Major contributions of comparative endocrinology to the development and exploitation of the incretin concept

J. Michael Conlon, Steven Patterson, Peter Flatt

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9 Citations (Scopus)

Abstract

An incretin is a factor released by the gut in response to nutrients that facilitates uptake of glucose by peripheral tissues. The incretin concept predates the discovery of insulin but it is now clear that incretins act by stimulating secretion of this hormone. As glucagon has insulin-releasing activity, it was speculated that intestinal glucagon-like immunoreactivity (enteroglucagon) was involved in the incretin effect but it was an achievement in the field of comparative endocrinology that led to the demonstration that the preproglucagon gene encodes the most potent incretin in the human. Characterization of cloned cDNAs encoding two preproglucagons from the Brockmann body of the anglerfish Lophius americanus demonstrated that the glucagon sequence is flanked by a 34 amino-acid-residue sequence with appreciable structural similarity to glucagon that was termed glucagon-like peptide (GLP). A 36 amino-acid-residue ortholog of anglerfish GLP was subsequently identified in human preproglucagon but this peptide had only weak insulin-releasing activity. However, alignment of GLP sequences from human and teleost fish showed that the human ortholog is extended from its N-terminus by a hexapeptide. Removal of this extension by an endogenous protease generates GLP-1-(7-36)amide, the potent and effective form of the incretin. More recently, comparative endocrinology has contributed to the exploitation of incretins as antidiabetic drugs. Exendin-4, a GLP-1 receptor agonist first isolated from the venom of the Gila monster Heloderma suspectum, is a clinically valuable, long-acting incretin and the skins of several species of frogs synthesize potent insulin-releasing peptides with therapeutic potential.
LanguageEnglish
Pages781-786
JournalJournal of Experimental Zoology Part A: Comparative Experimental Biology
Volume305A
Issue number9
DOIs
Publication statusPublished - Sep 2006

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Incretins
Endocrinology
Glucagon-Like Peptides
Proglucagon
Glucagon
Insulin
proctolin
Peptides
Lizards
Venoms
Prednisolone
Hypoglycemic Agents
Anura
Amino Acid Sequence
Fishes
Peptide Hydrolases
Complementary DNA
Hormones
Amino Acids
Glucose

Cite this

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title = "Major contributions of comparative endocrinology to the development and exploitation of the incretin concept",
abstract = "An incretin is a factor released by the gut in response to nutrients that facilitates uptake of glucose by peripheral tissues. The incretin concept predates the discovery of insulin but it is now clear that incretins act by stimulating secretion of this hormone. As glucagon has insulin-releasing activity, it was speculated that intestinal glucagon-like immunoreactivity (enteroglucagon) was involved in the incretin effect but it was an achievement in the field of comparative endocrinology that led to the demonstration that the preproglucagon gene encodes the most potent incretin in the human. Characterization of cloned cDNAs encoding two preproglucagons from the Brockmann body of the anglerfish Lophius americanus demonstrated that the glucagon sequence is flanked by a 34 amino-acid-residue sequence with appreciable structural similarity to glucagon that was termed glucagon-like peptide (GLP). A 36 amino-acid-residue ortholog of anglerfish GLP was subsequently identified in human preproglucagon but this peptide had only weak insulin-releasing activity. However, alignment of GLP sequences from human and teleost fish showed that the human ortholog is extended from its N-terminus by a hexapeptide. Removal of this extension by an endogenous protease generates GLP-1-(7-36)amide, the potent and effective form of the incretin. More recently, comparative endocrinology has contributed to the exploitation of incretins as antidiabetic drugs. Exendin-4, a GLP-1 receptor agonist first isolated from the venom of the Gila monster Heloderma suspectum, is a clinically valuable, long-acting incretin and the skins of several species of frogs synthesize potent insulin-releasing peptides with therapeutic potential.",
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N2 - An incretin is a factor released by the gut in response to nutrients that facilitates uptake of glucose by peripheral tissues. The incretin concept predates the discovery of insulin but it is now clear that incretins act by stimulating secretion of this hormone. As glucagon has insulin-releasing activity, it was speculated that intestinal glucagon-like immunoreactivity (enteroglucagon) was involved in the incretin effect but it was an achievement in the field of comparative endocrinology that led to the demonstration that the preproglucagon gene encodes the most potent incretin in the human. Characterization of cloned cDNAs encoding two preproglucagons from the Brockmann body of the anglerfish Lophius americanus demonstrated that the glucagon sequence is flanked by a 34 amino-acid-residue sequence with appreciable structural similarity to glucagon that was termed glucagon-like peptide (GLP). A 36 amino-acid-residue ortholog of anglerfish GLP was subsequently identified in human preproglucagon but this peptide had only weak insulin-releasing activity. However, alignment of GLP sequences from human and teleost fish showed that the human ortholog is extended from its N-terminus by a hexapeptide. Removal of this extension by an endogenous protease generates GLP-1-(7-36)amide, the potent and effective form of the incretin. More recently, comparative endocrinology has contributed to the exploitation of incretins as antidiabetic drugs. Exendin-4, a GLP-1 receptor agonist first isolated from the venom of the Gila monster Heloderma suspectum, is a clinically valuable, long-acting incretin and the skins of several species of frogs synthesize potent insulin-releasing peptides with therapeutic potential.

AB - An incretin is a factor released by the gut in response to nutrients that facilitates uptake of glucose by peripheral tissues. The incretin concept predates the discovery of insulin but it is now clear that incretins act by stimulating secretion of this hormone. As glucagon has insulin-releasing activity, it was speculated that intestinal glucagon-like immunoreactivity (enteroglucagon) was involved in the incretin effect but it was an achievement in the field of comparative endocrinology that led to the demonstration that the preproglucagon gene encodes the most potent incretin in the human. Characterization of cloned cDNAs encoding two preproglucagons from the Brockmann body of the anglerfish Lophius americanus demonstrated that the glucagon sequence is flanked by a 34 amino-acid-residue sequence with appreciable structural similarity to glucagon that was termed glucagon-like peptide (GLP). A 36 amino-acid-residue ortholog of anglerfish GLP was subsequently identified in human preproglucagon but this peptide had only weak insulin-releasing activity. However, alignment of GLP sequences from human and teleost fish showed that the human ortholog is extended from its N-terminus by a hexapeptide. Removal of this extension by an endogenous protease generates GLP-1-(7-36)amide, the potent and effective form of the incretin. More recently, comparative endocrinology has contributed to the exploitation of incretins as antidiabetic drugs. Exendin-4, a GLP-1 receptor agonist first isolated from the venom of the Gila monster Heloderma suspectum, is a clinically valuable, long-acting incretin and the skins of several species of frogs synthesize potent insulin-releasing peptides with therapeutic potential.

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