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

The accumulation of macrophages (M Phi) and dendritic cells (DC) in the pancreas plays a crucial role in the pathogenesis of autoimmune diabetes. We studied the recruitment of monocytes, M Phi and DC to sites of inflammation, i.e. the peritoneal cavity and a subcutaneously elicited air pouch in the NOD mouse model of autoimmune diabetes. The leukocyte recruitment was studied from 1 to 7 days after injection of thioglycollate (peritoneum), C5a (peritoneum, air pouch), CCL2 and CCL3 (air pouch). C57BL/6 and BALB/c mice served as controls. Morphological and flow cytometric analysis of the recruited cells was performed, IL-1 beta, TNF-alpha, IL-6, IL-12 and IL-10 in exudates measured, and in vitro CCL2-chemotaxis of exudate M Phi (Boyden chamber) determined. NOD mice were strongly impaired in the recruitment of M Phi, DC, monocytes, and granulocytes. Chemokine-injected air pouches of NOD mice showed an increased IL-10 and a decreased IL-1 beta level, while the other cytokines were normally or very lowly expressed. In addition, NOD exudate M Phi displayed an impaired in vitro CCL2-induced migration. Our data show that NOD mice have an impaired ability to recruit leukocytes into sites of inflammation elicited in the peritoneum and the air pouch. A raised IL-10/IL-1 beta ratio at these sites and a deficient migratory capacity of NOD monocytes are important determinants in this impairment.
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PMID:NOD mice have a severely impaired ability to recruit leukocytes into sites of inflammation. 1559 24

Gestational diabetes mellitus (GDM) is a risk factor for both Type 2 diabetes (DM2) and insulin-resistance syndrome (IRS). C-reactive protein (CRP), fibrinogen and leukocyte count are increased in the IRS and predict DM2 and cardiovascular disease (CVD). The chemochine monocyte chemoattractant protein-1 (MCP-1/CCL2) is also elevated in DM2 and CVD. Recent evidence suggests a relation between chronic inflammation and GDM, but post-delivery information on inflammatory markers in these high-risk women is lacking. Serum levels of CRP, fibrinogen, MCP-1/ CCL2, and leukocyte blood count have been assessed in 26 women with and 26 women without a recent history of GDM, matched for age, body mass index (BMI), post-partum duration and parity. DM2 was excluded in all the participants by an oral glucose tolerance test (OGTT). Women with previous GDM showed significantly higher CRP (p=0.007) and fibrinogen (p=0.02) serum concentrations, whereas MCP-1/CCL2 serum levels and leukocyte blood count were comparable in the two groups. Overall, CRP levels significantly correlated with BMI (r=0.40, p=0.03), waist-to-hip ratio (WHR) (r=0.44, p=0.001), fasting insulin (r=0.27, p=0.04), insulin-resistance assessed by means of the homeostatic model (HOMA) (r=0.28, p=0.04), and fibrinogen concentration (r=0.49, p=0.0001). At linear regression analysis, only WHR and fibrinogen were independently associated with CRP levels. In conclusion, the increase of inflammatory markers may be one of the first detectable disorders in healthy women at high risk of DM2 and IRS, like those with a GDM history.
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PMID:Inflammatory markers in women with a recent history of gestational diabetes mellitus. 1581 69

In the early development of type 1 diabetes macrophages and dendritic cells accumulate around the islets of Langerhans at sites of fibronectin expression. It is thought that these macrophages and dendritic cells are derived from blood monocytes. Previously, we showed an increased serum level of MRP8/14 in type 1 diabetes patients that induced healthy monocytes to adhere more strongly to fibronectin (FN). Here we show that MRP8/14 is expressed and produced at a higher level by type 1 diabetes monocytes, particularly after adhesion to FN, creating a positive feedback mechanism for a high fibronectin-adhesive capacity. Also adhesion to endothelial cells was increased in type 1 diabetes monocytes. Despite this increased adhesion the transendothelial migration of monocytes of type 1 diabetes patients was decreased towards the proinflammatory chemokines CCL2 and CCL3. Because non-obese diabetic (NOD) mouse monocytes show a similar defective proinflammatory migration, we argue that an impaired monocyte migration towards proinflammatory chemokines might be a hallmark of autoimmune diabetes. This hampered monocyte response to proinflammatory chemokines questions whether the early macrophage and dendritic cell accumulation in the diabetic pancreas originates from an inflammatory-driven influx of monocytes. We also show that the migration of type 1 diabetes monocytes towards the lymphoid tissue-related CCL19 was increased and correlated with an increased CCR7 surface expression on the monocytes. Because NOD mice show a high expression of these lymphoid tissue-related chemokines in the early pancreas it is more likely that the early macrophage and dendritic cell accumulation in the diabetic pancreas is related to an aberrant high expression of lymphoid tissue-related chemokines in the pancreas.
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PMID:An increased MRP8/14 expression and adhesion, but a decreased migration towards proinflammatory chemokines of type 1 diabetes monocytes. 1604 41

The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. The lymphocytic (peri-)insulitis is preceded by an early accumulation of dendritic cells (DC) around the islets of Langerhans. This DC accumulation is thought to derive from an influx of monocytes attracted by pro-inflammatory chemokines. Besides chemokines, extracellular matrix (ECM) proteins play an important role in the accumulation of leukocytes in tissues. We studied the expression of the chemokines CCL2, CCL5, CXCL10, CCL19 and CCL21 over time in pancreases of NOD and control mice by ELISA on pancreas lysates as well as by immunohistochemistry. In addition, we studied the adhesive capacity of bone marrow-derived DC (BMDC) to ECM components. DC in the NOD pancreas accumulated at sites with an intense expression of fibronectin. In vitro, NOD BMDC showed increased fibronectin adhesion and increased VLA-5 expression. At the time of early DC accumulation (<10 wk), the lymphoid tissue-related chemokines CCL19 and CCL21 were increased. Our findings support the view that the early accumulation of DC around the NOD islets is not the consequence of an enhanced attraction of precursors and immature DC by pro-inflammatory chemokines. It rather might be the consequence of an aberrantly enhanced adhesion and retention of NOD DC.
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PMID:Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice. 1604 41

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial, rate-limiting step of tryptophan (Trp) catabolism along the kynurenine (KYN) pathway, and its induction in cells of the immune system in response to cytokines has been implicated in the regulation of antigen presentation and responses to cell-mediated immune attack. Microarray and quantitative PCR analyses of isolated human islets incubated with interferon (IFN)-gamma for 24 h revealed increased expression of IDO mRNA (>139-fold) and Trp-tRNA synthase (WARS) (>17-fold) along with 975 other transcripts more than threefold, notably the downstream effectors janus kinase (JAK)2, signal transducer and activator of transcription (STAT)1, IFN-gamma regulatory factor-1, and several chemokines (CXCL9/MIG, CXCL10/IP10, CXCL11/1-TAC, CCL2, and CCL5/RANTES) and their receptors. IDO protein expression was upregulated in IFN-gamma-treated islets and accompanied by increased intracellular IDO enzyme activity and the release of KYN into the media. The response to IFN-gamma was countered by interleukin-4 and 1alpha-methyl Trp. Immunohistochemical localization showed IDO to be induced in cells of both endocrine, including pancreatic duodenal homeobox 1-positive beta-cells, and nonendocrine origin. We postulate that in the short term, IDO activation may protect islets from cytotoxic damage, although chronic exposure to various Trp metabolites could equally lead to beta-cell attrition.
Diabetes 2007 Jan
PMID:Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human islets. 1719 67

Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2, or monocyte chemoattractant protein-1), an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2(-/-) and wild-type mice (n = 11-14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12-16 and 25-29 weeks of age, blood was collected for plasma glucose and hormone measurements, and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly, CCL2(-/-) mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2(-/-) mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet, CCL2(-/-) mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2(-/-) mice, the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2(-/-) mice, despite no changes in adipose tissue macrophage levels, suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly, we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.
Diabetes 2007 Sep
PMID:Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. 1747 19

Diabetic nephropathy is increasingly considered as an inflammatory disease characterized by leukocyte infiltration at every stage of renal involvement. Chemokines are important participators in the recruitment of specific subpopulations of inflammatory cells into renal compartments. MCP-1/CCL2 has been identified as having a key role in monocyte/macrophage recruitment in animal models of diabetic nephropathy, as well as in renal biopsies from patients with type 1 and 2 diabetes. Various factors of the diabetic milieu can induce renal expression of MCP-1/CCL2 and cell adhesion molecules, and thereby mediate the macrophage responses that ultimately cause renal injury. Possibly fractalkine/CX3CL1 functions as an arrest chemokine in monocyte/macrophage adhesion before migration into the kidney. T lymphocyte recruitment is influenced by up-regulation of RANTES/CCL5 throughout glomerular as well as tubulointerstitial structures as well as IP-10/CXCL10 mainly in the tubulointerstitium. Improved knowledge of gene polymorphisms of chemokines and their receptors could be useful to predict onset of diabetic nephropathy and define its progression. Blockade of the renin-angiotensin-aldosterone system is currently the only clinically used strategy to treat the inflammatory process in diabetic nephropathy. Newer strategies point to chemokine receptor antagonists and even to immunosuppressive therapy, but still remain in the experimental stage.
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PMID:The role of chemokines and chemokine receptors in diabetic nephropathy. 1798 2

This study was undertaken to test the hypothesis that short-term exposure (4 h) to physiological hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response independently of glycemic status. Twelve normal glucose tolerant subjects received a 4-h euglycemic hyperinsulinemic clamp with biopsies of the vastus lateralis muscle. Microarray analysis identified 121 probe sets that were significantly altered in response to physiological hyperinsulinemia while maintaining euglycemia. In normal, healthy human subjects insulin increased the mRNAs of a number of inflammatory genes (CCL2, CXCL2 and THBD) and transcription factors (ATF3, BHLHB2, HES1, KLF10, JUNB, FOS, and FOSB). A number of other genes were upregulated in response to insulin, including RRAD, MT, and SGK. CITED2, a known coactivator of PPARalpha, was significantly downregulated. SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to fasting plasma insulin concentrations. We independently validated the mRNA expression changes in an additional five subjects and closely paralleled the results observed in the original 12 subjects. A saline infusion in healthy, normal glucose-tolerant subjects without family history of diabetes demonstrated that the genes altered during the euglycemic hyperinsulinemic clamp were due to hyperinsulinemia and were unrelated to the biopsy procedure per se. The results of the present study demonstrate that insulin acutely regulates the levels of mRNAs involved in inflammation and transcription and identifies several candidate genes, including HES1 and BHLHB2, for further investigation.
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PMID:Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo. 1833 11

The synthetic cannabinoid CB1 receptor antagonist rimonabant (sold in the United Kingdom under the brand name Acomplia) was reported to improve the profile of cardiovascular risk factors in obese patients with the metabolic syndrome, a cluster of metabolic disorders that often precedes the onset of type II diabetes. Rimonabant is shown in the current issue of British Journal of Pharmacology to attenuate weight gain in Zucker rats, an experimental model of insulin resistance. Neutrophil and monocyte counts were lowered by rimonabant administration. Both platelet activation (by ADP) and aggregation (in response to thrombin) were inhibited. Circulating pro-inflammatory cytokine levels (monocyte chemotactic protein 1, MCP1 and Regulated upon Activation, Normal T-cell Expressed and Secreted, RANTES) were also reduced. Furthermore, fibrinogen levels returned to normal. These favourable anti-inflammatory and anti-thrombotic actions imply for rimonabant a peripheral, direct action on some cardiovascular risk factors.
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PMID:Rimonabant in rats with a metabolic syndrome: good news after the depression. 1846 48

Approximately a third of patients with diabetes develop diabetic kidney disease, and diabetes is the leading cause of end-stage renal disease in most developed countries. Hyperglycaemia is known to activate genes that ultimately lead to extracellular matrix accumulation, the hallmark of diabetic nephropathy. Several transcription factors have been implicated in glucose-mediated expression of genes involved in diabetic nephropathy. This review focuses on the transcription factors upstream stimulatory factors 1 and 2 (USF1 and 2), activator protein 1 (AP-1), nuclear factor (NF)-kappaB, cAMP-response-element-binding protein (CREB), nuclear factor of activated T cells (NFAT), and stimulating protein 1 (Sp1). In response to high glucose, several of these transcription factors regulate the gene encoding the profibrotic cytokine transforming growth factor beta, as well as genes for a range of other proteins implicated in inflammation and extracellular matrix turnover, including thrombospondin 1, the chemokine CCL2, osteopontin, fibronectin, decorin, plasminogen activator inhibitor 1 and aldose reductase. Identifying the molecular mechanisms by which diabetic nephropathy occurs has important clinical implications as therapies can then be tailored to target those at risk. Strategies to specifically target transcription factor activation and function may be employed to halt the progression of diabetic nephropathy.
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PMID:Transcription factors in the pathogenesis of diabetic nephropathy. 1939 38


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