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)

Fibroblast growth factor-2 (FGF-2) is a potent mitogen expressed widely during embryogenesis and in tissues of the human fetus. It is recognized as an endothelial cell mitogen and is angiogenic in vivo. Expression of FGF-2 mRNA has also been shown within the human term placenta, and FGF-2 isolated from placental tissue, suggesting a role in placental growth including angiogenesis. The purpose of this study was to quantify and localize the sites of expression of FGF-2 and its high-affinity receptor, FGFR1, within placentae from normal term human pregnancies (n=8, 39-42 weeks), and pregnancies complicated by pregestational, type 1 diabetes (n=8, 36-40 weeks). Tissues were collected immediately following delivery and were either snap-frozen for RNA isolation, or fixed for either in situ hybridization using a 35S-labelled cRNAs encoding human FGF-2 or FGFR1, or immunocytochemistry using antibodies against human FGF-2 or FGFR1. Northern blot hybridization showed a significantly increased abundance of mRNAs for both FGF-2 and FGFR1 in placentae from diabetic women compared to those from normal women. In normal term placenta FGF-2 mRNA was present at low abundance in fetal villous tissue, in the vascular endothelium of blood vessels, and in the syncytiotrophoblast. FGF-2 mRNA was considerably more abundant in the syncytiotrophoblast and villous tissue of placentae from diabetic patients. Messenger RNA for FGFR1 was similarly distributed to that encoding FGF-2. Immunocytochemistry revealed abundant FGF-2 and FGFR1 peptides in villous vascular endothelial cells, and associated with the cell membranes of stromal tissues in placentae from control pregnancies. Little immunoreactive FGF-2 was present in the syncytiotrophoblast at term. In pregnancies complicated by diabetes intense staining for immunoreactive FGF-2 and for FGFR1 additionally existed in syncytiotrophoblast. The results suggest that FGF-2 acting as an autocrine agent contributes to placental angiogenesis, but may be released from the syncytium into the maternal circulation. Expression is elevated in placentae from diabetic pregnancies, and is particularly associated with the syncytiotrophoblast. This suggests a placental source for the elevated circulating maternal FGF-2 previously described in diabetic pregnancy.
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PMID:Fibroblast growth factor-2 and fibroblast growth factor receptor-1 mRNA expression and peptide localization in placentae from normal and diabetic pregnancies. 954 79

Cytokines may contribute to beta-cell apoptosis in the early stages of type 1 diabetes mellitus. It has been reported recently that interleukin-1 beta (IL-1 beta) induces activation of the mitogen-activated protein kinases (MAPK) p38 and ERK1/2 in neonatal rat islets. Since these kinases may participate in cytokine-induced apoptosis, we evaluated whether cytokines induce activation of MAPKs in FACS-purified primary rat beta-cells, and whether blockers of p38 and/or ERK1/2 prevent beta-cell death. IL-1 beta, but not interferon-gamma (IFN-gamma), caused phosphorylation of the substrates Elk-1, ATF-2 and hsp25, and the phosphorylation of both Elk-1 and hsp25 were decreased by the p38 blocker SB203580 (p38i) and the MAPK/ERK blocker PD 098059 (MEKi). When added together, p38i and MEKi decreased IL-1 beta-induced nitrite production over 24 hours by 60%, but did not affect IL-1 beta-induced manganese superoxide dismutase (MnSOD) mRNA expression. To test the effects of MAPK inhibitors on beta-cell death by necrosis or apoptosis, these cells were exposed for 6 or 9 days to IL-1 beta + IFN-gamma. This treatment induced cell death, mostly by apoptosis. The MEKi, but not the p38i, significantly decreased cytokine-induced apoptosis, thus decreasing the total number of dead cells. This protection was only partial, suggesting that ERK1/2 activation is not the only mechanism by which cytokines induce beta-cell apoptosis. We conclude that IL-1 beta induces activation of both p38 and ERK1/2, and that ERK1/2 contributes to the pro-apoptotic effects of the cytokine in primary beta-cells.
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PMID:Activation of extracellular signal-regulated kinase (ERK)1/2 contributes to cytokine-induced apoptosis in purified rat pancreatic beta-cells. 1090 6

The SkyePharma PLC subsidiary SkyePharma Inc. (formerly DepoTech) is developing a sustained-release formulation of morphine sulphate [DepoMorphine, C 0401, D 0401, SKY 0401] using its DepoFoam proprietary drug delivery technology. It is intended for epidural administration in the treatment of acute postoperative pain. DepoFoam consists of microscopic spherical particles with internal aqueous chambers separated by lipid membranes containing the encapsulated drug. DepoFoam particles are synthetic replicas of natural lipids that are biodegradable and biocompatible. DepoFoam can be administered subcutaneously, intramuscularly and intrathecally. In December 2002, SkyePharma and Endo Pharmaceuticals signed a development and commercialisation agreement providing Endo Pharmaceuticals with exclusive marketing and distribution rights in the US and Canada for Depomorphine and another product, Propofol IDD-D trade mark, with options for other development products. Under the terms of the agreement, SkyePharma will receive an upfront payment and may receive further milestone payments. Skye-Pharma will also receive a share of each product's sales revenue. SkyePharma is responsible for clinical development towards the US FDA approval and for product manufacture and associated costs. Following the approval, SkyePharma will as act as a supplier, while Endo will market each product in the US and Canada. SkyePharma has received 30 million US dollars from Paul Capital Partners, a US private equity group, to develop DepoMorphine. This capital will enable SkyePharma to fund phase III clinical trials without raising extra funds. Paul Capital will have rights to 15% of any revenues from DepoMorphine until 2014, and also receive some royalties on three other SkyePharma products. However, if DepoMorphine fails in clinical trials or is declined for registration, Paul Capital will not be compensated for the investment. SkyePharma expect to conclude a European license by the end of 2003, and are also in discussions with potential Japanese licensees. In July 2003, SkyePharma submitted an NDA to the US FDA for DepoMorphine in the treatment of moderate to severe postoperative pain. The FDA accepted the filing in September, triggering a milestone payment to Skye-Pharma. Positive results from two phase III trials in 750 patients after hip surgery and lower abdominal surgery released in June 2003 report that DepoMorphine is effective in providing sustained dose-related analgesia. DepoMorphine demonstrated sustained dose-related analgesia and achieved its primary endpoint and also statistical significance on several secondary endpoints such as patient perception of pain intensity and adequacy of pain relief. The Financial Times in January 2001 reported that analysts have forecast DepoMorphine to reach peak sales of more than 200 million US dollars. In April 2001, the Wall Street Journal quoted the CEO of SkyePharma predicting that DepoMorphine has the potential to reach combined annual sales, in the US and Europe, of approximately 350 million US dollars.
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PMID:Morphine Liposomal--SkyePharma: C 0401, D 0401, morphine--DepoFoam, SKY 0401. 1458 69

Pancreatic islet transplantation is an emerging therapy for type 1 diabetes. To survive and function, transplanted islets must revascularize because islet isolation severs arterial and venous connections; the current paradigm is that islet revascularization originates from the transplant recipient. Because isolated islets retain intraislet endothelial cells, we determined whether these endothelial cells contribute to the revascularization using a murine model with tagged endothelial cells (lacZ knock-in to Flk-1/VEGFR2 gene) and using transplanted human islets. At 3-5 weeks after transplantation beneath the renal capsule, we found that islets were revascularized and that the transplant recipient vasculature indeed contributed to the revascularization process. Using the lacZ-tagged endothelial cell model, we found that intraislet endothelial cells not only survived after transplantation but became a functional part of revascularized islet graft. A similar contribution of intraislet endothelial cells was also seen with human islets transplanted into an immunodeficient mouse model. In the murine model, individual blood vessels within the islet graft consisted of donor or recipient endothelial cells or were a chimera of donor and recipient endothelial cells, indicating that both sources of endothelial cells contribute to the new vasculature. These observations suggest that interventions to activate, amplify, or sustain intraislet endothelial cells before and after transplantation may facilitate islet revascularization, enhance islet survival, and improve islet transplantation.
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PMID:Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. 1511 2

Understanding mechanisms underlying apoptotic destruction of insulin-secreting cells is critical to validate therapeutic targets for type 1 diabetes mellitus. We recently reported insulin-like growth factor binding protein-3 (IGFBP-3) as a novel mediator of apoptosis in insulin-secreting cells. In light of emerging IGF-independent roles for IGFBP-3, we investigated the mechanisms underlying actions of the novel, recombinant human mutant G(56)G(80)G(81)-IGFBP-3, which lacks intrinsic IGF binding affinity. Using the rat insulinoma RINm5F cell line, we report the first studies in insulin-secreting cells that IGFBP-3 selectively suppresses multiple, key intracellular phosphorelays. By immunoblot, we demonstrate that G(56)G(80)G(81)-IGFBP-3 suppresses phosphorylation of c-raf-MEK-ERK pathway and p38 kinase in time-dependent and dose-dependent manners. SAPK/JNK signaling was unaffected. These data delineate several novel intracellular sites of action for IGFBP-3 in insulin-secreting cells.
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PMID:Novel actions of IGFBP-3 on intracellular signaling pathways of insulin-secreting cells. 1627 48

The aim of the present investigation was to characterize the role of the MAPK kinase kinase-1 (MEKK-1) in stress-induced cell death of insulin producing cells. We observed that transient overexpression of the wild type MEKK-1 protein in the insulin-producing cell lines RIN-5AH and betaTC-6 increased c-Jun N-terminal kinase (JNK) phosphorylation and augmented cell death induced by diethylenetriamine/nitroso-1-propylhydrazino)-1-propanamine (DETA/NO), streptozotocin (STZ), and hydrogen peroxide (H2O2). Furthermore, DETA/NO or STZ induced a rapid threonine phosphorylation of MEKK-1. Silencing of MEKK-1 gene expression in betaTC-6 and human dispersed islet cells, using in vitro-generated diced small interfering RNA, resulted in protection from DETA/NO, STZ, H2O2, and tunicamycin induced cell death. Moreover, in DETA/NO-treated cells diced small interfering RNA-mediated down-regulation of MEKK-1 resulted in decreased activation of JNK but not p38 and ERK. Inhibition of JNK by treatment with SP600125 partially protected against DETA/NO- or STZ-induced cell death. In summary, our results support an essential role for MEKK-1 in JNK activation and stress-induced beta-cell death. Increased understanding of the signaling pathways that augment or diminish beta-cell MEKK-1 activity may aid in the generation of novel therapeutic strategies in the treatment of type 1 diabetes.
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PMID:The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death. 1830 48

Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.
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PMID:Mapping the genetic architecture of gene expression in human liver. 1846 17

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of beta-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within approximately 10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for approximately 175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-gamma-coactivator-1alpha may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.
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PMID:Making insulin-deficient type 1 diabetic rodents thrive without insulin. 1877 78

Berberine, an alkaloid derivative from Berberis vulgaris L., has been used extensively in traditional Chinese medicine to treat diarrhea and diabetes, but the underlying mechanisms for treating diabetes are not fully understood. Recent studies suggested that berberine has many beneficial biological effects, including anti-inflammation. Because type 1 diabetes is caused by T cell-mediated destruction of beta cells and severe islet inflammation, we hypothesized that berberine could ameliorate type 1 diabetes through its immune regulation properties. Here we reported that 2 weeks of oral administration of berberine prevented the progression of type 1 diabetes in half of the NOD mice and decreased Th17 and Th1 cytokine secretion. Berberine suppressed Th17 and Th1 differentiation by reducing the expression of lineage markers. We found that berberine inhibited Th17 differentiation by activating ERK1/2 and inhibited Th1 differentiation by inhibiting p38 MAPK and JNK activation. Berberine down-regulated the activity of STAT1 and STAT4 through the suppression of p38 MAPK and JNK activation, and it controlled the stability of STAT4 through the ubiquitin-proteasome pathway. Our findings indicate that berberine targets MAPK to suppress Th17 and Th1 differentiation in type 1 diabetic NOD mice. This study revealed a novel role of ERK in Th17 differentiation through down-regulation of STAT3 phosphorylation and RORgamma t expression.
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PMID:Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice. 1966 Oct 66

Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. VEGF expression is increased in proximal tubules of mice with type 1 diabetes. In mouse proximal tubular epithelial cells (MCT) cultured with 30 mM glucose (HG) for 24h, VEGF expression is increased at the protein and the mRNA level, suggesting a transcriptional mechanism. HG stimulation of VEGF synthesis is prevented by captopril, an inhibitor of angiotensin-converting enzyme, and, by losartan, a specific antagonist of angiotensin type 1 receptor (AT1), suggesting that VEGF synthesis is mediated by Ang II. Synthesis of angiotensinogen (AGT), a precursor of angiotensin II, is increased in MCTs cultured in HG. Although synthesis of renin and ACE is not affected by HG, their activity is increased in the conditioned medium. Concentrations of Ang I and Ang II are also increased in conditioned medium from HG-treated MCTs and captopril prevents increased Ang II, but not Ang I, synthesis. Finally, AT1 is activated in MCTs treated with HG, and its activation is prevented by captopril and losartan. The ERK pathway is activated by HG within minutes of stimulation and lasting for up to 24h. The initial phase of ERK activation is due to HG itself and leads to AGT upregulation and the sustained phase is mediated for the most part by Ang II-activated AT1 receptor and leads to increased VEGF synthesis. These data show that: (1) HG increases AGT synthesis and activation of renin and ACE by MCTs, leading to local production of Ang I and Ang II. (2) Ang II activates endogenous AT1 and stimulates synthesis of VEGF. (3) HG activation of ERK starts within minutes and lasts for up to 24h. Early ERK activation is involved in AGT upregulation and sustained ERK activation, mediated via AT1, is responsible for VEGF synthesis. In conclusion, our study shows that MCTs express an endogenous renin-angiotensin system that is activated by high glucose to stimulate the synthesis of VEGF, through activation of the ERK pathway.
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PMID:Mechanism of VEGF expression by high glucose in proximal tubule epithelial cells. 1976 32


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