Proglucagon-Derived Peptides: The Complete Family Behind GLP-1, GLP-2, and Glucagon Therapies | Research

The takeaway

Comprehensive review of all proglucagon-derived peptides — glucagon, GLP-1, GLP-2, oxyntomodulin, glicentin, and GRPP — covering their biology and therapeutic applications from diabetes to obesity to short bowel syndrome.

1 gene, 6+ medicines
One proglucagon gene produces at least 6 bioactive peptides, several of which are now FDA-approved drugs or clinical candidates — the most therapeutically productive gene family in medicine

What the researchers found

Proglucagon-derived peptide family includes glucagon, GLP-1, GLP-2, oxyntomodulin, glicentin, and GRPP. Each has distinct biology and therapeutic applications. GLP-1 dominates current therapeutics, while oxyntomodulin and glucagon combinations are emerging.

Why it matters

Understanding the full proglucagon family explains why multi-receptor agonists (like tirzepatide and cotadutide) are so effective — they harness multiple peptides from the same natural system for synergistic metabolic effects.

The numbers in context

Covers glucagon, GLP-1, GLP-2, OXM, glicentin, GRPP; approved drugs include semaglutide, liraglutide, exenatide, dulaglutide, teduglutide

How the study worked

Comprehensive narrative review of all proglucagon-derived peptides, their processing, biology, physiological functions, and therapeutic applications.

Who was studied

N/A (review of PGDP biology and therapeutics)

What this study cannot tell us

Broad review covering extensive biology. Some peptides (glicentin, GRPP) have poorly understood functions. Therapeutic applications are at different stages of development.

How to read the evidence

Not applicable (comprehensive review). Based on decades of established biology and clinical evidence.

When this study was published

Published 2021. Multi-receptor proglucagon-based therapies continue advancing rapidly.

The bigger picture

The proglucagon gene is arguably the most therapeutically productive gene in human biology. Understanding how nature processes one protein into multiple hormones with complementary functions has directly inspired the multi-receptor drug design strategy dominating metabolic medicine.

Questions still open

Will triple agonists (GLP-1/GIP/glucagon) dominate future obesity treatment?
What are the physiological roles of the less-studied PGDPs like glicentin and GRPP?
Could targeting all proglucagon peptides simultaneously provide optimal metabolic control?

Common questions

Are GLP-1 and glucagon related?

Yes — they come from the same precursor protein (proglucagon). GLP-1 lowers blood sugar and suppresses appetite, while glucagon raises blood sugar. Paradoxically, combining both in drugs like cotadutide may produce superior metabolic benefits through complementary mechanisms.

How many drugs come from this one gene?

The proglucagon gene has produced multiple approved drugs: GLP-1 analogues (semaglutide, liraglutide, exenatide, dulaglutide for diabetes/obesity), GLP-2 analogues (teduglutide for short bowel syndrome), and glucagon (for hypoglycemia rescue). More are in development.

Read the original research

Proglucagon-Derived Peptides as Therapeutics.

Frontiers in endocrinology, 12, 689678

View on PubMed ↗Publisher’s paper ↗

Citation

Lafferty, Ryan A; O'Harte, Finbarr P M; Irwin, Nigel; Gault, Victor A; Flatt, Peter R. (2021). Proglucagon-Derived Peptides as Therapeutics.. Frontiers in endocrinology, 12, 689678. https://doi.org/10.3389/fendo.2021.689678