Dose-Dependent Inhibition by Ghrelin of Insulin Secretion in the Mouse

Reimer, Martina Kvist; Pacini, Giovanni; Åhrén, Bo

doi:10.1210/en.2002-220819

Cited by 277 publications

(207 citation statements)

References 26 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 In this study we demonstrate that Nkx2.2 mutant endocrine cells have been replaced by cells that produce ghrelin, an appetite-promoting peptide predominantly found in the stomach.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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“…Some reports suggested that ghrelin either stimulates [18,19,22] or inhibits insulin secretion depending on the experimental condition [23,24]. There have been also some claims that insulin (and / or glucose) lowers circulating ghrelin [25].…”

Section: Ghrelin Level Versus Insulin Levelmentioning

confidence: 99%

“…Furthermore, many earlier studies showed that ghrelin has been shown to inhibit insulin release in some experimental situations [24,29]. However these inconsistencies may reflect species differences and/ or differences in experimental design as different doses, different times of observation and in vitro versus in vivo experiments [30,31].…”

Section: Ghrelin Level Versus Insulin Levelmentioning

confidence: 99%

The Relationship between Type 2 Diabetes and Total Ghrelin Level in a Population Sample in the United Arab Emirates

Farajallah¹,

Ahmed²,

Abdullah³

et al. 2014

iosrphr

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“…Previously called islet-activating protein (IAP), PTX was shown to lower glucose levels in the bloodstream by increasing insulin secretion from β cells (7). The enhanced secretion resulted from the removal of tonic inhibition exerted by neurotransmitters/hormones, including adrenaline (8), galanin (9), and ghrelin (10). PTX catalyzes the ADP ribosylation of a carboxyl-terminal cysteine present in the α subunits of the G protein subgroup now referred to as G i /G o (11).…”

mentioning

confidence: 99%

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Wang

Park

Bajpayee

et al. 2011

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

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Insulin secretion by pancreatic β cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G i and/or two G o proteins as suppressors of insulin secretion from β cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G i/o proteins involved has been elucidated. Here we show that one of the two splice variants of G o , G o2 , is a key player in the control of glucose-induced insulin secretion by β cells. Mice lacking G o2 α, but not those lacking α subunits of either G o1 or any G i proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G o2 protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin.D iabetes mellitus is characterized by abnormalities in insulin secretion that may be either a primary defect, as seen in type I diabetes, or a secondary defect, where secretion is inadequate to overcome primary insulin resistance seen in type II diabetes. In either case, individuals are hyperglycemic. Insulin is the master controller of glucose metabolism, and its release from β cells is tightly regulated. Many factors, including hormones, neuropeptides, and neurotransmitters regulate insulin secretion by activating heterotrimeric G proteins, which can control the output of insulin in response to physiological demands (1, 2). Activation of pathways mediated by G s and/or G q/11 stimulates insulin release from β cells (3, 4). The involvement of G i /G o proteins as inhibitors of insulin secretion from β cells was originally uncovered in studies on the Bordetella pertussis toxin (PTX) in animals and cells (5, 6). Previously called islet-activating protein (IAP), PTX was shown to lower glucose levels in the bloodstream by increasing insulin secretion from β cells (7). The enhanced secretion resulted from the removal of tonic inhibition exerted by neurotransmitters/hormones, including adrenaline (8), galanin (9), and ghrelin (10). PTX catalyzes the ADP ribosylation of a carboxyl-terminal cysteine present in the α subunits of the G protein subgroup now referred to as G i /G o (11). This event causes these G proteins to become uncoupled from receptors and thereby disrupts the signal transduction process. The nonsensory PTX-sensitive G i /G o G proteins encompass three G i 's (G i1 , G i2 , and G i3 ), and two G o 's (G o1 and G o2 ). The α subunits of G i and G o display extensive homology and are functionally similar as they can be activated by the same or similar receptors and appear to signal to partially overlapping sets of effectors (12). This has raised questions whether the individual G i and G o proteins function dis...

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Dose-Dependent Inhibition by Ghrelin of Insulin Secretion in the Mouse

Cited by 277 publications

References 26 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

The Relationship between Type 2 Diabetes and Total Ghrelin Level in a Population Sample in the United Arab Emirates

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

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Dose-Dependent Inhibition by Ghrelin of Insulin Secretion in the Mouse

Cited by 277 publications

References 26 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

The Relationship between Type 2 Diabetes and Total Ghrelin Level in a Population Sample in the United Arab Emirates

Augmented glucose-induced insulin release in mice lacking G o2 , but not G o1 or G i proteins

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Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins