Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Islet transplantation represents a promising therapeutic strategy for the treatment of type 1 diabetes mellitus (T1DM) [Hakim and Papalois (Ann Ital Chir 75:1-7, 2004); Jaeckel et al. (Internist (Berl) 45:1268-1280, 2004); Sutherland et al. (Transplant Proc 36:1697-1699, 2004)]. The insulin-secreting pancreatic beta cells of the islet allograft are, however, subject to recurrent immune-mediated damage. Principal among the molecular culprits involved in this destructive process is the proinflammatory cytokine IL-1beta. IL-1beta-induced beta cell destruction may be mediated by the generation of NO and/or ROS, although the relative importance of NO and ROS in this process remains unclear. This study broadly encompassed three arms of investigation: the first of these was geared toward the establishment of a robust in vitro cell system for the study of IL-1beta-induced pathophysiology; the second arm aimed to provide a comparative analysis of the gene transfer profiles of the three most commonly used gene transfer vehicles, namely plasmid vectors, adenoviral vectors, and lentiviral vectors, in the aforementioned cell system; the final arm aimed to screen an array of potentially cytoprotective gene transfer strategies incorporating the optimal gene transfer vectors. Briefly, we established an in vitro beta cell system that accurately reflected primary beta cell cytokine-induced pathophysiology. That is, IL-1beta exposure (100 U/ml) induced a time-dependent decrease in rat insulinoma (RIN) cell viability, which coincided with an induction in iNOS expression and nitrite accumulation. Gene transfer studies using plasmid, adenoviral, or lentiviral vectors underscored the superiority of viral vector-based gene transfer strategies for the manipulation of this beta cell line. Using these vectors, we provide evidence that NF-kappaB-based iNOS inhibition confers significant protection against IL-1beta-induced damage whereas antioxidant overexpression fails to provide protection. Conferred cytoprotection was associated with a suppression of iNOS expression and nitrite accumulation. From a therapeutic standpoint, gene transfer strategies employing efficient viral vectors to target iNOS activation may harbour therapeutic potential in preserving beta cell survival against proinflammatory cytokine exposure.
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PMID:The rational design of beta cell cytoprotective gene transfer strategies: targeting deleterious iNOS expression. 1791 62

Pro-inflammatory cytokines are implicated as the main mediators of beta-cell death during type 1 diabetes but the exact mechanisms remain unknown. This study examined the effects of interleukin-1beta (IL-1beta), interferon-gamma (IFNgamma) and tumour necrosis factor alpha (TNFalpha) on a rat insulinoma cell line (RIN-r) in order to identify the core mechanism of cytokine-induced beta-cell death. Treatment of cells with a combination of IL-1beta and IFNgamma (IL-1beta/IFNgamma)induced apoptotic cell death. TNFalpha neither induced beta-cell death nor did it potentiate the effects of IL-1beta, IFNgamma or IL-1beta/IFNgamma . The cytotoxic effect of IL-1beta/IFNgamma was associated with the expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide. Adenoviral-mediated expression of iNOS (AdiNOS) alone was sufficient to induce caspase activity and apoptosis. The broad range caspase inhibitor, Boc-D-fmk, blocked IL-1beta/IFNgamma -induced caspase activity, but not nitric oxide production nor cell death. However, pre-treatment with L-NIO, a NOS inhibitor, prevented nitric oxide production, caspase activity and reduced apoptosis. IL-1beta/IFNgamma -induced apoptosis was accompanied by loss of mitochondrial membrane potential, release of cytochrome c and cleavage of pro-caspase-9, -7 and -3. Transduction of cells with Ad-Bcl-X(L) blocked both iNOS and cytokine-mediated mitochondrial changes and subsequent apoptosis, downstream of nitric oxide. We conclude that cytokine-induced nitric oxide production is both essential and sufficient for caspase activation and beta-cell death, and have identified Bcl-X(L) as a potential target to combat beta-cell apoptosis.
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PMID:Cytokine-induced beta-cell apoptosis is NO-dependent, mitochondria-mediated and inhibited by BCL-XL. 1808 94

A relative decrease in beta-cell mass is key in the pathogenesis of type 1 diabetes, type 2 diabetes, and in the failure of transplanted islet grafts. It is now clear that beta-cell duplication plays a dominant role in the regulation of adult beta-cell mass. Therefore, knowledge of the endogenous regulators of beta-cell replication is critical for understanding the physiological control of beta-cell mass and for harnessing this process therapeutically. We have shown that concentrations of insulin known to exist in vivo act directly on beta-cells to promote survival. Whether insulin stimulates adult beta-cell proliferation remains unclear. We tested this hypothesis using dispersed primary mouse islet cells double labeled with 5-bromo-2-deoxyuridine and insulin antisera. Treating cells with 200-pm insulin significantly increased proliferation from a baseline rate of 0.15% per day. Elevating glucose from 5-15 mm did not significantly increase beta-cell replication. beta-Cell proliferation was inhibited by somatostatin as well as inhibitors of insulin signaling. Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by low, but not high (superphysiological), insulin doses. Insulin-stimulated mouse insulinoma cell proliferation was dependent on both phosphatidylinositol 3-kinase/Akt and Raf-1/MAPK kinase pathways. Overexpression of Raf-1 was sufficient to increase proliferation in the absence of insulin, whereas a dominant-negative Raf-1 reduced proliferation in the presence of 200-pm insulin. Together, these results demonstrate for the first time that insulin, at levels that have been measured in vivo, can directly stimulate beta-cell proliferation and that Raf-1 kinase is involved in this process. These findings have significant implications for the understanding of the regulation of beta-cell mass in both the hyperinsulinemic and insulin-deficient states that occur in the various forms of diabetes.
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PMID:Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. 1820 27

Major histocompatibility complex (MHC) class II antigen expression has been implicated in the pathogenesis of autoimmune type 1 diabetes. In this study we examined the role of various cytoldnes that may induce MHC class II surface antigen expression, using the rat insulinoma line RIN-5AH as a pertinent model system. As in another study, the ability of IFN-gamma to amplify MHC class II antigen expression 4-fold is demonstrated. At the same time we noted a 5-fold increase of these histocompatibility antigens by IL-6. Signal transduction analysis reveals that IL-6-induced MHC class II expression is specifically mediated by the G-protein system (activation of p21(ras) by IL-6) since mevalonic acid lactone (a Gprotein inhibitor) abolishes the action of IL-6. In contrast, IFN-gamma, which does not activate p21(ras), is not inhibited by protein kinase C (PKC) inhibitors but by those of the G-protein pathway. This finding raises the possibility that IFN-gamma induces RIN cells to secrete IL-6 (as shown previously, as well as in this paper) which, in turn, increases class II antigen expression via the G-protein pathway. This action may be unique to IL-6 or in synergy with IFN-gamma. Other cytokines such as IL-1alpha and beta, and TNF-alpha induce a smaller increase in MHC class II antigens on RIN cells, and appear to activate both the G-protein and the PKC signal transduction pathways to varying degrees. Therefore, injury of pancreatic beta-cells and possible induction of autoimmune type 1 diabetes via various cytokines may be caused by IL-6 or IFN-gamma, or by their ability to induce MHC class II antigen upregulation.
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PMID:IL-6-mediated MHC class II induction on RIN-5AH insulinoma cells by IFN-gamma occurs via the G-protein pathway. 1847 68

Endoplasmic reticulum (ER) stress-mediated apoptosis plays an important role in the destruction of pancreatic beta-cells and contributes to the development of type 1 diabetes. The chaperone molecule, glucose-regulated proteins 78 (Grp78), is required to maintain ER function during toxic insults. In this study, we investigated the changes of Grp78 expression in different phases of streptozotocin (STZ)-affected beta-cells to explore the relationship between Grp78 and the response of beta-cells to ER stress. An insulinoma cell line (NIT-1) treated with STZ for different time periods and STZ-induced diabetic Balb/C mice at different time points were used as the model system. The level of Grp78 and C/EBP homologous protein (CHOP) mRNA were detected by real-time polymerase chain reaction and their protein by immunoblot. Apoptosis and necrosis was measured by flow cytometry. In addition, the changes of Grp78 protein in STZ-treated nondiabetic mice were also detected by immunoblot. Grp78 expression significantly increased in the early phase but decreased in the later phase of affected beta-cells, while CHOP was induced and apoptosis occurred along with the decrease of Grp78. Interestingly, the Grp78 protein of STZ-treated nondiabetic mice increased stably compared with that of the control. From the results, we can conclude that Grp78 may contribute to the response of beta-cells to ER stress, and more attention should be paid to Grp78 in the improvement of diabetes.
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PMID:The altered expression of glucose-regulated proteins 78 in different phase of streptozotocin-affected pancreatic beta-cells. 1859 85

Type 1 diabetes mellitus (T1DM) was defined as a heterogeneous disorder characterized by severe beta-cell loss. The subtype 1A is characterized by abnormal autoimmue-mediated response and 1B is idiopathic etiology, and most of patients with T1DM are classified in 1A. There are three subtypes characterized by onset, fulminant, acute onset and slowly progressive in T1DM. Among these three subtypes, there are differences in genetic etiology, pathogenesis and prevalence of autoantibodies. Glutamic acid decarboxylase-65 (GAD65), insulinoma-associated antigen-2 (IA-2) and insulin are major autoantigens in T1DM and autoantibodies for former two are frequently used for clinical diagnosis. Also novel autoantibodies for T1DM have been found and clinical characteristics of the patients with each antibody will be made clearer. There have been eager efforts to develop immunotherapies to prevent islet destruction and to cure the disorder with islet transplantation, and new treatment with inhaled insulin regimen. Continuous glucose monitoring system(CGMS) has been established to make clearer the daily profile of blood glucose of the patients and to improve the metabolic control. Most efficient treatment for T1DM is a still insulin injection. However, the development of new medical devices and novel treatment rather than insulin injection has been done and the progression will promise improved prognosis of vascular complications.
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PMID:[Latest overview of type 1 diabetes mellitus]. 1861 34

It is well-documented that melatonin influences insulin secretion. The effects are mediated by specific, high-affinity, pertussis-toxin-sensitive, G protein-coupled membrane receptors (MT(1) as well MT(2)), which are present in both the pancreatic tissue and islets of rats and humans, as well as in rat insulinoma cells (INS1). Via the Gi-protein-adenylatecyclase-3',5'-cyclic adenosine monophosphate (cAMP) and, possibly, the guanylatecyclase-cGMP pathways, melatonin decreases insulin secretion, whereas, by activating the Gq-protein-phospholipase C-IP(3) pathway, it has the opposite effect. For further analysis of the interactions between melatonin and insulin, diabetic rats were investigated with respect to melatonin synthesis in the pineal gland and plasma insulin levels. In this context, recent investigations have proven that type 2 diabetic rats and humans display decreased melatonin levels, whereas type 1 diabetic IDDM rats or those with diabetes induced by streptozotocin (STZ) of the present study show increased plasma melatonin levels and elevated AA-NAT-mRNA. Furthermore, the mRNA of pineal insulin receptors and beta1-adrenoceptors, including the clock genes Per1 and Bmal1 and the clock-controlled output gene Dbp, increases in both young and middle-aged STZ rats. The results therefore indicate that the decreased insulin levels in STZ-induced type 1 diabetes are associated with higher melatonin plasma levels. In good agreement with earlier investigations, it was shown that the elevated insulin levels observed in type 2 diabetes, are associated with decreased melatonin levels. The results thus prove that a melatonin-insulin antagonism exists. Astonishingly, notwithstanding the drastic metabolic disturbances in STZ-diabetic rats, the diurnal rhythms of the parameters investigated are maintained.
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PMID:Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes. 1862 57

Although Radix clematidis has commonly been used in Chinese medicine for the treatment of arthralgia, the anti-diabetic effects of Radix clematidis have not yet been reported. In the present study, we demonstrated that Radix clematidis extract (RCE) could prevent cytokine-induced beta-cell damage and streptozotocin (STZ)-induced diabetes in mice. Treatment of RINm5F insulinoma cells with interleukin-1beta and interferon-gamma reduced cell viability; however, RCE protected the cells from this cytokine-mediated viability reduction in a concentration-dependent manner. Additionally, incubation with RCE resulted in a significant suppression of cytokine-induced nitric oxide (NO) production, which was correlated with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism by which RCE inhibited iNOS gene expression appeared to involve inhibition of NF-kappaB activation. Furthermore, RCE abolished the cytokine-induced increases in NF-kappaB binding activity and p65 subunit levels in the nucleus, as well as IkappaBalphadegradation in the cytosol when compared to unstimulated cells. The protective effect of RCE was further demonstrated by the observed suppression of NF-kappaB-dependent iNOS expression and normal insulin secreting responses to glucose in cytokines-treated islets. The anti-diabetic effect of RCE was even more striking in vivo, where nearly complete protection against STZ-induced diabetes was observed. Treatment of mice with STZ resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining; however, pretreatment of mice with RCE blocked the destruction of STZ-induced islets and the development of type 1 diabetes.
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PMID:Radix clematidis extract protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. 1869 94

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP/G6PC2) is a major autoantigen in both mouse and human type 1 diabetes. IGRP is selectively expressed in islet beta cells and polymorphisms in the IGRP gene have recently been associated with variations in fasting blood glucose levels and cardiovascular-associated mortality in humans. Chromatin immunoprecipitation (ChIP) assays have shown that the IGRP promoter binds the islet-enriched transcription factors Pax-6 and BETA2. We show here, again using ChIP assays, that the IGRP promoter also binds the islet-enriched transcription factors MafA and Foxa2. Single binding sites for these factors were identified in the proximal IGRP promoter, mutation of which resulted in decreased IGRP fusion gene expression in betaTC-3, Hamster insulinoma tumor (HIT), and Min6 cells. ChiP assays have shown that the islet-enriched transcription factor Pdx-1 also binds the IGRP promoter, but mutational analysis of four Pdx-1 binding sites in the proximal IGRP promoter revealed surprisingly little effect of Pdx-1 binding on IGRP fusion gene expression in betaTC-3 cells. In contrast, in both HIT and Min6 cells mutation of these four Pdx-1 binding sites resulted in a approximately 50% reduction in fusion gene expression. These data suggest that the same group of islet-enriched transcription factors, namely Pdx-1, Pax-6, MafA, BETA2, and Foxa2, directly or indirectly regulate expression of the two major autoantigens in type 1 diabetes.
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PMID:Foxa2 and MafA regulate islet-specific glucose-6-phosphatase catalytic subunit-related protein gene expression. 1875 9

In the present study, Flos magnoliae extract (FME) was evaluated to determine if it could protect pancreatic beta-cells against multiple low dose streptozotocin (MLDS) and interleukin-1beta and interferon-gamma. Injection of mice with MLDS resulted in hyperglycemia and hypoinsulinemia, which was confirmed by immunohistochemical staining. However, the induction of diabetes by MLDS was completely prevented when mice were pretreated with FME. FME also effectively protected beta-cells against cytokine toxicity, which was demonstrated by an increase in the viability of rat insulinoma RINm5F cells and by preserved insulin secreting responses to glucose in isolated rat islets. Moreover, cytokine-induced nitric oxide production and iNOS mRNA and protein expression were significantly reduced in RINm5F cells and islets that were preincubated with FME. The molecular mechanism by which FME inhibits iNOS gene expression in in vitro and in vivo appears to involve inhibition of NF-kappaB activation. Taken together, these results reveal the possible therapeutic value of FME for the prevention of type 1 diabetes progression.
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PMID:Beneficial effect of Flos magnoliae extract on multiple low dose streptozotocin-induced type 1 diabetes development and cytokine-induced beta-cell damage. 1881 55


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