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A Tale of Two Islets

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A Tale of Two Islets -~-2------------------------------------N8NSANDVI8NS,--------------------N_A_~--_V_OL_.~_I_I_7_Am__ RU_M_Y __ I~_ Growth honnone-releasing factor The work reported from Guillemin's group in this issue 3 (p.607) has come close to clinching the deal by showing that in the monkey and human, nerve fibres around A tale of two islets the primary capillary plexus of the from George Fink hypophysial portal vessels stain immuno­ histochemically with an antiserum raised in l THE two recent reports ,2 of the isolation residues long and had the sequence H-Tyr­ rabbits against hpGRFI -40' Cell bodies in and sequencing of human pancreatic Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr­ the tuberal nuclei were also immuno­ growth hormone-releasing factor (hpORF) Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala­ reactive. The antiserum did not stain fibres from the laboratories of Roger Guillemin Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser­ or cell bodies in the hypothalamus of either and Wylie Vale have rapidly been followed Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu­ the rat or the ox, perhaps not surprising by immunohistochemical evidence from Arg-Gly-A1a-Arg-A1a-Arg-Leu-NH 2' The since the antiserum was raised against a Guillemin's group that hpGRF is the same peptide isolated by Vale 2 was 40 amino acid human peptide. Bloch et 01.3 speculate that as the hypothalamic factor that normally residues long and had a sequence identical this may be due to species differences in the stimulates growth hormone release. In this to the first 40 residues of Guillemin's 28-40 region of the molecule which is issue of Nature (p. 607) , Bloch and col­ peptide. The two other factors found by devoid of GRF bioactivity. Species dif­ leagues3 show that an antiserum against the Guillemin to release growth hormone com­ ferences may also explain some of the dif­ hpGRF peptide specifically stains neural prised the 1-37 and 1-40 sequences of the ferences in the GRF activity of extracts of cell bodies in areas of the primate 44-residue hpGRF. porcine stalk median eminence compared hypothalamus associated with the Both Vale and Guillemin agree that the with that of GRF partially purified from hypothalamic peptide (GRF). N-terminus is essential for biological islet tumour tissue9. The isolation and sequencing of hpGRF activity [deletion of -Tyr (ref. 4), or Tyr­ Peptide isolation aside, there is much was only made possible by the existence of Ala or Tyr-Ala-Asp (ref.l) leads to almost fundamental biology to be learned from two islet cell tumours, one in a patient at total loss of activity) but whereas Guillemin the studies carried out on Thorner's 6 Charlottesville, Virginia and another in a found that hpGRFI_37 had only 12 per cent patient as well as from the elegant case 2 patient at Lyon. Carcinomas of the of the activity of hpGRFI _ 44, Vale reports of Lawrence Frohman 10 whose pancreatic islets (the islets of Langerhans) reported that the first 29 residues were work on extrapituitary GRF activity must are relatively infrequent (less than sufficient for full expression of activity in be considered as the stimulus and model for 11100,000 of the population4) and because vitro. The peptide has several sequence the studies by Guillemin and Vale. they often secrete large amounts of homologies with peptides of the glucagon­ Thorner's patient showed the hallmarks of different types of peptide hormones they secretin family, but none of these peptides acromegaly due to a pituitary adenoma: are extremely difficult to diagnose. The has growth hormone-releasing activity. plasma growth hormone concentrations tumours most commonly secrete the The greatest homology is with a 27-residue were increased in response to glucose hormones indigenous to the pancreas - peptide recently isolated from porcine gut, (instead of suppressed), increased after insulin (symptoms of hypoglycaemia), PHI-27 (ref. 7), which has 12 residues that TRH administration (instead of no change) gastrin (gastric or duodenal ulceration and are also present in equivalent positions in and decreased with dopamine infusion diarrhoea; Zollinger-Ellison syndrome), hpGRFI_27 • (instead of increased), Were these abnor­ glucagon (mild diabetes mellitus and The isolation of hypothalamic GRF, like mal responses due to intrinsic changes in dermatitis) and somatostatin (hypochlor­ the other hypothalamic regulatory the hypertrophic pituitary somatotrophs or hydria. steatorrhoea and diabetes peptides, has been a will-o-the-wisp. changes in ligand-receptor interactions mellitus)4,5. Less frequently they secrete Andrew Schally caused a flurry of interest brought about by excessive exposure to hormones ectopic to the pancreas such as when in 1971 he published the structure of GRF, or did these factors (glucose, TRH secretin (leading to 'pancreatic cholera'), GRF (from porcine hypothalamus)8 as and dopamine) act on the tumour directly adrenocorticotropin (presenting with H-Val-His-Leu-Ser-Ala-Glu-G1u-Lys­ to affect hpGRF release? What happens to features of Cushing's syndrome), sero­ Glu-Ala-OH, but although his peptide somatostatin (in brain and pancreas) in tonin (associated with watery diarrhoea, appeared to release growth hormone as these situations in view of the fact that flushes and tachycardia)4 and in the present assessed by bioassays (which used, in the somatostatin inhibits the growth hormone case, hpGRF (associated with acromegaly). main, the capricious pituitary growth response to GRF release in a non­ The isolation of hpGRF was carried out hormone depletion-tibia assay), it was competitive manner5,9? Whatever the quite separately by two teams at the same never found to release growth hormone as answers to these and other questions institute - the Salk Institute - and headed measured by radioimmunoassay. regarding GRF biosynthesis and its role in respectively by Wylie Vale (Peptide Guillemin attributes the difficulty of gut and pancreas, the diagnosis and Biology Laboratory) and his former isolating GRF from hypothalamus to the removal of two islet cell carcinomas has mentor Roger Guillemin (Laboratories for incredibly small tissue concentration in made two patients, two peptide chemists Neuroendocrinology). Peptide isolation, comparison with that of other and several biological firms very happy. 0 like the Americas Cup, offers no second hypothalamic neuropeptides (femtomoles place, but in this case the race appears to compared with pico- and nanomoles). George Fink is Director of the MRC Brain have been a dead heat. Metabolism Unit, University Department of Guillemin and Vale both argued that Phamacology, 1 George Square, Edinburgh Vale's tumour was removed from a hpGRF is likely to be identical to the EH89JZ. 21-year-old woman who presented at Mike hypothalamic GRF by analogy with other I. Guill.min, R. el al. Science 218, 585 (1982). Thorner's (formerly of Bart's) clinic in ectopic hormones, the structure of which 2. Rivier. J., Spiess, J . t Thorner, M. & Vale. W. NQIUTt Charlottesville with Turner's syndrome has always been similar or identical to the 300.276 (1982). 3. Bloch, B. el al. Biochem. biophys. Res. Commun. 45, and the signs and symptoms of structure of the same hormone produced 23S (1971). acromegaly6, Guillemin obtained his by the tissue to which it is indigenous. 4. Schein, P.S., ., al. Ann. inl. Med. 79,239 (1973). tumour by way of the 'French connection'; S. Larsson. LA . • , al. Lilncel i, 666 (1977). Further, both groups had shown that 6. Thorner, M.O. el al. J. din. Invesl. 70. 96S (1982) . it was removed from a man who presented partially purified rat hypothalamic GRF 7. Tatemoto, K. & Mutt, V. Pro<:. naln. Acad. Sci. U.S.A. with acromegaly at the clinic of G. Sassolas (rGRF) co-eluted with hpGRF on 71.6603 (1981). 8. Schally, A.V ., Baba, Y., Nair, R.M.G. & Bennett. C.A. at Lyon I. Both teams used essentially the chromatography and that in terms of J. bioi. Chem. 246,6647 (1971). same methods - gel filtration, HPLC and growth hormone released, the dose­ 9. Szabo, M., Chu, L. & Frohman, L. Endocrinology III, 123S (1982). Edman degradation. Guillemin 1 isolated response curves for rGRF were parallel to 10. Frohman, L.A., Szabo. M., Berelowilz, M. & Slachura. three peptides, the largest of which was 44 those for hpGRF. M.E. J. C/in. Invesl. 65,43 (1980). 0028·0836/ 83 / 070562·0ISOI.00 Cl 1983 Macmillan Journal. Ltd .
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