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

Abstract

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 In this study we demonstrate that Nkx2.2 mutant endocrine cells have been replaced by cells that produce ghrelin, an appetite-promoting peptide predominantly found in the stomach.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

Pancreas organogenesis: From bud to plexus to gland

“…In Pax4 null mice, b and d-cells are lost concomitant with a remarkable increase in a-cell and ghrelin þ e-cell numbers. The increased e-cell number is similar to the Nkx2.2 null pancreas, suggesting possible genetic interactions between Pax4 and Nkx2.2 (Prado et al, 2004).…”

“…Total endocrine cell number is almost normal but the majority of the b-cells, and a substantial fraction of both acells and PP-cells are replaced by ghrelin-producing e-cells in Nkx2.2 mutant mice (Sussel et al1998;Prado et al 2004). In Pax4 null mice, b and d-cells are lost concomitant with a remarkable increase in a-cell and ghrelin þ e-cell numbers.…”

“…The endocrine cells aggregate to form the islets of Langerhans, which are intermingled with blood vessels, neurons, and a mesodermally-derived stromal component. The intimate interaction between endocrine and vascular cells regulates hormone release, establishing a fine-tuned glucose homeostasis in the body (Slack, 1995;Prado et al, 2004, Konstantinova et al, 2007.…”

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

“…The alpha cells synthesise glucagon, beta cells synthesise insulin, delta cells synthesise somatostatin and pancreatic polypeptide (PP) cells synthesise PP [1][2][3]. A few years ago, a fifth mammalian islet cell type, the ghrelin-producing epsilon cell, was described [4,5].…”

Ghrelin and the growth hormone secretagogue receptor in growth and development

“…However, in the absence of Nkx2.2, a transcription factor required for the specification and maintenance of insulinproducing b-cells, and, to a lesser extent, of glucagonproducing a-cells, a marked increase in the number of ghrelin cells is observed, suggesting that the specification of these three cell types is closely linked. 13 In humans, immunoreactive ghrelin is present in umbilical cord blood samples as early as by the twentieth week of gestation in concentrations that are of the same magnitude as those reported in adults. Ghrelin levels are higher in small-for-gestational-age neonates compared with appropriatefor-gestational-age neonates.…”