core Physiological Actions
Upon its release and before its rapid degradation, GLP-1 exerts its primary effects by binding to the GLP-1 receptor (GLP-1R), which is expressed on various cell types throughout the body. The most recognized action occurs in the pancreas, where GLP-1 acts as a glucose-dependent stimulator of insulin secretion. This means that the hormone only triggers insulin release when blood glucose levels are elevated, a mechanism that helps prevent dangerously low blood sugar.
Simultaneously, GLP-1 acts on the alpha cells of the pancreas to suppress the release of glucagon, the hormone that instructs the liver to release stored glucose. By both stimulating insulin and inhibiting glucagon, GLP-1 provides a dual-action mechanism to normalize high blood sugar after a meal. This coordinated response is known as the incretin effect and accounts for a significant portion of the body’s ability to handle oral glucose.
Beyond the pancreas, the hormone influences the gastrointestinal tract by slowing the rate of gastric emptying. This effect reduces the speed at which nutrients enter the small intestine, thus allowing for a more gradual and manageable absorption of glucose. GLP-1 also acts directly on the central nervous system, specifically in the brain stem and hypothalamus, which are regions involved in appetite regulation. Activation of the GLP-1 receptor in these areas promotes satiety, leading to reduced food intake.
Sequence Modification in Therapeutics
The short half-life of the native GLP-1 sequence necessitated engineering to create effective therapeutic agents, known as GLP-1 Receptor Agonists. Researchers employed two major strategies to overcome the rapid inactivation by the DPP-4 enzyme and the quick renal clearance.
The first strategy involved making strategic amino acid substitutions in the native sequence to physically block the DPP-4 enzyme from cleaving the molecule. For example, the alanine at position 8, the site of DPP-4 cleavage, was replaced with a different, non-cleavable amino acid. This small structural modification, such as the substitution with 2-aminoisobutyric acid (Aib) in some compounds, dramatically increases resistance to degradation, extending the half-life from minutes to hours.
The second strategy involved conjugating the modified peptide with a large molecule, most commonly a fatty acid chain. In drugs like Liraglutide, a fatty acid chain is attached to a specific lysine residue on the peptide. This fatty acid acts as a biological tether, allowing the molecule to bind tightly and reversibly to albumin, a large protein abundant in the blood plasma.
This albumin binding protects the GLP-1 analogue from both enzymatic degradation by DPP-4 and filtration by the kidneys. The result is a substantial extension of the molecule’s half-life. Agents like Liraglutide achieve a half-life of approximately 13 hours, allowing for once-daily dosing. Further advancements, such as the larger C18 diacid chain used in Semaglutide, have enabled a half-life of about one week, making once-weekly dosing possible and transforming the therapeutic landscape for metabolic diseases.