Table of Contents

    The Generation and Function of Active GLP-1

    The Generation and Function of Active GLP-1

    Active glucagon-like peptide-1 (GLP-1) is a member of the incretin hormone family and is generated as a result of post translational modifications during proglucagon processing1,2. Active GLP-1 plays a key role in the incretin effect and is vital for maintaining glucose homeostasis1,2. As such, both the generation and function of active GLP-1 have become important aspects of type 2 diabetes (T2D) research2.

    This process map outlines the synthesis of active glp-1 and the incretin effect.

    Proglucagon Processing

    The process of generating active GLP-1 is referred to as proglucagon processing. This begins with the synthesis of preproglucagon (PPG), the single precursor to all of the proglucagon peptides3. The synthesis of preproglucagon is highly regulated and occurs in the gut, brain, and pancreas3-7. A post translational modification (PTM) enzymatically cleaves preproglucagon into proglucagon3.

    Active GLP-1 Forms Generated by the Gut and Brain

    In the gut and brain, proglucagon is then further processed into various proglucagon peptides, including active GLP-18,9. Two active forms of GLP-1 are generated in the gut and brain: active GLP-1 (7-36) amide and active GLP-1 (7-37) non-amide10. However, research indicates that active GLP-1 (7-36) amide is the most predominant form in circulation and can provide an accurate representation of active GLP-1 levels11, 12.

    This diagram illustrates the generation of active GLP-1 forms in the gut and brain.

    The Incretin Effect and Active GLP-1

    Research indicates that active GLP-1 has many physiological effects on the body such as the incretin effect. Following the intake of nutrients, the beginning of the incretin effect is marked by rising levels of active GLP-1 which promote the synthesis and release of insulin 1,2,4. This cyclical pathway is vital to maintain energy homeostasis 1,2,4.

    This chart outlines the mechanisms of the incretin effect.

    The Generation of Active GLP-1 Metabolites and Isoforms

    Multiple metabolites and isoforms of active GLP-1 exist in circulation. The enzyme dipeptidyl peptidase 4 (DPP-4) cleaves active GLP-1 (7-36) amide and (7-37) non-amide after secretion from the gut and brain, forming two GLP-1 metabolites8,10,12,13. Additionally, research indicates that the pancreas can secrete two isoforms of active GLP-1 under metabolic stress12,13,14.

    Diabetes Research and GLP-1

    Active GLP-1 is highly conserved across mammalian species, allowing investigators to study the hormone across different model organisms such as rodents and humans for over 20 years2,10,15.  Early research discovered a reduced incretin effect in individuals with type 2 diabetes following oral glucose intake16,17,18.

    More recently, researchers are trying to understand the connection between active GLP-1 and sweet taste transmission to uncover new treatments for diabetes and obesity19,20,21,22.

    Conclusion

    Active GLP-1 is a gut hormone derived as a result of proglucagon processing1,2. Once active GLP-1 is secreted, the enzyme DPP-4 quickly cleaves the majority of the hormone10 and the remaining active GLP-1 enters circulation. Active GLP-1 then flows to peripheral organs where it stimulates the incretin effect1,2,10. The unique generation and function of active GLP-1 has influenced growing interest in the hormone, and its reputation as an important biomarker in type 2 diabetes research16,21,23.

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    References

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