Effects of Ghrelin and Other Neuropeptides (CART, MCH, Orexin A and B, and GLP-1) on the Release of Insulin From Isolated Rat Islets

Colombo, Michele; Gregersen, Søren; Xiao, Jianzhong; Hermansen, Kjeld

doi:10.1097/00006676-200308000-00009

Cited by 105 publications

(87 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.

416

442

View full text Add to dashboard Cite

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 In this study we demonstrate that Nkx2.2 mutant endocrine cells have been replaced by cells that produce ghrelin, an appetite-promoting peptide predominantly found in the stomach.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...

show abstract

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.

416

442

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Ghrelin is expressed in both the alpha [28] and beta [9,29] cells of the pancreas. Recently, ghrelin was also identified in epsilon cells [30].…”

Section: Discussionmentioning

confidence: 99%

Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis: Ghrelin, a stomach-derived hormone, functions in multiple biological processes, including glucose metabolism and cellular differentiation and proliferation. In this study, we examined whether early treatment with ghrelin can regenerate beta cells of the pancreas in an animal model of diabetes mellitus, the n0-STZ model, in which neonatal rats are injected with streptozotocin (STZ) at birth.Methods: Following administration of ghrelin to n0-STZ rats from postnatal days 2 to 8, we examined beta cell mass, mRNA expression levels of insulin and of pancreatic and duodenal homeobox 1 (Pdx1) gene, and pancreatic morphology on days 21 and 70. In addition, we investigated the effects of ghrelin on beta cell replication. Results: By day 21, ghrelin treatment increased pancreatic expression of insulin and Pdx1 mRNA in n0-STZ rats. The number of replicating cells was also significantly increased in the ghrelin-treated n0-STZ model. At day 70, n0-STZ rats exhibited hyperglycaemia, despite slight increases in plasma insulin levels. Ghrelin treatment resulted in the improvement of plasma glucose levels, which were associated with normal plasma insulin levels. Pancreatic insulin mRNA and protein levels were significantly increased in ghrelin-treated n0-STZ model animals. Conclusions/interpretation: These findings suggest that ghrelin promotes regeneration of beta cells in STZ-treated newborn rats. Thus, early administration of ghrelin may help prevent the development of diabetes in disease-prone subjects after beta cell destruction.

show abstract

Effects of Ghrelin and Other Neuropeptides (CART, MCH, Orexin A and B, and GLP-1) on the Release of Insulin From Isolated Rat Islets

Abstract: Ghrelin inhibits the insulin secretion in vitro in a dose- and glucose-dependent manner. Beta cells contain ghrelin receptors. CART fragments did not affect the insulin secretion. Ghrelin may play a physiological role for the regulation of insulin secretion.

Cited by 105 publications

References 25 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

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

Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats

Contact Info

Product

Resources

About