Ghrelin Expression in Islet Cell Tumors: Augmented Expression of Ghrelin in a Case of Glucagonoma with Multiple Endocrine Neoplasm Type I

Iwakura, Hiroshi; Hosoda, Kiminori; Doi, Ryuichiro; Komoto, Izumi; Nishimura, Haruo; Son, Choel; Fujikura, Junji; Tomita, Tsutomu; Takaya, Kazuhiko; Ogawa, Yoshihiro; Hayashi, Tatsuya; Inoue, Gen; Akamizu, Takashi; Hosoda, Hiroshi; Kojima, Masayasu; Kangawa, Kenji; Imamura, Masayuki; Nakao, Kazuwa

doi:10.1210/jc.2002-020882

Cited by 48 publications

(33 citation statements)

References 34 publications

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“…Several similar observations have been reported in the literature, including a case of pancreatic glucagonoma (29) and one of an ACTH-producing lung carcinoid (30). In addition, several previous immunohistochemical studies have shown that low amounts of ghrelinproducing cells may be found in association with the major hormone-producing population in many examples of functioning endocrine tumors (10).…”

Section: Discussionsupporting

confidence: 76%

Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases

Walter

Chardon²,

Hervieu³

et al. 2009

European Journal of Endocrinology

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Objective: We aimed to gain insight into the functional consequences of ghrelin overproduction in patients with neuroendocrine tumors and its relations with disease characteristics and evolution. Design: We retrospectively analyzed three cases of neuroendocrine carcinomas associated with very high levels of circulating ghrelin. Methods: Between February and October 2007, serum ghrelin levels were determined in all patients with well-differentiated endocrine carcinoma referred to our center (nZ72). Three patients were found to have circulating ghrelin levels O10-fold the upper limit of normal. The clinical, biochemical, and pathological characteristics of these three patients were reviewed. The ratio between circulating acyl and total ghrelin was determined, and tumor tissue expression of ghrelin was assayed by immunohistochemistry. Results: The three patients had massive hyperghrelinemia (respectively 49 028, 63 711, and 101 996 pg/ml), with !10% of acyl ghrelin. The corresponding primary tumors were located in the pancreas, rectum, and gallbladder; all were metastatic. There was no acromegaly; there was a decrease in appetite; and body mass index was low. Serum GH levels were only slightly increased and serum IGF1 levels were normal. Immunoreactive ghrelin was detected in the tumor tissue in the two cases in which tissue material was available. All three patients died before 12 months after the diagnosis of hyperghrelinemia. Conclusion: Well-differentiated neuroendocrine carcinomas of various origins may produce markedly high levels of circulating ghrelin, without evidence of clinical or functional consequences.

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Section: Discussionsupporting

confidence: 76%

Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases

Walter

Chardon²,

Hervieu³

et al. 2009

European Journal of Endocrinology

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“…Immunohistochemistry-Formalin-fixed, paraffin-embedded tissue sections were immunostained using the avidin-biotin peroxidase complex method (Vectastain "ABC" Elite kit, Vector Laboratories, Burlingame, CA) as described previously (36). Serial sections were used, and the thickness of each section was 5 m. Sections were incubated with anti-C-terminal ghrelin [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (1:1000 at final dilution), anti-N-terminal ghrelin [1][2][3][4][5][6][7][8][9][10][11] (1:2000) (1), which recognizes the n-octanoylated portion of ghrelin, anti-glucagon (1:500), anti-insulin (1:500), anti-somatostatin (1:500), anti-pancreatic polypeptide (PP, 1:500, DAKO, Glostrup, Denmark), anti-PDX-1 (1:2000, kindly provided by Christopher V. E. Wright) (37), and anti-GLUT2 (1:200, kindly provided by Bernard Thorens) (38) antisera.…”

Section: Methodsmentioning

confidence: 99%

Analysis of Rat Insulin II Promoter-Ghrelin Transgenic Mice and Rat Glucagon Promoter-Ghrelin Transgenic Mice

Iwakura¹,

Hosoda²,

Son³

et al. 2005

Journal of Biological Chemistry

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We developed and analyzed two types of transgenic mice: rat insulin II promoter-ghrelin transgenic (RIP-G Tg) and rat glucagon promoter-ghrelin transgenic mice (RGP-G Tg). The pancreatic tissue ghrelin concentration measured by C-terminal radioimmunoassay (RIA) and plasma desacyl ghrelin concentration of RIP-G Tg were about 1000 and 3.4 times higher than those of nontransgenic littermates, respectively. The pancreatic tissue n-octanoylated ghrelin concentration measured by N-terminal RIA and plasma n-octanoylated ghrelin concentration of RIP-G Tg were not distinguishable from those of nontransgenic littermates. RIP-G Tg showed suppression of glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion, pancreatic insulin mRNA and peptide levels, ␤ cell mass, islet architecture, and GLUT2 and PDX-1 immunoreactivity in RIP-G Tg pancreas were not significantly different from those of nontransgenic littermates. Islet batch incubation study did not show suppression of insulin secretion of RIP-G Tg in vitro. The insulin tolerance test showed lower tendency of blood glucose levels in RIP-G Tg. Taking lower tendency of triglyceride level of RIP-G Tg into consideration, these results may indicate that the suppression of insulin secretion is likely due to the effect of desacyl ghrelin on insulin sensitivity. RGP-G Tg, in which the pancreatic tissue ghrelin concentration measured by C-RIA was about 50 times higher than that of nontransgenic littermates, showed no significant changes in insulin secretion, glucose metabolism, islet mass, and islet architecture. The present study raises the possibility that desacyl ghrelin may have influence on glucose metabolism.Ghrelin is a 28-amino acid peptide with unique modification of acylation, which is essential for its biological action (1). Ghrelin was originally identified in rat stomach as an endogenous ligand for an orphan receptor, which has been so far called growth hormone secretagogue receptor (GHS-R) 1 (1). Ghrelin expression is detected in the stomach, intestine, hypothalamus, pituitary gland, kidney, placenta, and testis (2-6). Ghrelin is involved in a wide variety of the functions, including the regulation of growth hormone release, food intake, gastric acid secretion, gastric motility, blood pressure, and cardiac output (7-19).Recently Date et al. (20) reported that ghrelin is present in ␣ cells of normal human and rat pancreatic islets. Volante et al. (20,31,32). Salehi et al. have reported ghrelin has both inhibitory and stimulatory effects depending on its concentration (33). Therefore, there is still a lot of controversy about the localization of ghrelin in the pancreas and the effects of ghrelin on the insulin secretion. As for the effects of desacyl ghrelin on insulin secretion, Broglio et al. (34) have reported that acute desacyl ghrelin administration has no effect on insulin secretion in human but that it counteracts the inhibitory effect of n-octanoylated ghrelin on insulin secretion when co-administrated with n-octanoylated ghrelin (35).Here...

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“…Acetic acid was added to each solution to adjust the final concentration to 1 M before tissue homogenization. We determine the tissue ghrelin concentration in supernatants obtained after centrifugation by radioimmunoassay (RIA) using anti-ghrelin [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (C-RIA) and anti-ghrelin [1][2][3][4][5][6][7][8][9][10][11] (N-RIA) antisera, as described previously (12,15).…”

Section: Measurement Of Plasma and Tissue Ghrelin Concentrationsmentioning

confidence: 99%

Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo

Bando

Iwakura

Ariyasu

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Whereas ghrelin is produced primarily in the stomach, a small amount of it is produced in pancreatic islets. Although exogenous administration of ghrelin suppresses insulin secretion in vitro or in vivo, the role of intraislet ghrelin in the regulation of insulin secretion in vivo remains unclear. To understand the physiological role of intraislet ghrelin in insulin secretion and glucose metabolism, we developed a transgenic (Tg) mouse model, rat insulin II promoter ghrelin-internal ribosomal entry site-ghrelin O-acyl transferase (RIP-GG) Tg mice, in which mouse ghrelin cDNA and ghrelin O-acyltransferase are overexpressed under the control of the rat insulin II promoter. Although pancreatic desacyl ghrelin levels were elevated in RIP-GG Tg mice, pancreatic ghrelin levels were not altered in animals on a standard diet. However, when Tg mice were fed a medium-chain triglyceride-rich diet (MCTD), pancreatic ghrelin levels were elevated to ϳ16 times that seen in control animals. It seems likely that the gastric ghrelin cells possess specific machinery to provide the octanoyl acid necessary for ghrelin acylation but that this machinery is absent from pancreatic ␤-cells. Despite the overexpression of ghrelin, plasma ghrelin levels in the portal veins of RIP-GG Tg mice were unchanged from control levels. Glucose tolerance, insulin secretion, and islet architecture in RIP-GG Tg mice were not significantly different even when the mice were fed a MCTD. These results indicate that intraislet ghrelin does not play a major role in the regulation of insulin secretion in vivo.pancreas; ghrelin D-acyltransferase GHRELIN IS A 28-AMINO ACID PEPTIDE HORMONE, with a unique modification of acylation at the third serine residue, first described by Kojima et al. (17) in 1999. The acyl modification of ghrelin is mediated by the recently discovered enzyme ghrelin O-acyl transferase (29), and the modification is essential for ghrelin binding to its cognate receptor (12). Ghrelin is produced primarily in the stomach, but small amounts of ghrelin are also produced in pancreatic islets (1,5,8,10,12,26,27). Controversy remains about which type of islet cell produces ghrelin (5,20,26,27). Date et al. (5) reported that ghrelin is present in ␣-cells in humans and rats, whereas Volante et al. (26) reported that ghrelin is produced by ␤-cells in humans. In contrast, Wierup and colleagues (27, 28) and Prado et al. (20) reported that ghrelin-expressing cells comprise a new islet cell type distinct from ␣-, ␤-, and ␦-cells and PP cells in human, rat, and mouse islets.Exogenous ghrelin suppresses insulin secretion from pancreatic ␤-cells in vitro (4, 9, 22) or in vivo (3,22,25). Although several studies have demonstrated contradictory results (1,5,11,18,24), data from genetically engineered mice are consistent with this concept. Chronic elevation of plasma ghrelin levels suppresses insulin secretion, inducing glucose intolerance in transgenic mice (2, 13, 21), whereas ablation of ghrelin improves glucose tolerance by enhancing insulin secretion in...

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Ghrelin Expression in Islet Cell Tumors: Augmented Expression of Ghrelin in a Case of Glucagonoma with Multiple Endocrine Neoplasm Type I

Cited by 48 publications

References 34 publications

Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases

Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases

Analysis of Rat Insulin II Promoter-Ghrelin Transgenic Mice and Rat Glucagon Promoter-Ghrelin Transgenic Mice

Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo

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