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)

Plasma from 126 patients with various autoimmune diseases and 118 healthy subjects were examined to determine the presence of autoantibodies to FKBP12, one of immunophilins. The frequency of IgG and/or IgM anti-FKBP12 autoantibodies detected by ELISA was as follows; SLE (15/39), SSc (11/27), CREST (4/7), RA (2/8), MCTD (0/5), Graves' disease (4/12), IDDM (2/6), PM/DM (0/3), MG (1/4), AIH (2/6), PBC (4/9), and healthy subjects (5/118). The specificity of the autoantibodies was demonstrated by absorption of the plasma samples with r-FKBP12 and other recombinant proteins. In immunoblotting, IgM anti-FKBP12 autoantibodies reacted with two bands of 12 and 24 kD, the latter representing the dimer. Anti-FKBP12 autoantibodies in some patients reacted more strongly with the dimer than the monomer, suggesting that FKBP12 may also exist as the dimer in vivo. The majority of anti-FKBP12 autoantibodies bound to two synthetic peptides corresponding to amino acid residues of FKBP12, Pro16 approximate to Tyr26 and Thr27 approximate to Phe46. These epitopes are phylogenetically well conserved and responsible for the binding to calcineurin and FK506. The autoantibodies inhibited pentamerization of FKBP12 with FK506, calcineurin, calmodulin, and Ca2+ in vitro. These data define the frequent occurrence of a novel set of autoantibodies to a cytosolic protein involved in the regulation of the immune response.
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PMID:Autoantibodies to FK506 binding protein 12 (FKBP12) in autoimmune diseases. 1043 96

For more than two decades, islet transplantation has been pursued as a curative treatment for type 1 diabetes mellitus (T1DM) with little success. It is likely that the failures of the past have involved technical difficulties in harvesting human islets, transplantation of insufficient amounts of islet tissue, the antagonistic effects of immune suppressive drugs, including calcineurin inhibitors and glucocorticoids, graft rejection and recurrent autoimmune disease. More recently, success has been reported in seven out of seven consecutive transplants using approaches that overcome the technical and therapeutic problems of the past. Although this success is noteworthy, issues remain that preclude the general application of islet transplants for treatment of the majority of patients with T1DM. These include the need for chronic immunosuppression and the requirement of large numbers of islets. Efforts are under way, using a variety of immunological, molecular and cellular strategies, to make this promising treatment available to the majority of patients with this disease.
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PMID:Transplantation of the islets of Langerhans: new hope for treatment of type 1 diabetes mellitus. 1104 69

Diabetic muscle infarction (DMI) is a rare entity that occurs in patients with long-standing type 1 insulin dependent diabetes mellitus (IDDM). We describe DMI occurring on an average of 5 months after SPK in four patients with IDDM and end stage renal disease (ESRD). These patients had evidence of other long-term diabetic complications including retinopathy and neuropathy, as well as microangiopathy and hypercoagulability, both of which are pre-disposing factors for DMI. The etiology of DMI is not well understood. Despite establishment of normoglycemia after kidney-pancreas transplantation, DMI may occur as a result of tissue damage/fragility secondary to the pre-existing long-term labile glycemic control and hypertension. This may be exacerbated by the pro-coagulant effects of the calcineurin-inhibitors and the use of steroids as part of the immunosuppressive regimen.
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PMID:Diabetic muscle infarction after simultaneous pancreas-kidney transplant. 1209 87

Type 1 diabetes mellitus affects about 1 in 300 people in North America and Europe. Epidemiological studies indicate that the incidence and thus prevalence of type 1 diabetes is rising worldwide. Intervention in autoimmune type 1a diabetes could occur at the time of diagnosis or, preferably, prior to clinical presentation during the 'prediabetic' period (e.g. prevention). Prediabetes is best recognised by the detection of islet autoantibodies in the serum. Promising intervention strategies include monoclonal antibody therapies (e.g. anti-CD3, anti-CD25, anti-CD52 or anti-CD20 monoclonal antibodies), immunosuppression (e.g. calcineurin inhibitors, B7 blockade, glucocorticoids, sirolimus (rapamycin), azathioprine or mycophenolate mofetil), immunomodulatory therapies (e.g. plasmapheresis, intravenous immunoglobulin, cytokine administration, adoptive cellular gene therapy) and tolerisation interventions (e.g. autoantigen administration or avoidance, altered peptide ligand or peptide-based therapies). To date, islet and pancreas transplantation have essentially been reserved for patients with long-standing diabetes who have complications and are also in need of a concurrent kidney transplant. None of the therapies attempted to date has produced long-term remissions in new-onset type 1 diabetes patients and no therapies have been shown to prevent the disease. Nevertheless, with advances in our understanding of basic immunology and the cellular and molecular mechanisms of tolerance induction and maintenance, successful intervention therapies will be developed. The balance between safety and efficacy is critical. Higher rates of adverse events might be more tolerable in new-onset type 1 diabetes patients if the therapy is extremely effective at inducing a permanent remission. However, therapies must not harm the beta-cells themselves or any organ system that is a potential target of diabetes complications, such as the nervous system, retina, cardiovascular system or kidney. In the treatment of prediabetes, successful therapies should provide a level of safety similar to that of currently used vaccines and a high level of efficacy.
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PMID:Prevention strategies for type 1 diabetes mellitus: current status and future directions. 1253 19

We studied the intracellular events associated with pancreatic beta cell apoptosis by IFN-gamma/TNF-alpha synergism. IFN-gamma/TNF-alpha treatment of MIN6N8 insulinoma cells increased the amplitude of high voltage-activated Ca(2+) currents, while treatment with IFN-gamma or TNF-alpha alone did not. Cytosolic Ca(2+) concentration ([Ca(2+)](c)) was also increased by IFN-gamma/TNF-alpha treatment. Blockade of L-type Ca(2+) channel by nifedipine abrogated death of insulinoma cells by IFN-gamma/TNF-alpha. Diazoxide that attenuates voltage-activated Ca(2+) currents inhibited MIN6N8 cell death by IFN-gamma/TNF-alpha, while glibenclamide that accentuates voltage-activated Ca(2+) currents augmented insulinoma cell death. A protein kinase C inhibitor attenuated MIN6N8 cell death and the increase in [Ca(2+)](c) by IFN-gamma/TNF-alpha. Following the increase in [Ca(2+)](c), calpain was activated, and calpain inhibitors decreased insulinoma cell death by IFN-gamma/TNF-alpha. As a downstream of calpain, calcineurin was activated and the inhibition of calcineurin activation by FK506 diminished insulinoma cell death by IFN-gamma/TNF-alpha. BAD phosphorylation was decreased by IFN-gamma/TNF-alpha because of the increased calcineurin activity, which was reversed by FK506. IFN-gamma/TNF-alpha induced cytochrome c translocation from mitochondria to cytoplasm and activation of caspase-9. Effector caspases such as caspase-3 or -7 were also activated by IFN-gamma/TNF-alpha treatment. These results indicate that IFN-gamma/TNF-alpha synergism induces pancreatic beta cell apoptosis by Ca(2+) channel activation followed by downstream intracellular events such as mitochondrial events and caspase activation and also suggest the therapeutic potential of Ca(2+) modulation in type 1 diabetes.
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PMID:Role of calcium in pancreatic islet cell death by IFN-gamma/TNF-alpha. 1515 22

Using biochemical/pharmacological approaches, we previously showed that type 2 ryanodine receptors (RyR2) become dysfunctional in hearts of streptozotocin-induced type 1 diabetic rats. However, the functional consequence of this observation remains incompletely understood. Here we use laser confocal microscopy to investigate whether RyR2 dysfunction during diabetes alters evoked and spontaneous Ca(2+) release from the sarcoplasmic reticulum (SR). After 7-8 weeks of diabetes, steady-state levels of RyR2 remain unchanged in hearts of male Sprague-Dawley rats, but the number of functional receptors decreased by >37%. Interestingly, residual functional RyR2 from diabetic rat hearts exhibited increased sensitivity to Ca(2+) activation (EC(50activation) decreased from 80 microM to 40 microM, peak Ca(2+) activation decreased from 425 microM to 160 microM). When field stimulated, intracellular Ca(2+) release in diabetic ventricular myocytes was dyssynchronous (non-uniform) and this was independent of L-type Ca(2+) currents. Time to peak Ca(2+) increased 3.7-fold. Diabetic myocytes also exhibited diastolic Ca(2+) release and 2-fold higher frequency of spontaneous Ca(2+) sparks, albeit at a lower amplitude. The amplitude of caffeine-releasable Ca(2+) was also lower in diabetic myocytes. RyR2 from diabetic rat hearts exhibited increased phosphorylation at Ser2809 and contained reduced levels of FKBP12.6 (calstablin2). Collectively, these data suggest that RyR2 becomes leaky during diabetes and this defect may be responsible to the reduced SR Ca(2+) load. Diastolic Ca(2+) release could also serve as a substrate for delayed after-depolarizations, contributing to the increased incidence of arrhythmias and sudden cardiac death in type 1 diabetes.
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PMID:Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats. 1702 51

For reducing the corticosteroid (CS)-related side-effects, especially cardiovascular events, CS-sparing protocols have become increasingly common in pancreas transplantation (PT). Lympho-depleting induction antibodies, such as rabbit anti-thymocyte globulin (rATG) or alemtuzumab, have been widely used in successful trials. The results of various CS-sparing protocols combining calcineurin inhibitors (CNI) and mycophenolate or sirolimus, have been mixed for rejection and survival rates. Most of the studies were uncontrolled trials of low-risk patients, therefore the grade of evidence is limited. Large-scale prospective studies with long-term follow up are necessary to assess risks and benefits of CS-sparing regimens in PT before recommending such strategies as standard practice. Islet allo-transplantation for patients with brittle type 1 diabetes mellitus, less invasive and safer procedure than PT, has been attempted since late 1980s, but diabetogenic immunosuppressants at maintenance, mainly CS and high-dose CNI, prevented satisfactory results (10% insulin-independence at 1-year post-transplant). Since 2000, CS-free and CNI-reducing protocols, including more potent induction [daclizumab, OKT3gamma1(ala-ala) anti-CD3 antibody, rATG] and maintenance (sirolimus, mycophenolate) agents, have significantly improved short-term outcomes whereas long-term are still inadequate (from 80% to 20% insulin-independence from 1- to 5-year post-transplant). Main limitations are allo- and autoimmunity, immunosuppression-related islet and systemic toxicity and transplant site unsuitability, which tolerogenic protocols and biotechnological solutions may solve.
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PMID:Minimization and withdrawal of steroids in pancreas and islet transplantation. 1885 50

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders.
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PMID:Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. 1910 61

The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen-1 antibody efalizumab which permits long-term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single-islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long-term follow-up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid-free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long-term islet allograft survival.
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PMID:Islet transplantation in type 1 diabetics using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. 2175 35

To determine the role of Gq signaling and calcineurin (CN) activation in promoting apoptosis of glomerular podocytes, constitutively active Gq [Gq(+)] or CN [CN(+)] proteins were introduced into cultured podocytes using protein transduction by tagging the proteins with the transactivator of transcription peptide. To investigate the role of CN in promoting podocyte apoptosis in vivo, a genetic model of type 1 diabetes mellitus (Akita mice) was treated with the CN inhibitor FK506. In cultured podocytes, Gq(+) stimulated nuclear translocation of nuclear factor of activated T cells (NFAT) family members, activated an NFAT reporter construct, and enhanced podocyte apoptosis in a CN-dependent fashion. CN(+) similarly promoted podocyte apoptosis, and apoptosis induced by either angiotensin II or endothelin-1 was blocked by FK506. Induction of apoptosis required NFAT-induced gene transcription because apoptosis induced by either Gq(+) or CN(+) was blocked by an inhibitor that prevented CN-dependent NFAT activation without affecting CN phosphatase activity. Podocyte apoptosis was mediated, in part, by the NFAT-responsive gene cyclooxygenase 2 (COX2) and prostaglandin E(2) generation because apoptosis induced by Gq(+) was attenuated by either COX2 inhibition or blockade of the Gq-coupled E-series prostaglandins receptor. The findings appeared relevant to podocyte apoptosis in diabetic nephropathy because apoptosis was significantly reduced in Akita mice by treatment with FK506. These data suggest that Gq stimulates CN and promotes podocyte apoptosis both in vitro and in vivo. Apoptosis requires NFAT-dependent gene transcription and is mediated, in part, by CN-dependent COX2 induction, prostaglandin E(2) generation, and autocrine activation of the Gq-coupled E-series prostaglandins receptor.
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PMID:Calcineurin (CN) activation promotes apoptosis of glomerular podocytes both in vitro and in vivo. 2162 31


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