Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80098 (monocyte chemoattractant protein)
 1,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study identifies monocyte chemoattractant protein 1 (MCP-1) as an insulin-responsive gene. It also shows that insulin induces substantial expression and secretion of MCP-1 both in vitro in insulin-resistant (IR) 3T3-L1 adipocytes and in vivo in IR obese mice (ob/ob). Thus, MCP-1 resembles other previously described genes (e.g., PAI-1 and SREBP-1c) that remain sensitive to insulin in IR states. The hyperinsulinemia that frequently accompanies obesity and insulin resistance may therefore contribute to the altered expression of these and other genes in insulin target tissues. In vivo studies also demonstrate that MCP-1 is overexpressed in obese mice compared with their lean controls, and that white adipose tissue is a major source of MCP-1. The elevated MCP-1 may alter adipocyte function because addition of MCP-1 to differentiated adipocytes in vitro decreases insulin-stimulated glucose uptake and the expression of several adipogenic genes (LpL, adipsin, GLUT-4, aP2, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma). These results suggest that elevated MCP-1 may induce adipocyte dedifferentiation and contribute to pathologies associated with hyperinsulinemia and obesity, including type II diabetes.
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PMID:Monocyte chemoattractant protein 1 in obesity and insulin resistance. 1275 99

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. PPAR-gamma in the human kidney has been described. However, the role of PPAR-gamma in proximal tubular cells with respect to cell growth and inflammation in diabetic nephropathy is largely unknown. We evaluated the effect of high (30 mM) D-glucose, thiazolidinedione pioglitazone (10 microM), and the selective PPAR-gamma agonist L-805645 (8 microM) on PPAR-gamma expression, growth, and inflammatory parameters in the proximal tubular model of HK-2 cells. PPAR-gamma was present in HK-2 cells and upregulated with 30 mM D-glucose to 177 +/- 31.2% of control (P < 0.05). PPAR-gamma activation was induced by pioglitazone to a similar level to that observed by exposure to high glucose but maximally induced by the selective agonist L-805645. However, L-805645 reduced cell viability in both 5 and 30 mM d-glucose to 73.8 +/- 3.1 and 77.6 +/- 1.4% of control (both P < 0.0001). In parallel, thymidine incorporation was reduced with L-805645 in both 5 and 30 mM D-glucose to 33.3 +/- 3.4 and 37.9 +/- 2.2%, respectively (both P < 0.0001). Flow cytometry demonstrated increased apoptosis and G(1) phase arrest in association with an increase in p21(cip1/waf1) in cells exposed to L-805645. Exposure to 30 mM D-glucose did not significantly change AP-1 promoter activity (89.0 +/- 5.5% of control); however, the addition of L-805645 significantly reduced it to 62.2 +/- 2.7% of control (P < 0.0001). Thirty nanomolar D-glucose induced transforming growth factor-beta(1) to 137.7 +/- 16.9% of control (P < 0.05), and L-805645 was able to suppress this to 68.7 +/- 5.7% of control (P < 0.01 vs. d-glucose). Exposure to 30 mM D-glucose reduced monocyte chemoattractant protein 1 levels to 78.6 +/- 7.1% (P < 0.05) of control, with the reduction more marked in the presence of either pioglitazone (P < 0.01) or L-805645 (P < 0.01). In summary, high glucose upregulates PPAR-gamma and when significantly induced demonstrates anti-proliferative and anti-inflammatory effects.
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PMID:The effect of high glucose and PPAR-gamma agonists on PPAR-gamma expression and function in HK-2 cells. 1511 52

Atherosclerosis has highly important chronic inflammatory aspects. We investigated anti-inflammatory effects upon initiating insulin therapy by measuring serum high-sensitivity C-reactive protein (hsCRP) and plasma fibrinogen and serum monocyte chemoattractant protein (MCP)-1in patients with poorly controlled type 2 diabetes. In 18 inpatients with type 2 diabetes, we measured serum hsCRP, plasma fibrinogen, serum MCP-1, body weight (BW), girth, and fasting plasma glucose (FPG) before and 2 weeks (14.0 +/- 2.5 days) after initiation of insulin therapy. Daily insulin doses (in units) were approximately 0.2 x BW (in kilograms). Various changes (ratio) were calculated as the ratio of the value during treatment to the pretreatment value. Significant decreases occurred for log(10) hsCRP and FPG (-0.025 +/- 0.557 mg/L, 215 +/- 64.3 mg/dL v -0.213 +/- 0.571 mg/L, 129.8 +/- 32.1 mg/dL; P =.0121, and P =.00002, respectively). This was particularly true for log(10) hsCRP in patients whose BW was unchanged or increased between measurement (P =.0050). There were no significant differences between pretreatment and treatment values for fibrinogen and MCP-1. However, MCP-1 decreased significantly in the group with high-value in the first time point (MCP-1 > 250 pg/mL, n = 9; P =.0224) compared with the low-value group (MCP-1 < 250 pg/mL, n = 9; P =.3164). No significant correlation was found between hsCRP ratio and fibrinogen ratio, MCP-1 ratio, BW ratio, waist girth ratio, or FPG ratio. In conclusion, newly initiated insulin therapy in patients with poorly controlled type 2 diabetes decreased serum hsCRP. The decrease in hsCRP may have resulted largely from anti-inflammatory effects of insulin.
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PMID:Initiation of insulin therapy reduces serum concentrations of high-sensitivity C-reactive protein in patients with type 2 diabetes. 1516 14

beta-cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for beta-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1-/- mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1beta)-mediated cell death (92 +/- 4% viable cells in STAT-1-/- mice vs. 56 +/- 3% viable cells in wild-type controls, P < or = 0.001) and had preserved insulin release after exposure to IL-1beta and IFN-gamma. Moreover, analysis of cell death in cytokine-exposed purified beta-cells confirmed that protection was due to absence of STAT-1 in the beta-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein 1 and macrophage inflammatory protein 3alpha expression. In vivo, STAT-1-/- mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 +/- 28 vs. 283 +/- 81 mg/dl in wild-type controls, P < or = 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73% in wild-type controls, P < or = 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-gamma-mediated beta-cell death and the subsequent development of immune-mediated diabetes.
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PMID:Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells. 1604 7

Different degrees of beta-cell failure and apoptosis are present in type 1 and type 2 diabetes. It has been recently suggested that high glucose-induced beta-cell apoptosis in type 2 diabetes shares a final common pathway with type 1 diabetes, involving interleukin-1beta (IL-1beta) production by beta-cells, nuclear factor-kappaB (NF-kappaB) activation, and death via Fas-FasL. The aim of this study was to test whether human islet exposure to high glucose in vitro, or to the type 2 diabetes environment in vivo, induces IL-1beta expression and consequent activation of NF-kappaB-dependent genes. Human islets were isolated from five normoglycemic organ donors. The islets were cultured for 48 h to 7 days at 5.6, 11, or 28 mmol/l glucose. For comparative purposes, islets were also exposed to IL-1beta. Gene mRNA expression levels were assessed by real-time RT-PCR in a blinded fashion. Culture of the human islets at 11 and 28 mmol/l glucose induced a four- to fivefold increase in medium insulin as compared with 5.6 mmol/l glucose, but neither IL-1beta nor IL-1 receptor antagonist (IL-1ra) expression changed. IL-1beta and IL-1ra protein release to the medium was also unchanged. Stimulated human monocytes, studied in parallel, released >50-fold more IL-1beta than the islets. There was also no glucose-induced islet Fas expression. Expression of the NF-kappaB-dependent genes IkappaB-alpha and monocyte chemoattractant protein (MCP)-1 was induced in human islets by IL-1beta but not by high glucose. In a second set of experiments, human islets were isolated from seven type 2 diabetic patients and eight control subjects. The findings on mRNA levels were essentially the same as in the in vitro experiments, namely the in vivo diabetic state did not induce IL-1beta, Fas, or MCP-1 expression in human islets, and also did not modify IL-1ra expression. The present findings suggest that high glucose in vitro, or the diabetic milieu in vivo, does not induce IL-1beta production or NF-kappaB activation in human islets. This makes it unlikely that locally produced IL-1beta is an important mediator of glucotoxicity to human islets and argues against the IL-1beta-NF-kappaB-Fas pathway as a common mediator for beta-cell death in type 1 and type 2 diabetes.
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PMID:Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? 1624 50

In 70 nonobese inpatients with Type 2 diabetes [body mass index (BMI): 24.0+/-4.4 kg/m(2)], we examined circulating monocyte chemoattractant protein (MCP) -1 as a candidate marker of atherosclerosis by comparison with established markers: serum high-sensitivity C-reactive protein (hsCRP), plasma fibrinogen, and combined carotid artery intimal-medial thickness (IMT). In addition, an association was sought between circulating MCP-1 and urinary albumin excretion (UAE), reflecting diabetic renal microangiopathy. Serum MCP-1 was determined by enzyme-linked immunosorbent assay (ELISA). Patients were grouped by UAE: normoalbuminuria, below 30 mg/g of creatinine (Cr); microalbuminuria, 30 to 300 mg/g Cr; or macroalbuminuria, over 300 mg/g Cr. Serum MCP-1 for all participants, men, and women was 280.0+/-78.9, 269.0+/-68.8, and 294.9+/-87.9 pg/ml, respectively, showing no difference between genders. No correlation was noted between MCP-1 and hsCRP, fibrinogen, or carotid artery IMT. No correlation of MCP-1 was observed with age, duration of diabetes, fasting plasma glucose (FPG), hemoglobin (Hb) A(1C), BMI, diastolic blood pressure (DBP), or serum lipid concentrations, but significant correlations were found with systolic blood pressure (SBP; R=.2723, P=.0225) and with log(10)-transformed (log) UAE (R=.3343, P=.0047). Patients with macroalbuminuria had significant higher circulating MCP-1 than did those with normo- or microalbuminuria (P=.0063 and P=.0188, respectively). By stepwise regression analysis, only log UAE independently predicted serum MCP-1 (beta=.3700, P=.0020). Thus, in nonobese Type 2 diabetic patients, MCP-1 might not be a marker of atherosclerosis and might be influenced significantly by diabetic nephropathy.
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PMID:Association between circulating monocyte chemoattractant protein-1 and urinary albumin excretion in nonobese Type 2 diabetic patients. 1650 38

Increased monocyte recruitment into subendothelial space in atherosclerotic lesions is one of the hallmarks of diabetic angiopathy. The aim of this study was to determine the state of peripheral blood monocytes in diabetes associated with atherosclerosis. Diabetic patients treated with/without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n=106). We also included 24 non-diabetic control subjects. We measured serum levels of monocyte chemoattractant protein (MCP)-1, fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, body mass index (BMI), high sensitivity CRP (hs-CRP) and evaluated CCR2, CD36, CD68 expression on the surface of monocytes. Serum MCP-1 levels were significantly (p<0.05) higher in diabetic patients than in normal subjects. In diabetic patients, serum MCP-1 levels correlated significantly with FPG, HbA1c, triglyceride, BMI, and hs-CRP. The expression levels of CCR2, CD36, and CD68 on monocytes were significantly increased in diabetic patients and were more upregulated by MCP-1 stimulation. Our data suggest that elevated serum MCP-1 levels and increased monocyte CCR2, CD36, CD68 expression correlate with poor blood glucose control and potentially contribute to increased recruitment of monocytes to the vessel wall in diabetes mellitus.
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PMID:Increased expression levels of monocyte CCR2 and monocyte chemoattractant protein-1 in patients with diabetes mellitus. 1663 Nov 14

Amoeboid microglial cells (AMC) which transiently exist in the corpus callosum in the postnatal rat brain expressed endothelins (ETs), specifically endothelin-1 (ET-1) and ET3 as revealed by real time RT-PCR. ET immunoreactive AMC occurred in large numbers at birth, but were progressively reduced with age and were undetected in 14 days. In rats subjected to hypoxia exposure, ET immunoexpression in AMC was reduced but the incidence of apoptotic cells was not increased when compared with the control suggesting that this was due to its downregulation that may help regulate the constriction of blood vessels bearing ET-A receptor. AMC were endowed ET-B receptor indicating that ET released by the cells may also act via an autocrine manner. In microglia activated by lipopolysaccharide (LPS), ET-1 mNA expression coupled with that of monocyte chemoattractant protein (MCP-1) and stromal derived factor-1 (SDF-1) was markedly increased; ET-3 mRNA, however, remained unaffected. AMC exposed to oxygen glucose deprivation (OGD) in vitro resulted in increase in both ET-1 and ET-3 mRNA expression. It is suggested that the downregulated ETs expression in vivo of AMC subjected to hypoxia as opposed to its upregulated expression in vitro may be due to the complexity of the brain tissue. Furthermore, the differential ET-1 and ET-3 mRNA expression in LPS and OGD treatments may be due to different signaling pathways independently regulating the two isoforms. The present novel finding has added microglia as a new cellular source of ET that may take part in multiple functions including regulating vascular constriction and chemokines release.
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PMID:Transient expression of endothelins in the amoeboid microglial cells in the developing rat brain. 1689 76

Accumulation of hyaluronan (HA) around smooth muscle cells in lesions of atherosclerosis in diabetic patients suggests that this protein plays an important role in diabetic angiopathy. The aim of this study was to determine the correlation between serum HA concentrations and diabetic angiopathy. Diabetic patients treated with or without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n = 95). We also included 20 non-diabetic control subjects. We measured serum levels of HA, body mass index (BMI), fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, glycated albumin (GA), high sensitivity CRP (hs-CRP), monocyte chemoattractant protein (MCP)-1 and evaluated diabetes mellitus history, drug use and presence of related complications. Serum HA levels were significantly (P<0.05) higher in diabetic patients (83.6 +/- 5.6 ng/ml, mean +/- SEM) than in normal subjects (41.7 +/- 12 ng/ml). In diabetic patients, serum HA concentration significantly correlated with FPG, HbA1c, GA, triglyceride and also significantly correlated with BMI, hs-CRP and MCP-1 and tended to be higher in diabetic patients with complications than in those without such complications. Our data suggest that serum HA level correlates with poor blood glucose control and diabetic angiopathy and that it could be used as a marker of diabetic angiopathy.
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PMID:Serum hyaluronan concentration as a marker of angiopathy in patients with diabetes mellitus. 1696 27

There is evidence that strongly suggests that inflammation plays an important role in diabetes and cardiovascular diseases. The high glucose-induced inflammatory process is characterised by the cooperation of a complex network of inflammatory molecules such as cytokines, adhesion molecules, growth factors, and chemokines. Among the chemokine family, monocyte chemoattractant protein (MCP-1) is a potent chemotactic factor, which is upregulated at sites of inflammation being in control of leukocytes trafficking. Here, we review the current knowledge on MCP-1 and its regulation by high glucose level in vascular cells involved in diabetes-induced accelerated atherosclerosis. The signalling pathways involved in MCP-1 modulation by high glucose, the proximal signalling events that stimulate downstream effects and the role of this chemokine in the pathophysiology of diabetes and its complications, are discussed.
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PMID:Monocyte chemoattractant protein-1--a major contributor to the inflammatory process associated with diabetes. 1717 97


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