Elsevier

Regulatory Peptides

Volume 93, Issues 1–3, 25 September 2000, Pages 45-51
Regulatory Peptides

Gut hormones as pharmaceuticals: From enteroglucagon to GLP-1 and GLP-2

https://doi.org/10.1016/S0167-0115(00)00185-3Get rights and content

Introduction

Close to twenty years ago, I reviewed the field of what I had previously designated “extrapancreatic glucagons” for Gastroenterology[1]. At that time, the molecular nature of the enteroglucagons, glucagon-like molecules from the gut — had just been elucidated, but the functions of the L-cells, the endocrine cells of the gut epithelium which produce these molecules, were largely unknown. We also knew that the enteroglucagons and glucagon from the pancreas were likely to derive from the same precursor molecule [2], and that this molecule (it was designated “proglucagon” already then) contained a large sequence of approximately 10 kDa, the nature of which was largely unknown. I remember assuring the editors of Gastroenterology that my review was completely up-to-date and that major breakthroughs were unlikely to occur within the foreseeable future. My review appeared in early April 1983, and in that same month, Graham Bell and coworkers published the full sequence of hamster proglucagon cDNA [3] (and later that summer, the structure of the human glucagon gene [4]), revealing the complete structure of the C-terminal part of proglucagon, containing the sequences of the glucagon-like peptides GLP-l and GLP-2. It is difficult to make prophesies, particularly about the future. Today, I think it is fair to conclude that the function of the L-cell is to produce the glucagon-like peptides whereas the glucagon-containing “enteroglucagons” appear to be waste products. (In the pancreas we have the opposite situation — here secretion of glucagon is the important function whereas the two glucagon-like peptide are lumped together in another waste product, the “major proglucagon fragment” (MPGF) which corresponds to the 10 kDa fragment mentioned above [5].) This review tells the story of the glucagon-like peptides of the gut and their remarkable physiological and pharmaceutical potential.

Section snippets

The enteroglucagons

Glucagon was discovered already in 1923, and in 1947, Sutherland and deDuve [6] found evidence of the presence of a similar hyperglycemic substance in the gastrointestinal mucosa. Roger Unger, one of the pioneers of radioimmunological analysis of hormones, and varying co-workers confirmed that gut mucosal extracts contained at least two substances with glucagon-like immunoreactivity (“GLI” or “gut GLI”) but also found that the substances differed from glucagon with respect to molecular size and

The glucagon-like peptides (GLP-1 and GLP-2)

As mentioned, the GLPs are the major constituents of the 10 kDa C-terminal fragment of proglucagon, now most often designated the major proglucagon fragment (MPGF) [5]. They are glucagon-like because of about 50% sequence homology with glucagon [4]. Actually the existence of GLP-1 was predicted already around 1980 when Lund and associates cloned glucagon-encoding cDNA from anglerfish pancreas [23]. After the equivalent of a glicentin sequence the anglerfish pancreatic proglucagon contains a

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