Potential of GLP-1 in Diabetes Management

As reviewed in Chap. 3, this volume, glucagon-like peptide-1 (GLP-1) is the designation given to the sequence in proglucagon corresponding to residues Nos. 72–108 (Bell et al. 1983a, 1983b). In proglucagon, this sequence is flanked by pairs of basic amino acid residues, i.e., typical processing cleavage sites, and shows an almost 50% homology with glucagon itself; hence its designation. Early immunochemical studies indicated that the proteolytic processing of proglucagon would, indeed, lead to the formation of this peptide, but mainly in the intestinal mucosa, whereas in the pancreas this sequence was contained in the “major proglucagon fragment” as predicted by Patzelt (Mojsov et al. 1986; Orskov et al. 1986; Patzelt and Schiltz 1984). Synthetic replicas of this sequence, which were soon made available after the structure of proglucagon had been deduced (Bell et al. 1983b), were reported to exhibit weak insulinotropic activity (Schmidt et al. 1985), but most investigators found the peptide inactive (Orskov 1992). Physiological and pathophysiological studies had clearly shown that the distal intestinal mucosa, in which the glucagon gene is being expressed in the so-called L cells (Mojsov et al. 1986; Novak et al. 1987), contained an insulinotropic hormone distinct from gastric inhibitory polypeptide (GIP) (Ebert 1990; Lauritsen et al. 1980; Moody et al. 1970; Novak et al. 1987). Therefore, a search for alternative products of intestinal expression of the glucagon gene was carried out, and it turned out that intestinal extracts contained a peptide with GLP-1-like immunoreactivity which was potently insulinotropic (Holst et al. 1986, 1987).