Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide.

Corbett, John A.; Wang, Jin Lin; Sweetland, Michael A.; Lancaster, Jack R.; McDaniel, Michael L.

doi:10.1172/jci116129

Cited by 287 publications

(196 citation statements)

References 40 publications

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“…Mock-or AdPC1͞3-transduced islets were challenged with high (20 mM) glucose, and glucose-stimulated insulin output was assessed in a perifusion system. AdPC1͞3-transduced islets (moi ϭ 100) had a greater insulin response to glucose stimulation than mocktransduced islets, with greater peak insulin levels ( We also examined whether transduction with AdPC1͞3 offered islets protection against IL-1␤, which induces ␤ cell apoptosis and may be involved in islet cell death in the early stages after islet transplantation (26). Although there was no detectable difference in the number of live cells in islets that received virus and͞or cytokine treatment compared with untreated islets, there was a trend toward increased cell death in virus-transduced islets (both AdPC1͞3 and Ad5lacZ); however, this trend did not reach statistical significance (Fig.…”

Section: Resultsmentioning

confidence: 99%

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Wideman¹,

Yu²,

Webber³

et al. 2006

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

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Glucagon-like peptide 1 (GLP-1) is a hormone that has received significant attention as a therapy for diabetes because of its ability to stimulate insulin biosynthesis and release and to promote growth and survival of insulin-producing ␤ cells. While GLP-1 is produced from the proglucagon precursor by means of prohormone convertase (PC) 1͞3 activity in enteroendocrine L cells, the same precursor is differentially processed by PC2 in pancreatic islet ␣ cells to release glucagon, leaving GLP-1 trapped within a larger fragment with no known function. We hypothesized that we could induce GLP-1 production directly within pancreatic islets by means of delivery of PC1͞3 and, further, that this intervention would improve the viability and function of islets. Here, we show that adenovirus-mediated expression of PC1͞3 in ␣ cells increases islet GLP-1 secretion, resulting in improved glucose-stimulated insulin secretion and enhanced survival in response to cytokine treatment. PC1͞3 expression in ␣ cells also improved performance after islet transplantation in a mouse model of type 1 diabetes, possibly by enhancing nuclear Pdx1 and insulin content of islet ␤ cells. These results demonstrate a unique strategy for liberating GLP-1 from directly within the target organ and highlight the potential for up-regulating islet GLP-1 production as a means of treating diabetes.diabetes ͉ islet transplantation ͉ prohormone convertase 1͞3

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Section: Resultsmentioning

confidence: 99%

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Wideman¹,

Yu²,

Webber³

et al. 2006

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

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“…It is known that beta cell destruction by cytokines such as IL-1β [34,35] can be prevented by inhibition of the JNK pathway [24,36], implying that JNK plays a role in the autoimmune beta cell destruction found in the early stage of type 1 diabetes. In addition, the JNK pathway is activated in various tissues, including pancreatic islets, in the diabetic state, and suppression of that pathway reduces insulin resistance and ameliorates glucose intolerance in type 2 diabetic animal models [37].…”

Section: Discussionmentioning

confidence: 99%

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

Noguchi

Nakai

Ueda³

et al. 2007

Diabetologia

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Aims/hypothesis Although application of the Edmonton protocol has markedly improved the outcome for pancreatic islet transplantation, the insulin independence rate after islet transplantation from one donor pancreas has remained low. During the isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. The aim of this study was to map the c-Jun NH 2 -terminal kinase (JNK) pathway that mediates islet loss during islet transplantation and to clarify whether intraportal injection with JNK inhibitor during islet transplantation can prevent islet graft loss. Methods We measured JNK activity in the liver, fat and muscle of diabetic mice and in the liver immediately after islet transplantation. We examined the effect of intraportal injection of JNK inhibitory peptide at islet transplantation. Results JNK activity became progressively higher at least until 24 h after transplantation. The cell-permeable peptide of JNK inhibitor was delivered not only in the liver but also in other insulin target organs, preventing JNK activation in the liver at least until 24 h after transplantation and reducing JNK activity in these insulin target organs. Moreover, the peptide inhibitor prevented islet graft loss immediately after transplantation and improved islet transplant outcome. Conclusions/interpretation These findings suggest that control of the JNK pathway is extremely important in islet transplantation and that intraportal injection of JNK inhibitor during islet transplantation (addition of JNK inhibitor to transplant media) could prevent the impairment of islet cells, leading to improved outcome for pancreatic islet transplantation.

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“…The rat insulinoma cell line Rinm5F has often been used as a model in the study of IL-1 effects, since they have a high density of IL-1 receptors. 42,43 The NFkB decoy approach can further be applied on other types of cells. The importance of NFkB in regulating IL-6 gene expression in primary glial cells has also been suggested by Ye and Johnson, 22 based on a study where cells were pretreated with NFkB decoy.…”

Section: Cellular Delivery Of Nfjb Decoy L Fisher Et Almentioning

confidence: 99%

Cellular delivery of a double-stranded oligonucleotide

et al. 2004

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The activation of nuclear factor kB (NFkB) is a key event in immune and inflammatory responses. In this study, a cellpenetrating transport peptide, transportan (TP) or its shorter analogue TP 10, was used to facilitate the cellular uptake of an NFkB decoy. Peptide nucleic acid (PNA) hexamer or nonamer was linked to the transport peptide by a disulfide bond. NFkB decoy oligonucleotide consisted of a doublestranded consensus sequence corresponding to the kB site localized in the IL-6 gene promoter, 5 0 -GGGACTTTCCC-3 0 , with a single-stranded protruding 3 0 -terminal sequence complementary to the PNA sequence was hybridized to the transport peptide-PNA construct. The ability of the transport peptide-PNA-NFkB decoy complex to block the effect of interleukin (IL)-1b-induced NFkB activation and IL-6 gene expression was analyzed by electrophoretic mobility shift assay and reverse transcriptase-polymerase chain reaction in rat Rinm5F insulinoma cells. Preincubation with transport peptide-PNA-NFkB decoy (1 mM, 1 h) blocked IL-1b-induced NFkB-binding activity and significantly reduced the IL-6 mRNA expression. The same concentration of NFkB decoy in the absence of transport peptide-PNA had no effect even after longer incubations. Our results showed that binding of the oligonucleotide NFkB decoy to the nonamer PNA sequence resulted in a stable complex that was efficiently translocated across the plasma membrane.

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Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide.

Abstract: IntroductionNitric oxide has recently been implicated as the effector molecule that mediates IL-1(3-induced inhibition of glucose-stimulated insulin secretion and (3-cell specific destruction. The pancreatic islet represents a heterogeneous cell population con-

Cited by 287 publications

References 40 publications

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

Cellular delivery of a double-stranded oligonucleotide

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