Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood little increase in the beta cell number seems to occur. In pregnancy, however, a marked hyperplasia of the beta cells is observed both in rodents and man. Increased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (GH). Receptors for both GH and PRL are expressed in islet cells and are upregulated during pregnancy. By mutational analysis we have identified different functional domains of the cytoplasmic part of the GH receptor. Thus the mitotic signaling only requires the membrane proximal part of the receptor and activation of the tyrosine kinase JAK2 and the transcription factors STAT1 and 3. The activation of the insulin gene however also requires the distal part of the receptor and activation of calcium uptake and STAT5. In order to identify putative autocrine growth factors or targets for growth factors we have cloned a novel GH/PRL stimulated rat islet gene product, Pref-1 (preadipocyte factor-1). This protein contains six EGF-like motifs and may play a role both in embryonic pancreas differentiation and in beta cell growth and function. In summary, the increasing knowledge about the mechanisms involved in beta cell differentiation and proliferation may lead to new ways of forming beta cells for treatment of diabetes in man.
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PMID:Beta cell proliferation and growth factors. 993 Sep 29

Interferon-gamma (IFN-gamma) is known to exert deleterious effects on pancreatic beta-cells and is implicated in the development of type 1 (autoimmune) diabetes mellitus. In this study, we investigated signaling mechanisms mediating the effects of IFN-gamma in pancreatic beta-cells using a differentiated rat insulin-secreting cell line, INS-1, with special reference to the activation of transcription factors STAT (signal transducers and activators of transcription)1 and NF-kappaB. Exposure of INS-1 cells to 100 IU/ml IFN-gamma for 24 h resulted in significant inhibition of nutrient-induced insulin secretion associated with impaired metabolism. In combination with tumor necrosis factor-alpha (TNF-alpha) (50 ng/ml), IFN-gamma elicited severe cytotoxicity and induced the expression of the inducible isoform of nitric oxide synthase (iNOS) mRNA. IFN-gamma promoted tyrosine phosphorylation and DNA-binding of STAT1 through Janus kinase (JAK)1 activation without apparent phosphorylation of JAK2. TNF-alpha did not affect STAT1 activation, but stimulated DNA-binding and transcriptional activity of NF-kappaB, both of which were further increased by IFN-gamma. These effects of IFN-gamma and TNF-alpha seem physiologically relevant, because either inhibition of STAT1 by the tyrosine kinase inhibitor herbimycin A or that of NF-kappaB by sulfasalazine resulted in the reduction of iNOS mRNA expression. In conclusion, IFN-gamma activates STAT1 and potentiates TNF-alpha-induced NF-kappaB activation in INS-1 cells, thereby inducing iNOS and cell destruction.
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PMID:Synergistic activation of NF-kappab and inducible isoform of nitric oxide synthase induction by interferon-gamma and tumor necrosis factor-alpha in INS-1 cells. 1082 33

Fas ligand (FasL), perforin, TNF-alpha, IL-1, and NO have been considered as effector molecule(s) leading to beta cell death in autoimmune diabetes. However, the real culprit(s) in beta cell destruction have long been elusive, despite intense investigation. We and others have demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN-gamma/TNF-alpha synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFN-gamma and TNF-alpha, but neither cytokine alone, induced classical caspase-dependent apoptosis in insulinoma and pancreatic islet cells. IFN-gamma treatment conferred susceptibility to TNF-alpha-induced apoptosis on otherwise resistant insulinoma cells by STAT1 activation followed by IFN regulatory factor (IRF)-1 induction. IRF-1 played a central role in IFN-gamma/TNF-alpha-induced cytotoxicity because inhibition of IRF-1 induction by antisense oligonucleotides blocked IFN-gamma/TNF-alpha-induced cytotoxicity, and transfection of IRF-1 rendered insulinoma cells susceptible to TNF-alpha-induced cytotoxicity. STAT1 and IRF-1 were expressed in pancreatic islets of diabetic NOD mice and colocalized with apoptotic cells. Moreover, anti-TNF-alpha Ab inhibited the development of diabetes after adoptive transfer. Taken together, our results indicate that IFN-gamma/TNF-alpha synergism is responsible for autoimmune diabetes in vivo as well as beta cell apoptosis in vitro and suggest a novel signal transduction in IFN-gamma/TNF-alpha synergism that may have relevance in other autoimmune diseases and synergistic anti-tumor effects of the two cytokines.
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PMID:IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. 1125 4

High glucose (HG) causes glomerular mesangial cell (GMC) growth, production of transforming growth factor (TGF)-beta, and increased synthesis of matrix proteins such as fibronectin, contributing to diabetic nephropathy. We recently found that exposure of cells to HG also activates the growth-promoting enzyme janus kinase 2 (JAK2) and its latent signal transducers and activators of transcription (STAT) transcription factors (STAT1, STAT3, and STAT5). Our purpose was to determine the effect that inhibition of JAK2 and these STAT transcription factors has on the HG-induced increase in TGF-beta and fibronectin synthesis in GMC. Exposure of GMC to 25 mmol/l glucose caused the activation of JAK2, STAT1, STAT3, and STAT5 plus an increase in TGF-beta and fibronectin synthesis, as compared with 5.5 mmol/l glucose. This HG-induced increase in synthesis of TGF-beta and fibronectin was prevented by concomitant incubation with AG-490, a specific JAK2 inhibitor. The HG-induced JAK2, STAT1, and STAT3 tyrosine phosphorylations in GMC were also abolished by AG-490. Preincubation of GMC cultured in 25 mmol/l glucose with a specific JAK2 or STAT1 antisense oligonucleotide also prevented both TGF-beta and fibronectin synthesis. These results provide direct evidence for linkages between JAK2, STAT1, and the glucose-induced overproduction of TGF-beta and fibronectin in GMC.
Diabetes 2002 Dec
PMID:Inhibition of the Jak/STAT signaling pathway prevents the high glucose-induced increase in tgf-beta and fibronectin synthesis in mesangial cells. 1245 7

Clinical and animal studies show that treatment with angiotensin-converting enzyme (ACE) inhibitors or ANG II-receptor antagonists slows progression of nephropathy in diabetes, indicating ANG II plays an important role in its development. We previously reported that hyperglycemia augments both ANG II-induced growth and activation of Janus kinase (JAK)2 and signal transducers and activators of transcription (STAT) proteins in cultured rat mesangial cells. Furthermore, we demonstrated that the tyrosine kinase enzyme JAK2 plays a key role in both ANG II- and hyperglycemia-induced growth in these cells. We hypothesized that the ACE inhibitor captopril and the ANG II-receptor antagonist candesartan would hinder hyperglycemic-induced activation of JAK and STAT proteins in rat glomeruli, demonstrating that ANG II plays an important role in the activation of these proteins in vivo. Adult male Sprague-Dawley rats were given either streptozotocin (STZ; 60 mg/kg iv) or vehicle, and glomeruli were isolated 2 wk later. Activation of JAK and STAT proteins was evaluated by Western blot analysis for specific tyrosine phosphorylation. Groups of rats were given captopril (75-85 mg x kg(-1) x day(-1)), candesartan (10 mg x kg(-1) x day(-1)), or the JAK2 inhibitor AG-490 (5 mg x kg(-1) x day(-1)) for the study's duration. STZ stimulated glomerular phosphorylation of JAK2, STAT1, STAT3, and STAT5. Phosphorylation was reduced in rats treated with captopril, candesartan, and AG-490. Furthermore, both candesartan and AG-490 inhibited STZ-induced increases in urinary protein excretion. In conclusion, our studies demonstrate that hyperglycemia induces activation of JAK2 and the STATs in vivo via an ANG II-dependent mechanism and that these proteins may be involved in the early kidney damage associated with diabetes.
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PMID:Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli. 1467 47

Prediabetes and diabetes in nonobese diabetic (NOD) mice have been targeted by a variety of immunotherapies, including the use of a soluble form of cytotoxic T lymphocyte antigen 4 (CTLA-4) and interferon (IFN)-gamma. The cytokine, however, fails to activate tolerogenic properties in dendritic cells (DCs) from highly susceptible female mice early in prediabetes. The defect is characterized by impaired induction of immunosuppressive tryptophan catabolism, is related to transient blockade of the signal transducer and activator of transcription (STAT)1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production. Here, we show that soluble CTLA-4 imparts suppressive properties to DCs from early prediabetic NOD female mice through mechanisms that rely on autocrine signaling by IFN-gamma. Although phosphorylation of STAT1 in response to IFN-gamma is compromised in those mice, CTLA-4 obviates the defect. IFN-gamma-driven expression of tryptophan catabolism by CTLA-4-immunoglobulin is made possible through the concomitant activation of the Forkhead Box class O (FOXO) transcription factor FOXO3a, induction of the superoxide dismutase gene, and prevention of peroxynitrite formation.
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PMID:CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice. 1549 27

Serotonin (5-hydroxytryptamine, 5-HT) is a vasoconstrictor and mitogen whose levels are elevated in diabetes. Previous studies have shown the presence of 5-HT2A, 5-HT2B, and 5-HT1B receptors in vascular smooth muscle cells (VSMCs). There are currently no data regarding 5-HT2B and 5-HT1B receptor activation of the JAK/STAT pathway in VSMCs and resultant potential alterations in 5-HT signaling in diabetes. Therefore, we tested the hypothesis that 5-HT differentially activates the JAK/STAT pathway in VSMCs under conditions of normal (5 mM) and high (25 mM) glucose. Treatment of rat VSMCs with 5-HT (10(-6) M) resulted in time-dependent activation ( approximately 2-fold) of JAK2, JAK1, and STAT1, but not STAT3 (maximal at 5 min, returned to baseline by 30 min). The 5-HT2B receptor agonist BW723C86 and the 5-HT1B receptor agonist CGS12066A (10(-9)-10(-5) M, 5-min stimulation) did not activate the JAK/STAT pathway. Treatment with the 5-HT2A receptor antagonist ketanserin (10 nM) inhibited JAK2 activation by 5-HT. Treatment of streptozotocin-induced diabetic rats with ketanserin (5 mg.kg-1.day-1) reduced activation of JAK2 and STAT1 but not STAT3 in endothelium-denuded thoracic aorta in vivo. 5-HT (10(-6) M) treatment resulted in increased cell proliferation and increased DNA synthesis, which were inhibited by the JAK2 inhibitor AG490. Further studies with apocynin, diphenyleneiodonium chloride, catalase, and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK/STAT pathway by 5-HT. Therefore, we conclude that 5-HT activates JAK2, JAK1, and STAT1 via the 5-HT2A receptors in a reactive oxygen species-independent manner under both normal and high glucose conditions.
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PMID:Activation of the JAK/STAT pathway in vascular smooth muscle by serotonin. 1560 54

In the current study, we investigated the effect of simvastatin on the ability of high glucose (HG) and ANG II to activate the JAK2-STAT signaling cascade and induce glomerular mesangial cell (GMC) growth. We found that pretreatment with simvastatin significantly inhibited HG- and ANG II-induced collagen IV production, JAK2 activation, and phosphorylation of STAT1 and STAT3 in GMC. We also found that the activation of JAK2 by HG and ANG II was dependent on the Rho family of GTPases. Consistent with these in vitro results, both albumin protein excretion and phosphorylation of JAK2, STAT1, and STAT3 were attenuated in renal glomeruli by administration of simvastatin in a streptozotocin-induced rat model of HG diabetes. This study demonstrates that simvastatin blocks ANG II-induced activation of the JAK/STAT pathway in the diabetic environment, in vitro and in vivo, and, thereby, provides new insights into the molecular mechanisms underlying early diabetic nephropathy.
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PMID:Effect of simvastatin on high glucose- and angiotensin II-induced activation of the JAK/STAT pathway in mesangial cells. 1644 52

Epidemiological studies show that the obstructive sleep apnea syndrome (OSAS) is strongly associated with obesity, hypertension and diabetes, the three conditions characteristic of the metabolic syndrome. Since metabolic disorders usually involve altered homeostatic mechanisms both centrally and peripherally, it is likely that so it is in OSAS, but the underlying mechanisms remain largely unknown. We used an established rodent model to test whether chronic intermittent hypoxia (CIH) similar to that experienced by OSAS patients leads to distinct and relevant for metabolic regulation transcriptional changes in the posterior hypothalamus. Using quantitative reverse transcription-polymerase chain reaction, we found that rats exposed to CIH for 35 days (n=9) had twice higher levels of the adrenergic alpha2A receptor mRNA than the rats simultaneously submitted to a matching sham treatment (n=9). The mRNA levels of three members of the family of signal transducers and activators of transcription, STAT1, STAT3 and STAT5b, were also increased 2-4 times. The increases occurred only in the perifornical region, whereas no changes were detected in the ventromedial region comprising the ventromedial and arcuate nuclei or the dorsomedial region comprising the dorsomedial and paraventricular nuclei. These results show that, at least at the transcriptional level, CIH exerts a distinct and regionally selective central effect on the expression of selected mRNAs involved in metabolic regulation through adrenergic, leptinergic and inflammatory pathways.
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PMID:Chronic intermittent hypoxia alters hypothalamic transcription of genes involved in metabolic regulation. 1673 Feb 40

The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT(1) receptor antagonist, 10 mg x kg(-1) x day(-1) orally in drinking water), atrasentan (ET(A) receptor antagonist, 10 mg x kg(-1) x day(-1) orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg x kg(-1) x day(-1) intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 +/- 9.0, 130 +/- 3.3, 128 +/- 6.8, and 131 +/- 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 +/- 3.0, 92.6 +/- 7.4, 76.9 +/- 12.1, and 38.3 +/- 13.1% in sham, sham + AG-490, STZ + AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.
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PMID:Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation. 1752 54


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