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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of beta-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in beta-cell death. We investigated whether beta-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring beta-cells expressing the suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, have a markedly reduced incidence of diabetes. Similar to their non-transgenic (Tg) littermates, SOCS-1-Tg mice develop insulitis and their splenocytes transfer disease to NODscid recipients. Disease protection correlates with suppression of cytokine-induced STAT-1 phosphorylation in SOCS-1-expressing beta-cells and with a reduced sensitivity of these cells to destruction by diabetogenic cells in vivo. Interestingly, lymphocytes recruited to the pancreas of SOCS-1-Tg mice transferred diabetes to NODscid recipients with a reduced efficiency, suggesting that the pancreatic environment in SOCS-1-Tg mice does not support the maintenance of functionally differentiated T-cells. These results suggest that cytokines contribute to the development of type 1 diabetes by acting directly on the target beta-cell. Importantly, given that the SOCS-1-expressing mouse maintain normal blood glucose levels throughout life, this study also showed that SOCS-1 expression by beta-cells can represent a promising strategy to prevent type 1 diabetes.
Diabetes 2003 Nov
PMID:Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. 1457 88

Prostaglandin D(2) (PGD(2)) and its metabolites bind to the intracellular PPARs to regulate vasoactive substances involved in vascular remodeling through regulation of mRNAs transcription as well as through receptor-mediated mechanisms. PGD(2) decreases inducible NO, PAI-1, endothelin, and VCAM expression through inhibition to NF kappa B, STAT, or AP-1 transcription factors, which are regulated by cytokines/immune system. Moreover, transfer of L-PGDS (PGD(2) synthase) into the intracellular space of EC or SMC increases intracellular PGD(2), thereby decreasing these substances. PGD(2) attenuates in vivo organ injury mediated by cytokines and the immune system. The pretreatment with PGD(2) attenuates the liver damage and hemodynamic collapse following LPS. Dahl salt-sensitive rats, with decreased PGD(2) in the outer medulla of the kidney, are prone to hypertensive kidney injury. Serum L-PGDS level is increased in renal dysfunction through a decrease in glomerular filtration. L-PGDS in urine may be derived from a failure of tubular reabsorption or from in situ synthesis. Urinary L-PGDS excretion markedly increases in the early stage of kidney injury, and urinary L-PGDS is a useful predictor of the forthcoming renal injury. Indeed, urinary L-PGDS precedes clinically overt proteinuria or other parameters indicating renal dysfunction in hypertension, primary renal diseases, and diabetes in humans. PGD(2)/L-PGDS system is a Cinderella of vascular biology.
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PMID:[PGD(2)/L-PGDS system in hypertension and renal injury]. 1469 55

Data are not readily available on the accuracy of one of the most commonly used home blood glucose meters, the One Touch Ultra (LifeScan, Milpitas, California). The purpose of this report is to provide information on the accuracy of this home glucose meter in children with type 1 diabetes. During a 24-h clinical research center stay, the accuracy of the Ultra meter was assessed in 91 children, 3-17 years old, with type 1 diabetes by comparing the Ultra glucose values with concurrent reference serum glucose values measured in a central laboratory. The Pearson correlation between the 2,068 paired Ultra and reference values was 0.97, with the median relative absolute difference being 6%. Ninety-four percent of all Ultra values (96% of venous and 84% of capillary samples) met the proposed International Organisation for Standardisation (ISO) standard for instruments used for self-monitoring of glucose when compared with venous reference values. Ninety-nine percent of values were in zones A + B of the Modified Error Grid. A high degree of accuracy was seen across the full range of glucose values. For 353 data points during an insulin-induced hypoglycemia test, the Ultra meter was found to have accuracy that was comparable to concurrently used benchmark instruments (Beckman, YSI, or i-STAT); 95% and 96% of readings from the Ultra meter and the benchmark instruments met the proposed ISO criteria, respectively. These results confirm that the One Touch Ultra meter provides accurate glucose measurements for both hypoglycemia and hyperglycemia in children with type 1 diabetes.
Diabetes Technol Ther 2003
PMID:A multicenter study of the accuracy of the One Touch Ultra home glucose meter in children with type 1 diabetes. 1470 95

The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.
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PMID:Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. 1471 5

The International Society for Interferon and Cytokine Research held their meeting Cytokines, Signaling and Diseases in Cairns, Australia, October 26-30, 2003. As there were often parallel sessions, this report discusses selected symposia: STAT as a target for the treatment of cancer, Innate immunity, SOCS and c-CBL: Negative regulation, Tumor immunity, CNS disease, Cellular therapy with adult stem cells and Drug development. There were also a large number of presentations linking the cytokines to cancer and other diseases (e.g., asthma, diabetes), and these are discussed. Presentations considering new therapeutic targets (BAFF, and interleukin-17, -21 and -31) are also considered.
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PMID:Cytokines, signaling and diseases - a pharmacologist's view. 1499 36

We previously reported that sterol-regulatory-element-binding-protein-1c (SREBP-1c) mediates insulin upregulation of genes encoding glycolytic and lipogenic enzymes in rat skeletal muscle. Here, we assessed whether glucose could regulate gene expression in contracting myotubes deriving from cultured muscle satellite cells. Glucose uptake increased twofold after a 30 minute treatment with a high glucose concentration, suggesting an acute glucose-stimulated glucose uptake. Time-course experiments showed that, within 3 hours, glucose stimulated the expression of hexokinase II, fatty acid synthase and acetyl-CoA-carboxylase-2 proteins, leading to an increased lipogenic flux and intracellular lipid accumulation in contracting myotubes. Furthermore, kinetic experiments indicated that glucose upregulated SREBP-1c precursor and nuclear proteins within 30 minutes, SREBP-1c nuclear translocation being confirmed using immunocytochemistry. In addition, the knockdown of SREBP-1 mRNA using a RNA-interference technique totally abrogated the glucose-induced upregulation of lipogenic enzymes, indicating that SREBP-1c mediates the action of glucose on these genes in rat skeletal muscle. Finally, we found that glucose rapidly stimulated SREBP-1c maturation through a Jak/STAT dependent pathway. We propose that increased intramuscular lipid accumulation associated with muscle insulin resistance in obesity or type-2 diabetes could arise partly from de novo fatty acid synthesis in skeletal muscle.
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PMID:Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway. 1503 61

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

Viral infections and local production of cytokines probably contribute to the pathogenesis of Type 1 diabetes. The viral replicative intermediate double-stranded RNA (dsRNA, tested in the form of polyinosinic-polycytidylic acid, PIC), in combination with the cytokine interferon-gamma (IFN-gamma), triggers beta-cell apoptosis. We have previously observed by microarray analysis that PIC induces expression of several mRNAs encoding for genes downstream of Toll-like receptor 3 (TLR3) signaling pathway. In this report, we show that exposure of beta-cells to dsRNA in combination with IFN-alpha, -beta, or -gamma significantly increases apoptosis. Moreover, dsRNA induces TLR3 mRNA expression and activates NF-kappaB and the IFN-beta promoter in a TRIF-dependent manner. dsRNA also induces an early (1 h) and sustained increase in IFN-beta mRNA expression, and blocking IFN-beta with a specific antibody partially prevents PIC plus IFN-gamma-induced beta-cell death. On the other hand, dsRNA plus IFN-gamma does not induce apoptosis in INS-1E cells, and expression of TLR3 and type I IFNs mRNAs is not detected in these cells. Of note, disruption of the STAT-1 signaling pathway protects beta-cells against dsRNA plus IFN-gamma-induced beta-cell apoptosis. This study suggests that dsRNA plus IFN-gamma triggers beta-cell apoptosis by two complementary pathways, namely TLR3-TRIF-NF-kappaB and STAT-1.
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PMID:Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-gamma-induced apoptosis in primary pancreatic beta-cells. 1602 22

Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
Diabetes 2005 Dec
PMID:Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. 1630 47

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


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