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Gastric Inhibitory Polypeptide (GIP)*

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Gastric Inhibitory Polypeptide (GIP)* J Clin Pathol: first published as 10.1136/jcp.s1-8.1.31 on 1 January 1978. Downloaded from J. clin. Path., 33, Suppl. (Ass. Clin. Path.), 8, 31-37 Gastric inhibitory polypeptide (GIP) * D. L. SARSON From the Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 OHS As long ago as 1930, Kosaka and Lim proposed a sample with 8. 0 M urea. Thus, this peak may humoral agent capable of inhibiting gastric acid represent a protein/peptide complex. secretion after a meal. They coined the term entero- (2) A large molecular form which may correspond gastrone. Using crude preparations of cholecysto- to either a 'big GIP' or a precursor pro-GIP. kinin-pancreozymin (CCK PZ) in dogs they were (3) A 5000 dalton molecular form. This peak elutes able to inhibit the acid secretion normally stimulated in the same position as porcine standard and by a meat meal or histamine. They went on to 1251-labelled GIP. experiment with duodenal extracts, prepared after The exact nature and properties of these different the instillation into the duodenum of olive oil, molecular species require further analysis to deter- and found a similar effect to that seen with crude mine which form or forms of GIP are biologically CCK PZ. The effects of similar crude preparations active. ofCCK PZ in the dog were confirmed Brown On the basis of several by and amino-acid sequence copyright. Pederson in 1970, but further purification of this homologies GIP has been placed in the classical material led to a diminution of the acid inhibitory secretin-glucagon-VIP family of peptides. Indeed effect (Brown and Pederson, 1970). In 1971, Brown and Dryburgh purified and sequenced this gastric inhibitory fraction and found it to be a polypeptide 30 quite distinct from other known peptide hormones. By virtue of its acid inhibitory properties they 20 http://jcp.bmj.com/ named it gastric inhibitory polypeptide, GIP. 10 Chemistry GIP consists of 43 amino-acid residues in a single .0 30. Jejunal extract U chain, with a molecular weight of 5105 daltons. The 20- amino-acid sequence is shown below. Residues which have been underlined correspond to sequence homo- 0 10 on September 27, 2021 by guest. Protected logies with other members of the secretin-VIP- E_ glucagon family of peptides. L J . jA. af J . '-.a Tyrl-Ala-Glu-Gly-Thr5-Phe-Ile- Ser-Asp-Tyr10- 30 Ser-Ile-Ala-Met-Asp15-Lys-Ile-Arg-Gln-Gln2O- Normal fasting plasma Asp-Phe-Val-Asn-Trp25-Leu-LeuAla-Gln-G]n3k 20 A Lys-Gly-Lys-Lys-Ser35-Asp - Trp - Lys - His- Asn40-Ile-Thr-Gln Chromatographic analysis of jejunal extracts and A ..AA _.it of serum taken after a mixed meal has shown that Protein Cytochrome C Insulin GIP Glucagon GIP exists in more than one molecular form (Brown 125J et al., 1975; Sarson et al., 1979). Three distinct peaks 3j of immunoreactive GIP have been shown (Fig. 1). Fc3onumbe 45 50 5 (1) A high molecular weight fraction which occurs Fraction number in the void volume. A significant reduction in this peak is seen following Fig. 1 Chromatographic analysis ofjejunal extract pretreatment of the andfasting plasma showing the peaks of *Now often referred to as glucose-dependent insulinotropic poly- immunoreactive GIP. The position ofseveral markers is peptide. indicated below the plasma extract. 1 J Clin Pathol: first published as 10.1136/jcp.s1-8.1.31 on 1 January 1978. Downloaded from 32 D. L. Sarson these structural similarities are mirrored effectively in shared pharmacological activities. Examples of properties common to these substances are inhibition of gastric acid secretion and the in vivo and in vitro release of insulin. CELLULAR LOCALISATION AND DISTRIBUTION The availability of suitable antisera to GIP has made it possible to localise the GIP-containing cells by indirect immunofluorescence studies. Work reported in 1973 by Polak and colleagues tentatively identified the GIP cell as residing in the middle layer of the upper intestinal mucosa. Recently the site of anti- GIP antiserum activity has been shown to be the K cell, previously classified by electron microscopy according to the appearance of its granules (Buffa et al., 1975). Radioimmunoassay of GIP in extracts of homo- genised gut tissue has confirmed these histochemical findings. Immunoreactive GIP (IR GIP) has been found to be distributed throughout the upper small intestine (Fig. 2), with the greatest concentration in the jejunal mucosa (Bloom et al., 1975). copyright. MEAS UREMENT The crude bioassay employed by Brown and co- workers in the course of purifying GIP is far too insensitive to detect the small quantities in the circulation released by physiological stimuli. This is only possible by the use of a sensitive and highly http://jcp.bmj.com/ specific radioimmunoassay. Several such assays have 0 1-1i been reported (Kuzio et al., 1974; Lauritsen and o 11-30 *>31 Moody, 1978; Morgan et al., 1978; Sarson et al., No of cells per rnm2 1979), but there appears to be little agreement between different authors with regard to basal and Fig. 2 Distribution of GIP in the gastrointestinal tract of man. The numbers denote the concentration of postprandial serum concentrations. In some cases immunoreactive GIP, and the shading denotes the ten-fold differences have been reported. frequency of GIP-containing cells. on September 27, 2021 by guest. Protected Several factors probably contribute to these differences. Primarily, the affinity of the antisera for completely clear. A possible factor is the presence of each different molecular form of IR GIP needs to be two tyrosine residues which may result in excessive determined, and also whether the forms measured incorporation of 126iodine. Another is oxidation of reflect biological activity. the methionine residue during iodination. The Secondly, but of equal importance, are the diffi- resulting damaged peptide is poorly recognised by the culties arising from the poor antigenicity of GIP, antisera and is unstable, with a short shelf life. and the need to conjugate it with a larger molecule. Some assayists have also noted non-specific inter- The latter procedure may lead to conformational ference by plasma, and plasma extraction techniques damage to the molecule, resulting in subsequent have been introduced. Some authors have even been problems in the assay. Moreover, the shortage ofpure tempted to set up their standard curves in buffer GIP has led to the use oflarge amounts ofimpure pre- devoid of plasma, thereby effectively hiding the parations for the raising of antisera. The major con- problem. In several cases GIP antibodies have also sequence of this is the production of a heterogeneous been shown to be rapidly dissociated from 125I-GIP population of antibodies with low specificity. by charcoal slurry. This has necessitated the use of Another common difficulty is the preparation of alcohol precipitation or double antibody separation the radio-labelled peptide with high specific activity techniques, though it is a feature generally found and full immunogenicity. The reason for this is not with low affinity antisera. J Clin Pathol: first published as 10.1136/jcp.s1-8.1.31 on 1 January 1978. Downloaded from Gastric inhibitory polypeptide (GIP) 33 In spite of the difficulties encc)untered with GIP Intravenous administration of these nutrients does radioimmunoassays and the differences in reported not elicit a GIP response. values of circulating hormone, thiere has been con- siderable agreement on the nature cDfthestimuli which INHIBITION OF GASTRIC ACID SECRETION release GIP. The results so far haive provided much GIP was originally discovered and named as the acid useful and exciting information 'with regard to the inhibitory fraction of crude CCK PZ. Its release by physiology and pathology of this new hormone. fat and glucose, which are both potent inhibitors ofgastric acid secretion, further suggested an 'entero- Physiology gastrone' role. Much of the initial work was carried out in dogs, in which a clear relationship between There have been several actions described for GIP inhibition of acid secretion and GIP release was and these are listed below. seen. Thus, infusions of porcine GIP, to attain (l) The inhibition of gastric acid secretion. circulating levels within the physiological range, (2) The inhibition of pepsin secretion. inhibited pentagastrin-stimulated acid secretion in (3) The inhibition of gastric motcDr activity. dogs with denervated fundic pouches (Pederson and (4) The stimulation of insulin release. Brown, 1972); there was a good dose/response (5) The stimulation of glucagon rrelease. relationship. The instillation of lipomul, a trigly- (6) The stimulation of the flow offjejunal water and ceride suspension, into the duodenum evoked a rise electrolytes. in circulating plasma IR GIP and a reduction in acid Some of these actions are nomv considered to be secretion ofthe order of70 %. However, the hydrogen pharmacological rather than ph3ysiological as they ion secretion returned to normal while the circulating are only seen with plasma concenitrations far higher GIP levels remained substantially raised. This than those encountered after natiural stimuli. Thus, differed from the effect of intravenous GIP, after the role of GIP in gastric acid inhibition and as an which acid secretion returned to control levels copyright. enteric releaser of insulin have cormmanded the most concurrently with the fall in GIP. It was suggested attention. that the triglyceride mixture released the larger The ingestion of a mixed mteal results in an molecular form of GIP which had no enterogastrone increase of circulating GIP concentration, the peak activity (Pederson et al., 1978). occurring after about 45 minutes. Separation of the The role of GIP in the inhibition of acid secretion meal into its constituent nutrients showed that the in man is less well understood than in dogs, and has most potent stimuli to GIP release are carbohydrates given rise to conflicting reports.
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