Repurposing cAMP-Modulating Medications to Promote β-Cell Replication

Zhao, Zihao; Low, Yen; Armstrong, N.; Ryu, Jennifer Hyoje; Sun, Sara A.; Arvanites, Anthony C.; Hollister-Lock, Jennifer; Shah, Nigam H.; Weir, Gordon C.; Annes, Justin P.

doi:10.1210/me.2014-1120

Cited by 30 publications

(29 citation statements)

References 67 publications

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“…Furthermore, we show that A2a-specific agonists have a stronger effect on mouse β-cell proliferation than NECA, perhaps because NECA also activates the A1 and A3 receptors, which, in turn, activate Gαi and thereby counteract the downstream effects of A2a signaling (which is mediated by Gαs). This explanation is also consistent with findings showing that adenosine signaling is affected by phosphodiesterases (which degrade cAMP) and how adenosine promotes the basal level of β-cell proliferation in vitro [2], [21], [22]. Moreover, NECA was recently shown to increase human β-cell proliferation [24]; it would be interesting to examine whether A2a-specific agonists are more potent than non-specific adenosine agonists in increasing β-cell proliferation in human islets grown in vitro or transplanted to immunodeficient mice.…”

Section: Discussionsupporting

confidence: 91%

Critical role for adenosine receptor A2a in β-cell proliferation

Schulz

Liu

Charbord

et al. 2016

Molecular Metabolism

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ObjectivePharmacological activation of adenosine signaling has been shown to increase β-cell proliferation and thereby β-cell regeneration in zebrafish and rodent models of diabetes. However, whether adenosine has an endogenous role in regulating β-cell proliferation is unknown. The objective of this study was to determine whether endogenous adenosine regulates β-cell proliferation—either in the basal state or states of increased demand for insulin—and to delineate the mechanisms involved.MethodsWe analyzed the effect of pharmacological adenosine agonists on β-cell proliferation in in vitro cultures of mouse islets and in zebrafish models with β- or δ-cell ablation. In addition, we performed physiological and histological characterization of wild-type mice and mutant mice with pancreas- or β-cell-specific deficiency in Adora2a (the gene encoding adenosine receptor A2a). The mutant mice were used for in vivo studies on the role of adenosine in the basal state and during pregnancy (a state of increased demand for insulin), as well as for in vitro studies of cultured islets.ResultsPharmacological adenosine signaling in zebrafish had a stronger effect on β-cell proliferation during β-cell regeneration than in the basal state, an effect that was independent of the apoptotic microenvironment of the regeneration model. In mice, deficiency in Adora2a impaired glucose control and diminished compensatory β-cell proliferation during pregnancy but did not have any overt phenotype in the basal state. Islets isolated from Adora2a-deficient mice had a reduced baseline level of β-cell proliferation in vitro, consistent with our finding that UK432097, an A2a-specific agonist, promotes the proliferation of mouse β-cells in vitro.ConclusionsThis is the first study linking endogenously produced adenosine to β-cell proliferation. Moreover, we show that adenosine signaling via the A2a receptor has an important role in compensatory β-cell proliferation, a feature that could be harnessed pharmacologically for β-cell expansion and future therapeutic development for diabetes.

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Section: Discussionsupporting

confidence: 91%

Critical role for adenosine receptor A2a in β-cell proliferation

Schulz

Liu

Charbord

et al. 2016

Molecular Metabolism

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“…Regardless, the mechanism of IRS2 upregulation is unknown for most of the identified compounds, and a systematic mechanistic investigation of each compound was beyond the scope of this work; however, several of the identified compounds are consistent with known transcriptional control mechanisms. For example, forskolin, IBMX, trequinsin, YC-1 and zardaverine are expected to increase cAMP concentration to promote CREB→IRS2 signaling (18). Other compounds are thought to increase Ca 2+ concentrations by directly increasing Ca 2+ influx (A-23187, benzamil, U-50488), inhibiting K + efflux (repaglinide), or inhibiting Na + -Ca 2+ exchange (ouabain, digoxin, digoxigenin, strophanthidin).…”

Section: Resultsmentioning

confidence: 99%

“…Previous reports show that IRS2 expression is upregulated by glucose, incretins such as glucagon-like peptide 1 (GLP1), and other factors that increase cytosolic [Ca 2+ ] i or [cAMP] i in β cells such as phosphodiesterase inhibitors (18). Thus, some plausible signaling cascades might include GαscAMP→CREB→IRS2; Ca 2+ →calcineurin →NFAT →IRS2; PI3K→AKT˧FOXO1 →IRS2; or Gq→PLCβ→IRS2 (12–14, 20, 23, 45).…”

Section: Discussionmentioning

confidence: 99%

“…A drug that engages multiple targets might also have beneficial effects if the signals converge on a common signaling cascade (16). Whereas the immediate effect of cAMP or Ca 2+ usually increases insulin secretion, persistent effects include improved β cell function and growth that might be related, at least in part, to increased IRS2 expression (17, 18). We set out to identify small molecules — regardless of the mechanism — that increase the expression and synthesis of IRS2 in human pancreatic islets in vitro and then determine whether they can promote β cell growth and glucose homeostasis in mice.…”

Section: Introductionmentioning

confidence: 99%

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Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

Kuznetsova

Hollister-Lock

et al. 2016

JCI Insight

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The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote β cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, β cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and β cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes.

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“…Successful use of this platform has enabled identification of several compounds that promote β-cell replication 25,26 . Additionally, the assay has been used for structure-activity relationship studies and chemical epistasis experiments to provide mechanistic insights into the molecular regulation of β-cell replication.…”

Section: Introductionmentioning

confidence: 99%

A High-content <em>In Vitro</em> Pancreatic Islet β-cell Replication Discovery Platform

Zhao

Abdolazimi

Armstrong

et al. 2016

JoVE

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Loss of insulin-producing β-cells is a central feature of diabetes. While a variety of potential replacement therapies are being explored, expansion of endogenous insulin-producing pancreatic islet β-cells remains an attractive strategy. β-cells have limited spontaneous regenerative activity; consequently, a crucial research effort is to develop a precise understanding of the molecular pathways that restrain β-cell growth and to identify drugs capable of overcoming these restraints. Herein an automated high-content image-based primary-cell screening method to identify β-cell replication-promoting small molecules is presented. Several, limitations of prior methodologies are surmounted. First, use of primary islet cells rather than an immortalized cell-line maximizes retention of in vivo growth restraints. Second, use of mixed-composition islet-cell cultures rather than a β-cell-line allows identification of both lineage-restricted and general growth stimulators. Third, the technique makes practical the use of primary islets, a limiting resource, through use of a 384-well format. Fourth, detrimental experimental variability associated with erratic islet culture quality is overcome through optimization of isolation, dispersion, plating and culture parameters. Fifth, the difficulties of accurately and consistently measuring the low basal replication rate of islet endocrine-cells are surmounted with optimized immunostaining parameters, automated data acquisition and data analysis; automation simultaneously enhances throughput and limits experimenter bias. Notable limitations of this assay are the use of dispersed islet cultures which disrupts islet architecture, the use of rodent rather than human islets and the inherent limitations of throughput and cost associated with the use of primary cells. Importantly, the strategy is easily adapted for human islet replication studies. This assay is well suited for investigating the mitogenic effect of substances on β-cells and the molecular mechanisms that regulate β-cell growth.

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Repurposing cAMP-Modulating Medications to Promote β-Cell Replication

Cited by 30 publications

References 67 publications

Critical role for adenosine receptor A2a in β-cell proliferation

Critical role for adenosine receptor A2a in β-cell proliferation

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

A High-content <em>In Vitro</em> Pancreatic Islet β-cell Replication Discovery Platform

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Repurposing cAMP-Modulating Medications to Promote β-Cell Replication

Cited by 30 publications

References 67 publications

Critical role for adenosine receptor A2a in β-cell proliferation

Critical role for adenosine receptor A2a in β-cell proliferation

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

A High-content <em>In Vitro</em> Pancreatic Islet &#946;-cell Replication Discovery Platform

Contact Info

Product

Resources

About

A High-content <em>In Vitro</em> Pancreatic Islet β-cell Replication Discovery Platform