Expression of Ghrelin and of the GH Secretagogue Receptor by Pancreatic Islet Cells and Related Endocrine Tumors

Volante, Marco; Allìa, Elena; Gugliotta, Patrizia; Funaro, Ada; Broglio, Fabio; Deghenghi, Romano; Muccioli, Giampiero; Ghigo, Ezio; Papotti, Mauro

doi:10.1210/jcem.87.3.8279

Cited by 258 publications

(176 citation statements)

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“…Second, epsilon cells do not produce other pancreatic hormones (insulin, glucagon, somatostatin) at any time during development. Date et al [11] presented data indicating that ghrelin is co-localised with glucagon in adult human and rat pancreas, whereas results from Volante et al [12] indicated that ghrelin is co-localised with insulin in human. We were not able to confirm either of these results; instead, our data indicate that through to adult life ghrelin peptide production is confined to a distinct cell type [4,5,13,21].…”

Section: Discussionmentioning

confidence: 99%

“…The origin of epsilon cells in the rodent and human pancreas remains controversial. Ghrelin has variably been reported to be present in alpha cells in rats and humans [11], in beta cells in humans [12] or in separate cell types [4,13,14]. In human and rodent pancreases of neonates and adults, a few epsilon cells remain visible in marginal areas of the islets [4,5,13].…”

Section: Introductionmentioning

confidence: 99%

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Ghrelin-producing epsilon cells in the developing and adult human pancreas

Mercalli²,

et al. 2008

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Aims/hypothesis While the mechanisms of specification and the reciprocal relationships of the four types of endocrine cell (alpha, beta, delta and pancreatic polypeptide cells) within the human endocrine pancreas are well described in adults and during fetal development, ghrelin-immunoreactive cells (epsilon cells) remain poorly understood. Methods We studied epsilon cells in 24 human fetal pancreases between 11 and 39 weeks of development and in 32 pancreases from adult organ donors. Results We observed single epsilon cells scattered in primitive exocrine tissue from gestational week 13 in developing pancreas. Later in the developmental process, epsilon cells started to aggregate into clusters. From gestational week 21, epsilon cells were observed located around developing islets, forming an almost continuous layer at the peripheral rim of the islets. They remain localised on the mantle of the islets, although at different amounts, in the adult pancreas. Coproduction of ghrelin with insulin, glucagon or somatostatin was not detected during fetal development. Co-production with pancreatic polypeptide was evident sporadically. Epsilon cells co-produced NK2 homeobox 2 and ISL LIM homeobox 1, but not NK6 homeobox 1 and paired box 6. A quantitative analysis was performed in the adult pancreas: there was an average of 1.17+1.17 epsilon cells per islet, the relative epsilon cell volume was 0.14+0.16% and the epsilon cell mass was 0.13+0.15 g. Neither sex nor age affected the epsilon cell mass, although there was a significant inverse correlation with BMI. Conclusions/interpretation During fetal development epsilon cells show an ontogenetic and morphogenetic pattern that is distinct from that of alpha and beta cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ghrelin-producing epsilon cells in the developing and adult human pancreas

Mercalli²,

et al. 2008

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“…Limited evidence for the role of CST in tumour growth control has already been reported [16,17]. Since all immunohistochemically CST-positive tumours did not contain MrgX2 protein, whereas the expression of SRIF receptors (particularly SRIF receptors 2, 3, and 5) and/or GHSR-1a had previously been detected [20][21][22][23][24] in all samples (at either protein or mRNA level), the actions of CST were probably mediated by pathways other than CST/MrgX2 in the tumours investigated.…”

Section: Discussionmentioning

confidence: 99%

“…The SRIF receptors and GHS-R1a status of most cases of the current neuroendocrine tumour series have been reported previously [20][21][22][23][24]. Additional RT-PCR experiments for SRIF receptors and GHS-R1a were also performed in selected cases, with special reference to non-tumour and neoplastic parathyroid tissue, according to previously published protocols [20,21].…”

Section: Molecular Analysis Of Cst and Mrgx2 Transcriptsmentioning

confidence: 99%

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Expression of cortistatin and MrgX2, a specific cortistatin receptor, in human neuroendocrine tissues and related tumours

et al. 2005

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Cortistatin (CST), a novel hormone originally described in the rat, mouse, and human cerebral cortex, displays structural and functional similarities to somatostatin (SRIF). CST binds to all five somatostatin receptors and, differently from SRIF, also binds to MrgX2, which has recently been identified as its specific receptor. Little is known about the distribution of CST and MrgX2 in peripheral non-tumour and neoplastic tissues. The aim of the present study was therefore to determine by immunohistochemistry and mRNA analysis (RT-PCR) the distribution of CST and MrgX2 in 56 human non-tumour and 108 tumour tissues, with special reference to neuroendocrine tissue types. Despite the high level of CST mRNA expression in non-tumour and tumour (both neuroendocrine and nonneuroendocrine) tissues, the presence of immunoreactive CST was confirmed in a subset of gastroenteropancreatic, parathyroid, and pituitary non-tumour cells only, and showed a predominantly focal pattern in most neuroendocrine tumours. Co-localization experiments in the gastroenteropancreatic system demonstrated that the normal CST-producing cells are δ cells, while in the adenohypophysis no preferential co-localization of CST with any of the pituitary hormones was observed. MrgX2 mRNA was variably detected in the hypothalamus, pituitary, thyroid, lung, gastroenteropancreatic tract, testis, and ovary, and was negative in the cerebral cortex, parathyroid, and adrenal, as well as in a variety of tumour types. Conversely, immunolocalization of MrgX2 protein was restricted to neurohypophysis and testis, whilst all tumours analysed were negative. A possible explanation for the discrepancy between RT-PCR and immunohistochemistry is that MrgX2 protein was widely detected in blood vessels, scattered lymphocytes, and gastrointestinal ganglia in both normal and neoplastic samples. The findings demonstrate a selective distribution of CST in normal and neoplastic neuroendocrine tissues, suggesting that CST might have a broader functional role than previously assumed, whereas possible autocrine/paracrine actions via its recently described specific receptor MrgX2 are restricted to selected tissues.

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