Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion

Egido, Eva M.; Rodriguez-Gallardo, J.; Silvestre, RA; Marco, José

doi:10.1530/eje.0.1460241

Cited by 252 publications

(171 citation statements)

References 22 publications

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“…Second, we have demonstrated that, in two mouse models, an early block in the differentiation of insulin-producing ␤ cells leads to an enormous increase in ghrelin-producing cells, perhaps through a cell fate switch. Although the physiological role of ghrelin remains controversial, several studies have demonstrated that ghrelin functions to regulate insulin activity (28)(29)(30). Therefore, it is remarkable to find a genetic link between these two hormones.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin cells replace insulin-producing β cells in two mouse models of pancreas development

Prado

Pugh‐Bernard

Elghazi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

417

442

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The pancreatic islet is necessary for maintaining glucose homeostasis. Within the pancreatic islet, the homeodomain protein Nkx2.2 is essential for the differentiation of all insulin-producing ␤ cells and a subset of glucagon-producing ␣ cells (1). Mice lacking Nkx2.2 have relatively normal sized islets, but a large number of cells within the mutant islet fail to produce any of the four major islet hormones. In this study we demonstrate that Nkx2.2 mutant endocrine cells have been replaced by cells that produce ghrelin, an appetite-promoting peptide predominantly found in the stomach. Intriguingly, normal mouse pancreas also contains a small population of ghrelin-producing cells, defining a new islet '' '' cell population. The expansion of ghrelin-producing cells at the expense of ␤ cells may be a general phenomenon, because we demonstrate that Pax4 mutant mice display a similar phenotype. We propose that insulin and ghrelin cells share a common progenitor and that Nkx2.2 and Pax4 are required to specify or maintain differentiation of the ␤ cell fate. This finding also suggests that there is a genetic component underlying the balance between insulin and ghrelin in regulating glucose metabolism. 2). The mature cell types are defined by their unique hormone expression: glucagon, insulin, somatostatin, and PP, respectively. The ␤ cells are the most abundant cell type, constituting Ͼ75% of the islet, and are centrally located within the islet. ␣, ␦, and PP cells are intermixed at the periphery of the islet, with ␣ cells representing the majority of the remaining cell types. More recently, a fifth peptide hormone has been identified in the human islet. The hormone ghrelin is produced mainly in the stomach and functions to increase secretion of growth hormone and regulate food intake and energy balance (3). Expression of ghrelin in the human islet remains somewhat controversial, because it has variably been reported to be in the ␣ cells (4), ␤ cells (5), or in a unique islet cell type (6). The function of ghrelin within the islet is also unknown, but it may have a paracrine role in regulating insulin secretion.Extensive analyses of the pancreas have led to a tremendous understanding of islet morphology, islet function, and the physiological modulation of islet function and insulin secretion. More recently, there has been increasing interest in understanding the molecular mechanisms underlying embryonic pancreas development as a way to develop therapies to treat diabetes or to discover diagnostic tools for pancreatic cancer. This has led to a surge in the identification of many of the signaling pathways and transcription factors that are critical for the specification, differentiation, and maintenance of the developing pancreas (reviewed in refs. 7 and 8). Although mouse knockout studies have allowed significant progress in identifying many of the intrinsic factors regulating the specification and differentiation of each islet cell type, including Pax4, Pax6, Nkx6.1, Ngn3, Hlxb9, Pdx1, Nkx2.2, and NeuroD, the molecular...

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Section: Discussionmentioning

confidence: 99%

Ghrelin cells replace insulin-producing β cells in two mouse models of pancreas development

Prado

Pugh‐Bernard

Elghazi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

417

442

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“…Ghrelin has been reported to induce Antisteatotic effect of daidzein M-H Kim et al hyperglycemia and inhibits the release of insulin from b-cells in mice. 58,59 The hypolipidemic action of daidzein might be partially because of reduction of lipid absorption. Recent data showed that the fermented soygerm isoflavones (daidzein, genistein and glycitein) significantly inhibited pancreatic lipase activity in dose-dependent manner, thereby suppressing absorption of excessive lipid into a body.…”

Section: Discussionmentioning

confidence: 99%

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

et al. 2010

Int J Obes

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Introduction: Globally, non-alcoholic fatty liver disease (NAFLD) continues to rise and isoflavones exert antisteatotic effects by the regulation of hepatic lipogenesis/insulin resistance or adiposity/a variety of adipocytokines are related to hepatic steatosis. However, there is very little information regarding the potential effects of daidzein, the secondary abundant isoflavone, on NAFLD. Here, we have assessed the hepatic global transcription profiles, adipocytokines and adiposity in mice with high fat-induced NAFLD and their alteration by daidzein supplementation. Methods: C57BL/6J mice were fed with normal fat (16% fat of total energy), high fat (HF; 36% fat of total energy) and HF supplemented with daidzein (0.1, 0.5, 1 and 2 g per kg diet) for 12 weeks. Results: Daidzein supplementation (X0.5 g per kg diet) reduced hepatic lipid concentrations and alleviated hepatic steatosis. The hepatic microarray showed that daidzein supplementation (1 g per kg diet) downregulated carbohydrate responsive element binding protein, a determinant of de novo lipogenesis, its upstream gene liver X receptor b and its target genes encoding for lipogenic enzymes, thereby preventing hepatic steatosis and insulin resistance. These results were confirmed by lower insulin and blood glucose levels as well as homeostasis model assessment insulin resistance scores. In addition, daidzein supplementation inhibited adiposity by the upregulation of genes involved in fatty acid b-oxidation and the antiadipogeneis, and moreover augmented antisteatohepatitic leptin and adiponectin mRNA levels, whereas it reduced the mRNA or concentration of steatotic tumor necrosis factor a and ghrelin. Conclusions: These findings show that daidzein might alleviate NAFLD through the direct regulation of hepatic de novo lipogenesis and insulin signaling, and the indirect control of adiposity and adipocytokines by the alteration of adipocyte metabolism.

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“…An insulinostatic function of endogenous ghrelin within islets has been suggested [13,15,17,[29][30][31]. It was also recently shown to exert inhibitory effects on expression and production of inflammatory cytokines [32] and to attenuate the development of acute pancreatitis in rats by reducing inflammatory infiltrates of pancreatic tissues [33].…”

Section: Discussionmentioning

confidence: 99%

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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Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion

Cited by 252 publications

References 22 publications

Ghrelin cells replace insulin-producing β cells in two mouse models of pancreas development

Ghrelin cells replace insulin-producing β cells in two mouse models of pancreas development

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

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

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