While incretins are of great interest for the therapy of diabetes 2, the focus has recently been brought to the thyroid, since rodents treated with glucagon-like peptide-1 (GLP-1) analogs were found to occasionally develop medullary thyroid carcinomas. Incretin receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were therefore measured in various rodent and human thyroid conditions. In vitroGLP-1 and GIP receptor autoradiography were performed in normal thyroids, C-cell hyperplasia and medullary thyroid carcinomas in rodents. Receptor incidence and density were assessed and compared with the receptor expression in human thyroids, medullary thyroid carcinomas, and TT cells. GLP-1 receptors are expressed in C cells of normal rat and mice thyroids. Their density is markedly increased in rat C-cell hyperplasia and medullary thyroid carcinomas, where their incidence amounts to 100%. GIP receptors are neither detected in normal rodent thyroids nor in C-cell hyperplasia, but are present in all rat medullary thyroid carcinomas. No GLP-1 or GIP receptors are detected in normal human thyroids. Whereas only 27% of all human medullary thyroid carcinomas express GLP-1 receptors, up to 89% express GIP receptors in a high density. TT cells lack GLP-1 receptors but express GIP receptors. GLP-1 receptors are frequently expressed in non-neoplastic and neoplastic C cells in rodents while they are rarely detected in human C-cell neoplasia, suggesting species differences. Conversely, GIP receptors appear to be massively overexpressed in neoplastic C cells in both species. The presence of incretin receptors in thyroid C cell lesions suggests that this organ should be monitored before and during incretin-based therapy of diabetes.

Holst JJ: The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409–1439.
Irwin N, Flatt PR: Therapeutic potential for GIP receptor agonists and antagonists. Best Pract Res Clin Endocrinol Metab 2009;23:499–512.
Holst JJ, Vilsboll T, Deacon CF: The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 2009;297:127–136.
Kim SJ, Nian C, Widenmaier S, McIntosh CH: Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic bcl-2 gene expression is coordinated by cyclic amp (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol Cell Biol 2008;28:1644–1656.
Ehses JA, Casilla VR, Doty T, Pospisilik JA, Winter KD, Demuth HU, Pederson RA, McIntosh CH: Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase. Endocrinology 2003;144:4433–4445.
Ahren B: Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat Rev Drug Discov 2009;8:369–385.
Sebokova E, Christ AD, Wang H, Sewing S, Dong JZ, Taylor J, Cawthorne MA, Culler MD: Taspoglutide, an analog of human glucagon-like peptide-1 with enhanced stability and in vivo potency. Endocrinology 2010;151:2474–2482.
Knop FK, Vilsboll T, Holst JJ: Incretin-based therapy of type 2 diabetes mellitus. Curr Protein Pept Sci 2009;10:46–55.
Estall JL, Drucker DJ: Glucagon and glucagon-like peptide receptors as drug targets. Curr Pharm Des 2006;12:1731–1750.
Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, Gotfredsen C, Egerod FL, Hegelund AC, Jacobsen H, Jacobsen SD, Moses AC, Molck AM, Nielsen HS, Nowak J, Solberg H, Thi TD, Zdravkovic M: Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010;151:1473–1486.
Victoza® (liraglutide injection): human relevance of rodent thyroid C-cell tumors. http://www.fda.gov/downloads/AdvisoryCommittees/Committees%20MeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM151129.pdf2009; Accessed October 5, 2010.
Korner M, Stockli M, Waser B, Reubi JC: GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007;48:736–743.
Boorman GA, van Noord MJ, Hollander CF: Naturally occurring medullary thyroid carcinoma in the rat. Arch Pathol 1972;94:35–41.
Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend F, Graw J, Atkinson MJ: Germ-line mutations in p27kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci USA 2006;103:15558–15563.
Carlomagno F, Salvatore D, Santoro M, de Franciscis V, Quadro L, Panariello L, Colantuoni V, Fusco A: Point mutation of the RET proto-oncogene in the TT human medullary thyroid carcinoma cell line. Biochem Biophys Res Commun 1995;207:1022–1028.
Massart C, Gibassier J, Raoul M, Denais A, Maugendre S, Darcel F, Lucas C: Effect of S9788 on the efficiency of doxorubicin in vivo and in vitro in medullary thyroid carcinoma xenograft. Anticancer Drugs 1996;7:321–330.
Quazzani L, Reubi JC, Volle GE, Lausson S, Pidoux E, Moukhtar MS, Treilhou-Lahille F: Evaluation of somatostatin biosynthesis, somatostatin receptors and tumor growth in murine medullary thyroid carcinoma. Eur J Endocrinol 1994;131:522–530.
Reubi JC, Waser B: Unexpected high incidence of cholecystokinin-B/gastrin receptors in human medullary thyroid carcinomas. Int J Cancer 1996;67:644–647.
Reubi JC, Chayvialle JA, Franc B, Cohen R, Calmettes C, Modigliani E: Somatostatin receptors and somatostatin content in medullary thyroid carcinomas. Lab Invest 1991;64:567–573.
Thorens B: Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA 1992;89:8641–8645.
Asmar M, Holst JJ: Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: new advances. Curr Opin Endocrinol Diabetes Obes 2010;17:57–62.
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