ADA June 2012 Conference
Alpha cells and the origin of glucagon-like sequences and their receptors
David M. Irwin, Department of Laboratory Medicine and Pathobiology, University of Toronto
Summary of presentation:
Incretin Hormones – 2 known human incretin hormones
- Glucagon-like peptide 1 (GLP-1)
- Glucose-dependent insulinotropic peptide (GIP)
Other incretins = Exendin
- Long acting GLP-1 analogue
o Acts through the GLP-1 receptor
o Have increased circulating half-life
o Synthetic version marketed
- From the venom of a lizard (Gila monster)
- No known orthologs in vertebrates, not a product of the proglucagon gene
- Anole Lizard Exendin – sequence of peptides are not similar to GLP-1 or GIP (human genome)
- Other animals had similar exendin to lizard (chicken, turkey, duck, zebra finch, xenopus)
- Exendin 1, 2, 3,and 4 sequences – exendin 3 and 4 are GLP-1 like in their sequence and function; exendin 1 and 2 similar to the are GIP-like in sequence and function
- Expression of the exendin gene in the chicken and xenopus brain – who knows what it is duing there?
- No exendin gene in human genome!
- Exendin genes are found in birds, reptiles and frogs
- No obvious candidate receptor for exendin; glucagon, GLP1, GLP2, and GIP act through related receptors
- There are novel group of receptors present in fish, reptiles, birds that are NOT present in mammals – why do mammals not have this gene?
- GLP1 receptors not found in fish
- GCGR – duplicated in fish (glucagon receptors)
- GLP2R – single copy in all species
- GIPR – no intact gene found in birds
- GRLR – not found in mammals (glucagon-receptor-like-receptors
Conclusion
o Genomic data useful for identifying new genes
o Continues to yield surprises
o Hormone and receptor families are larger and more complex
- Open questions
o What does exendin do in other vertebrates?
o Is GRLR the receptor for exendin?
o Why do humans (all mammals) not have Exendin/GRLR?
o What ligand/receptor has replace the function of Exendin/GRLR in mammals?
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