Invited reviewMolecular evolution of proglucagon
Introduction
The proglucagon gene encodes several peptide hormones with essential roles in regulating carbohydrate, lipid and amino acid metabolism [1], [2], [3]. Glucagon is a 29-amino acid peptide hormone that is produced and secreted by pancreatic islet A-cells and plays a direct role in regulating metabolism [1]. Proglucagon encodes two additional glucagon-like peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) [4], [5], [6]. In mammals, GLP-1 is secreted by intestinal L-cells and indirectly regulates glucose metabolism by acting as an incretin hormone potentiating the release of insulin by pancreatic islet B-cells [7], [8]. In contrast, fish GLP-1 is secreted by both the intestine and pancreas and has a biological activity similar to glucagon [9], [10], [11]. To date, the biological activity of GLP-2 has only been identified in mammals, where it acts as an intestinal epithelial growth factor when administered to rodents [12].
Tissue-specific proteolytic processing in mammals [13], [14] regulates the production of glucagon, GLP-1, and GLP-2. Glucagon is secreted by pancreatic islet A cells, whereas glucagon-like peptides-1 and -2 are produced in the L-cells of the intestine and within selected neurons of the brain [2], [3]. In some non-mammalian vertebrates, alternative mRNA splicing may have a role in determining tissue-specific expression of GLP-2. For example, pancreatic proglucagon mRNAs from anglerfish (Lophus americanus), rainbow trout (Oncorhynchus mykiss), chicken (Gallus gallus), and gila monster (Heloderma suspectum) do not encode GLP-2, while intestinal proglucagon mRNAs encode GLP-2 [4], [15], [16], [17]. As a result, post-translational processing of preproglucagon in the pancreas of these species cannot yield GLP-2. In the frog Xenopus laevis, all proglucagon mRNAs in the intestine encode GLP-2, while only 50% of mRNA in the pancreas encodes GLP-2 [18]. Interestingly, proglucagon mRNA isolated from the Xenopus laevis stomach did not encode GLP-2. Frog proglucagons also differ from those of other vertebrates due to the presence of multiple GLP-1-like sequences encoded by the proglucagon gene [18], [19], [20]. The multiple GLP-1-like sequences are the result of duplication events that occurred on the frog lineage [20]. Characterization of mammalian proglucagon genes has shown that glucagon, GLP-1, and GLP-2 are each encoded by separate exons [21], [22]. This structure of the proglucagon gene suggests that these three peptides originated by triplication of an exon that encoded a glucagon-like sequence.
Previous evolutionary analyses of proglucagon sequences have indicated that the glucagon, GLP-1, and GLP-2 sequences within the proglucagon gene originated prior to the diversification of vertebrates more than 500 million years ago [23], [24]. These studies also demonstrated that the proglucagon gene has independently duplicated with the jawless fish (Agantha) and bony fish (Osteichthyes) lineages, resulting in the presence of two glucagon and/or GLP-1 sequences in many species. We have chosen to explore the evolution of all known proglucagon-derived sequences to better understand the origin and divergence of the unique biological function of glucagon, GLP-1 and GLP-2.
Section snippets
Sequences
Sequences for proglucagon, glucagon, GLP-1, and GLP-2, either deduced or predicted, are available in the literature or in GenBank from more than 50 species representing all classes of vertebrates. The species and numbers of peptide sequences used in this study are listed in Table 1. Incomplete sequences, sequences that contain internal deletions, or sequences that may not be functional are indicated in Table 1, and were not used in our analysis. All sequences used were readily alignable
Structure of proglucagon
The amino acid sequences of proglucagon-derived peptides have been deduced or predicted from 52 different vertebrate species (Table 1). In most of these species, the sequences of the individual peptide hormones, rather than the full-length proglucagon sequence is known. In 15 of the 52 species, one or two cDNA sequences (for a total of 19 cDNA sequences, see Table 1) have been determined, thereby allowing the prediction (in all but one species, see below) of full-length proglucagon sequences.
Conclusions
Our analysis of glucagon, GLP-1, and GLP-2 sequences has shown that each has evolved in a unique and independent fashion. Glucagon has evolved at an accelerated rate within bony fish. GLP-1 has either evolved at an accelerated rate in frogs, bony fish, and cartilaginous fish, or has slowed down within mammals, birds and reptiles (and few other species). In contrast, GLP-2 has experienced an episode of accelerated evolution on the lineage that leads to mammals. Some of these changes in
Acknowledgements
I thank Drs. R. Boushey, P. Brubaker, D. Drucker, H. Elshotz, T. Mommsen, M. Wheeler, and J. Youson for discussions and suggestions. This work was supported by a grant from the Natural Sciences and Engineering Research Council.
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2020, Prostaglandins and Other Lipid MediatorsCitation Excerpt :GLP-1 is an incretin hormone derived from posttranslational proteolysis of Preproglucagon, and is discharged from the intestine after food intake. The hormone has powerful trophic and insulinotropic effects on the beta cells of the pancreas and is currently used as an anti-diabetic agent in DM2 patients [191–193]. GLP-1 receptors are widely distributed including on endothelial cells in both coronary and skeletal muscle circulation and on the myocardium [194].