Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Szabat, Marta; Johnson, James D.; Piret, James M.

doi:10.1007/s00125-010-1758-0

Cited by 49 publications

(81 citation statements)

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“…One difference between the older studies and the new work is the onset and duration of activin stimulation. While the earlier work initiated activin A treatment at the same time as glucose stimulation, the later work preincubated islets in activin A for several hours prior to glucose treatment and prolonged the stimulation for an additional 2 h [4,15] to 3 days [16]. In line with the earlier work, we have treated islets with activins acutely and concomitantly with glucose stimulation.…”

Section: Discussionmentioning

confidence: 70%

“…Earlier studies indicated that activin A enhances insulin secretion [12,13,37]. However, more recent work reported that activin A has either no effect [4] or in fact decreases [15,16] GSIS by islets. One difference between the older studies and the new work is the onset and duration of activin stimulation.…”

Section: Discussionmentioning

confidence: 98%

“…Earlier work showed that exogenous activin A can increase the cytoplasmic free Ca 2+ concentration and stimulate insulin secretion in human and rat pancreatic islets, even at low levels of ambient glucose [12][13][14]. Those results have been challenged by more recent studies indicating that in mouse islets, activin A either has no effect [4] or may in fact decrease GSIS [15,16]. It has been assumed in several of these studies that activin A and B signal in a similar fashion and thus have similar functions in pancreatic islets.…”

Section: Introductionmentioning

confidence: 99%

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Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Mezghenna

Mármol

et al. 2013

Diabetologia

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Aims/hypothesis Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is regulated by paracrine factors, the identity and mechanisms of action of which are incompletely understood. Activins are expressed in pancreatic islets and have been implicated in the regulation of GSIS. Activins A and B signal through a common set of intracellular components, but it is unclear whether they display similar or distinct functions in glucose homeostasis. Methods We examined glucose homeostatic responses in mice lacking activin B and in pancreatic islets derived from these mutants. We compared the ability of activins A and B to regulate downstream signalling, ATP production and GSIS in islets and beta cells. Results Mice lacking activin B displayed elevated serum insulin levels and GSIS. Injection of a soluble activin B antagonist phenocopied these changes in wild-type mice. Isolated pancreatic islets from mutant mice showed enhanced GSIS, which could be rescued by exogenous activin B. Activin B negatively regulated GSIS and ATP production in wild-type islets, while activin A displayed the opposite effects. The downstream mediator Smad3 responded preferentially to activin B in pancreatic islets and beta cells, while Smad2 showed a preference for activin A, indicating distinct signalling effects of the two activins. In line with this, overexpression of Smad3, but not Smad2, decreased GSIS in pancreatic islets. Conclusions/interpretation These results reveal a tug-of-war between activin ligands in the regulation of insulin secretion by beta cells, and suggest that manipulation of activin signalling could be a useful strategy for the control of glucose homeostasis in diabetes and metabolic disease.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Mezghenna

Mármol

et al. 2013

Diabetologia

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“…Activation of the erythroblastic leukaemia viral oncogene (ErbB) receptor pathway with betacellulin has been shown to protect beta cells and increase beta cell proliferation in a number of systems [15]. Emerging evidence suggests important roles for locally produced members of the TGFβ family, such as activin, follistatin and bone morphogenic proteins [16,17]. These studies demonstrate that islet survival can be modulated by soluble factors, although in many cases it is not yet clear whether administration of these factors at doses that can be tolerated clinically will increase beta cell mass.…”

Section: Introductionmentioning

confidence: 99%

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors

et al. 2011

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Aims/hypothesis Adult pancreatic islets contain multiple cell types that produce and secrete well characterised hormones, including insulin, glucagon and somatostatin. Although it is increasingly apparent that islets release and respond to more secreted factors than previously thought, systematic analyses are lacking. We therefore sought to identify potential autocrine and/or paracrine islet growth factor loops, and to characterise the function of the netrin family of islet-secreted factors and their receptors, which have been previously unreported in adult islets. Methods Gene expression databases, islet-specific tag sequencing libraries and microarray datasets of FACS purified beta cells were used to compile a list of secreted factors and receptors present in mouse or human islets. Netrins and their receptors were further assessed using RT-PCR, Western blot analysis and immunofluorescence staining. The roles of netrin-1 and netrin-4 in beta cell function, apoptosis and proliferation were also examined. Results We identified 233 secreted factors and 234 secreted factor receptors in islets. The presence of netrins and their receptors was further confirmed. Downregulation of caspase-3 activation was observed when MIN6 cells were exposed to exogenous netrin-1 and netrin-4 under hyperglycaemic conditions. Reduction in caspase-3 cleavage was linked to the decrease in dependence receptors, neogenin and unc-5 homologue A, as well as the activation of Akt and extracellular signal-regulated protein kinase (ERK) signalling. Conclusions/interpretation Our results highlight the large number of potential islet growth factors and point to a context-dependent pro-survival role for netrins in adult beta cells. Since diabetes results from a deficiency in functional beta cell mass, these studies are important steps towards developing novel therapies to improve beta cell survival.

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“…programmed cell death | glucose metabolism | intracellular calcium signaling E merging evidence highlights the important role of locally released pancreatic islet peptide factors on beta-cell mass growth, maintenance, and survival (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). We have published a list of 233 ligands and 234 receptors expressed in islets and/or beta cells (12).…”

mentioning

confidence: 99%

Intraislet SLIT–ROBO signaling is required for beta-cell survival and potentiates insulin secretion

Yang

Fox

Zhang

et al. 2013

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

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We previously cataloged putative autocrine/paracrine signaling loops in pancreatic islets, including factors best known for their roles in axon guidance. Emerging evidence points to nonneuronal roles for these factors, including the Slit-Roundabout receptor (Robo) family, in cell growth, migration, and survival. We found SLIT1 and SLIT3 in both beta cells and alpha cells, whereas SLIT2 was predominantly expressed in beta cells. ROBO1 and ROBO2 receptors were detected in beta and alpha cells. Remarkably, even modest knockdown of Slit production resulted in significant betacell death, demonstrating a critical autocrine/paracrine survival role for this pathway. Indeed, recombinant SLIT1, SLIT2, and SLIT3 decreased serum deprivation, cytokine, and thapsigargin-induced cell death under hyperglycemic conditions. SLIT treatment also induced a gradual release of endoplasmic reticulum luminal Ca 2+ , suggesting a unique molecular mechanism capable of protecting beta cells from endoplasmic reticulum stress-induced apoptosis. SLIT treatment was also associated with rapid actin remodeling. SLITs potentiated glucose-stimulated insulin secretion and increased the frequency of glucose-induced Ca 2+ oscillations. These observations point to unexpected roles for local Slit secretion in the survival and function of pancreatic beta cells. Because diabetes results from a deficiency in functional beta-cell mass, these studies may contribute to therapeutic approaches for improving beta-cell survival and function.programmed cell death | glucose metabolism | intracellular calcium signaling E merging evidence highlights the important role of locally released pancreatic islet peptide factors on beta-cell mass growth, maintenance, and survival (1-12). We have published a list of 233 ligands and 234 receptors expressed in islets and/or beta cells (12). Although our list is undoubtedly not comprehensive, it provides a starting point for the investigation of factors in adult islets that had previously only been reported in other cell types or in fetal pancreas (12). We identified a group of secreted molecules known to provide axonal guidance cues during neuronal development, comprising members of the netrin, slit, semaphorin, and ephrin families (13). The parallels between cell fate decisions in neurons and the endocrine pancreas prompted us to examine some factors in detail and discover that netrin treatment modulates beta-cell survival signaling (12).The Slit ligands and their Roundabout receptors (Robo) were discovered in Drosophila as regulators of axon guidance during development (14-17). Mammalian homologs of Slit and Robo with functions outside of axon guidance have since been identified (18, 19). Slit ligands have been implicated in liver, kidney, lung, and mammary development by modulating cell adhesion, migration, differentiation, and death (18,20,21). It was not known whether Slit-Robo signaling functions in beta cells. Here, we report that Slit expression can be regulated by stress and that local Slit production is required for b...

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Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Cited by 49 publications

References 50 publications

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors

Intraislet SLIT–ROBO signaling is required for beta-cell survival and potentiates insulin secretion

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