UMLS:C0011860 - FACTA Search

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Query: UMLS:C0011860 (type 2 diabetes)
57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes is increasingly common worldwide and is beginning to strike younger age groups. Almost 90% of all patients with diabetes show insulin resistance, which also precedes the first symptoms of diabetes. The mechanisms underlying the development of insulin resistance are not well understood. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenetic factor in the development of insulin resistance and type 2 diabetes. This opens new perspectives for diagnosis and treatment of early insulin resistance and incipient glucose intolerance. Surrogate markers for this low-grade chronic inflammation include CRP, IL-6 and TNF-alpha. Some antidiabetic agents, for example, glitazones that reduce insulin resistance, and insulin itself, reduce inflammation. Conversely, antiinflammatory drugs (ASA/NSAID) may improve glucose tolerance. Vasoactive drugs that are often prescribed to people with diabetes, for example, statins and ACE inhibitors/angiotensin receptor antagonists, also counteract inflammation and reduce the risk of type 2 diabetes. More specific and sensitive biomarkers should be identified, which may predict early disturbances in insulin sensitivity and cardiovascular risk. Also, inflammatory signalling pathways need to be explored in greater detail, and may form the basis of drugable targets against the epidemic of insulin resistance and atherosclerosis.
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PMID:Inflammation and the etiology of type 2 diabetes. 1599 Dec 54

Patients with type 2 diabetes mellitus (NIDDM) are at risk for macrovascular disease complications, such as myocardial infarction (MI) or stroke from plaque rupture. Cytokines play a key role in plaque vulnerability. IFN-gamma inhibits collagen synthesis thereby affecting plaque stability. High IL-6, TNF-alpha, and dyslipidemia are risk factors for thrombosis. Abnormal increments of HSP70 in atherosclerotic plaques might lead to plaque instability and rupture caused by chronic inflammation, which up-regulates the expression of pro-inflammatory cytokines (IL-6 and TNF-alpha) in human monocytes. Studies of a polymorphic PstI site lying in the coding region at position 1267 of the HSP70-2 gene have shown that the BB genotype is associated with NIDDM. We screened 60 old NIDDM patients with carotid stenosis and 107 old healthy controls for 1267 HSP70-2 polymorphism in order to establish if an association with plaque frailty exists. Different genotypic distributions were observed between patients and healthy controls. An increased relative risk was associated with the B allele (p = 0.0107; odds ratio = 1.861). HSP70-2, IL-6, IFN-gamma, TNF-alpha gene expressions within the plaques and serum levels of triglyceride, total cholesterol and LDL cholesterol were tested from patients stratified according to their B+ (AB and BB) and B- (AA) genotypes. Plaque morphology (soft or fibrous-calcified) and the incidence of cerebral ischaemia were also assessed. B+ patients showed increased HSP70-2, IL-6, IFN-gamma, TNF-alpha and dyslipidemia as compared to B- carriers. The frequency of soft plaques increased in B+ in comparison to B- patients (67% versus 13%; odds ratio 13.0, p = 0.0006). A higher frequency of cerebral ischaemia (ictus or transient ischaemic attack (TIA)) was present in B+ than in B- genotype (53% versus 20%; odds ratio 4.57, p < 0.05) Hence, 1267 HSP70-2 polymorphism may be of use in identifying B+ NIDDM patients at risk for carotid plaque rupture and cerebral ischaemia.
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PMID:1267 HSP70-2 polymorphism as a risk factor for carotid plaque rupture and cerebral ischaemia in old type 2 diabetes-atherosclerotic patients. 1599 11

The matrix metalloproteinase system (MMP and the TIMP inhibitors), and the ADAM metalloproteinases, have roles in maintaining vascular plaque stability and the shedding of cell surface molecules, such as TNF-alpha and adhesion molecules; aspirin suppresses MMP expression and ADAM activity from some cell lines in vitro. In a randomised prospective controlled study, we examined peripheral venous monocyte MMP-9, TIMP-1 and ADAM mRNA levels, and protein expression, in subjects with type 2 diabetes (n=10) and controls (n=14) before and after oral aspirin therapy (150mg daily for 14 days) or no active intervention. Baseline monocyte TIMP-1 mRNA levels were significantly lower in the diabetes group (p=0.0014), although monocyte MMP-9 mRNA, and MMP-9 and TIMP-1 protein expression after culture did not differ significantly between groups. Plasma MMP-9 (p=0.027) and TIMP-1 (p=0.016) concentrations were significantly greater, and the ratio of plasma TIMP-1:MMP-9 concentrations significantly lower, in the diabetes group (p=0.023). ADAM mRNA levels did not differ significantly between groups and oral aspirin therapy had no significant effect on any variable. Type 2 diabetes is characterised by reduced monocyte TIMP-1 mRNA levels, and a lower plasma MMP-9 to TIMP-1 protein ratio compared to controls, a pattern that would promote coronary plaque instability if reproduced within vascular plaque. Monocyte ADAM mRNA levels do not differ between group and oral aspirin has no significant effect on these variables.
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PMID:Monocyte matrix and ADAM metalloproteinase expression in type 2 diabetes after aspirin therapy. 1602 59

Adipose tissue, in addition to the storage of lipids function for lipids, plays active roles in normal metabolic homeostasis and in the development of several diseases, such as type 2 diabetes, dyslipaemia and atherosclerosis. These roles are mediated by adipocytokines, factors secreted by adipose tissue. These include tumor necrosis factors (TNF)-alpha, leptin, resistin, adiponectin or visfatin. Adipocytokines act in an autocrine, paracrine and endocrine manner. Adiponectin is a peculiar adipocytokine because in contrast to the markedly increased levels of leptin, resistin or TNF-alpha in obesity, its level is negatively correlated with body mass index, and is decreased in presence of insulin resistance and in type 2 diabetes. Adiponectin may play a crucial role in the development of diabetes mellitus and high adiponectin levels should protect against impairment of glucose metabolism. Moreover, adipocytokines are involved in the pathogenesis of vascular diseases and may represent a link between obesity, diabetes, inflammation and atherosclerosis. Weight loss, exercise and some antidiabetic drugs also influence plasma adipocytokines levels. For instance, thiazolidinediones treatment in patients with type 2 diabetes resulted in an increased in plasma adiponectin levels and a decrease in circulating TNF-alpha concentrations.
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PMID:[Adipocytokines: link between obesity, type 2 diabetes and atherosclerosis]. 1603 96

Resistin, a recently discovered 92 amino acid protein involved in the development of insulin resistance, has been associated with obesity and type 2 diabetes. The elevated serum resistin in human diabetes is often associated with a pro-inflammatory milieu. However, the role of resistin in the development of inflammation is not well understood. Addition of recombinant human resistin protein (hResistin) to macrophages (both murine and human) resulted in enhanced secretion of pro-inflammatory cytokines, TNF-alpha and IL-12, similar to that obtained using 5 microg/ml lipopolysaccharide. Both oligomeric and dimeric forms of hResistin were able to activate these cytokines suggesting that the inflammatory action of resistin is independent of its conformation. Heat denatured hResistin abrogated cytokine induction while treatment of recombinant resistin with polymyxin B agarose beads had no effect thereby ruling out the role of endotoxin in the recombinant hResistin mediated cytokine induction. The pro-inflammatory nature of hResistin was further evident from the ability of this protein to induce the nuclear translocation of NF-kappaB transcription factor as seen from electrophoretic mobility shift assays. Induction of TNF-alpha in U937 cells by hResistin was markedly reduced in the presence of either dominant negative IkappaBalpha plasmid or PDTC, a pharmacological inhibitor of NF-kappaB. A protein involved in conferring insulin resistance is also a pro-inflammatory molecule that has important implications.
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PMID:Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. 1603 94

Elevated plasma IL-18 is present in several conditions sharing insulin-resistance as common trait, but the association with insulin-resistance per se is not established. Plasma/serum IL-6, IL-18, TNF-alpha, soluble TNF receptor II (sTNFR2), and C-reactive protein (CRP) were measured in 97 patients with type 2 diabetes (DM) and 84 non-diabetic controls (CON). The association with insulin-resistance-estimated using the homeostasis model assessment (HOMA-IR)-was analyzed using multivariate linear and logistic regression. Compared to CON, DM demonstrated higher plasma levels of IL-18 (P = 0.001), IL-6 (P < 0.001), sTNFR2 (P = 0.005), and CRP (P < 0.001), while TNF-alpha was lower (P = 0.017). Plasma IL-18 increased across HOMA-IR quartiles in both DM and CON, both with and without adjustment for confounders (all P < 0.05). In contrast, neither IL-6, TNF-alpha, sTNFR2, nor CRP was associated with HOMA-IR in CON when adjusting for confounders. Accordingly, 50% increase of IL-18 corresponded to a marked increase of HOMA-IR in both DM and CON (DM: 26%, P = 0.014; CON: 25%, P = 0.003) after adjustment for confounders. Our results show that plasma IL-18 was associated with HOMA-IR independent of obesity and type 2 diabetes.
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PMID:Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans. 1611 17

Prospective studies of prediabetic subjects have shown that obesity and its duration are major risk factors for type 2 diabetes. Longitudinal studies are consistent with an etiologic role of subclinical inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance. Inflammation is closely associated with endothelial dysfunction and is recognized as one of the cardiovascular risk factors clustering in the Insulin Resistance Syndrome or Metabolic Syndrome. The adipose tissue has been recognized as an important source of metabolically active secretory products (adipocytokines), free fatty acids, leptin, TNF-alpha, Iinterleucin-6, plasminogen activator inhibitor-1, adiponectin and resistin. Prevention of insulin resistance by weight loss, diet and exercise is very effective in reducing the progression from glucose intolerance to type 2 diabetes in obese subjects. Since insulin resistance is a key disturbance in early type 2 diabetes additional drug treatment with insulin-sensitizing drugs might be helpful to reduce the progression to both beta-cell failure and macrovascular late complications. The PROACTIVE study will determine if the effects of improving insulin sensitivity and reducing inflammation will translate into clinical benefits and reduce the cardiovascular morbidity and mortality associated with insulin resistance and Type 2 diabetes.
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PMID:Insulin resistance and inflammation in the early phase of type 2 diabetes: potential for therapeutic intervention. 1611 58

Mammalian tissues express beta-isoforms of glycosphingolipids and, among these, sulfatide (sulphated galactosylceramide) is present in the beta cells, and it is here that the short fatty acid chain (C16) isoform is predominately found. In vitro studies have shown that sulfatide preserves insulin crystals and facilitates insulin monomerisation under certain biochemical conditions. It also activates beta cell potassium channels and moderates insulin secretion. Anti-sulfatide antibodies are seen in type 1 diabetes, and immunological presentation of glycosphingolipids by the non-classical CD1 molecules has recently been reported. It is via this mechanism that alpha-galactosylceramide and sulfatide are able to influence the innate immune system and inhibit autoimmunity, possibly through regulatory natural killer T cells. Administration of sulfatide substantially reduces the incidence of diabetes in non-obese diabetic mice and prevents antigen-induced experimental autoimmune encephalomyelitis in wild-type mice. Sulfatide has specific anti-inflammatory properties, increasing the number of CD3+CD25+ regulatory T cells and reducing production of several cytokines, including TNF-alpha. Patients with type 2 diabetes have low serum concentrations of sulfatide, and some animal models of type 2 diabetes have low pancreatic expression of C16:0 sulfatide; administration of this increases insulin secretion and improves first-phase insulin response in Zucker fatty rats. Glycosphingolipids in general, and sulfatide in particular, appear relevant to both type 1 and type 2 diabetes.
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PMID:Involvement of sulfatide in beta cells and type 1 and type 2 diabetes. 1614 63

A variety of adipocytokines and peptides secreted from adipocytes have been considered to play a crucial role in obesity, insulin resistance, and type 2 diabetes. Recently, visfatin, a new adipocytokine, known as a pre-B cell colony-enhancing factor, has been isolated from visceral fat deposits. It has been shown to activate insulin receptors in a manner different from insulin. To understand the role of adipocytokines in improving insulin sensitivity via activation of the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and -gamma (PPAR-gamma), we examined the expression of visfatin, adiponectin, and TNF-alpha in visceral fat depots of Otsuka Long-Evans Tokushima fatty (OLETF) rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Serum glucose and insulin concentrations significantly (P<0.05) decreased in rosiglitazone or fenofibrate-treated OLETF rats compared to untreated OLETF rats. Rosiglitazone significantly increased serum adiponectin concentration from 20 to 40 weeks of age (P<0.05), whereas fenofibrate reduced TNF-alpha concentration. The expression of visfatin and adiponectin mRNA in visceral fat deposits was elevated by rosiglitazone or fenofibrate treatments when compared to untreated OLETF rats (P<0.05), whereas, TNF-alpha mRNA was down-regulated by these drugs (P<0.05). These results suggest that rosiglitazone and fenofibrate may prevent type 2 diabetes by regulating adipocytokines including visfatin, adiponectin, and TNF-alpha.
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PMID:Effect of PPAR-alpha and -gamma agonist on the expression of visfatin, adiponectin, and TNF-alpha in visceral fat of OLETF rats. 1615 99

Moderate alcohol consumption is associated with increased insulin sensitivity and a reduced risk for type 2 diabetes. An important endogenous mediator of insulin sensitivity is adiponectin (AN), an adipokine that displays numerous antiatherogenic, antidiabetogenic and antiinflammatory effects. Recently, acute increase in alcohol consumption has been shown to be associated with increase in plasma adiponectin and, concomitantly, insulin sensitivity. Whether chronic alcohol consumption predicts an increase in plasma AN and whether this is independent of adiposity, markers of liver dysfunction, and plasma adipokines such as tumor necrosis factor (TNF)-alpha is not known. We, therefore, investigated these relationships in 75 men who were diagnosed with liver steatosis using ultrasound/liver biopsy. We examined 75 men, who were diagnosed for having liver steatosis (ultrasound/liver biopsy). Each filled in a questionnaire on alcohol intake. Subjects were divided into two subgroups according to alcohol history and CDT concentrations--drinkers and non-drinkers. All individuals were examined for serum concentrations of AN, glucose, triglycerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate transferase (GMT) activity; carbohydrate-deficient transferrin (CDT%) a marker of chronic alcohol consumption, insulin and TNF-alpha. The Quicki insulin sensitivity index was calculated. Forty-eight individuals were found to be moderate drinkers and 27 subjects non-drinkers. Moderate drinkers had significantly higher concentrations of AN (13.8 +/- 3,7 versus 9.1 +/- 5.4 mg/l, means +/- SD, p = 0.012) compared with non-drinkers, independent of adiposity. Plasma AN concentrations in the whole group were positively correlated with TNF-alpha concentrations (r = 0.6; p = 0.0001), CDT (r = 0.26; p = 0.0084), AST/ALT index (r = 0.3, p = 0.009), AST (r = 0.29; p = 0.011) and GMT (r = 0.29; p = 0.011) and negatively with BMI (r = -0.48; p = 0.0002) and glycemia (r = -0.22; p = 0.049). The positive associations of AN with TNF-alpha (0.8; p = 0.001), CDT (0.55; p = 0.017), AST/ALT index (0.55; p = 0.019) and the negative correlation with glycemia (-0.35; p = 0.0158) were independent of BMI. Stratified according to alcohol intake, in moderate drinkers, a positive correlation was found between AN and TNF-alpha concentrations (r = 0.6, p = 0.0001, AST/ALT index (r = 0.34, p = 0.0295) whereas in non-drinkers no such correlations were found. The concentration of AN and BMI displayed a negative correlation in both drinker and nondrinker patients (r = -0.42, p = 0.01 and -0.61; p = 0.012, respectively). We concluded that plasma AN is higher in moderate drinkers compared to non-drinkers, even after correction for BMI. Drinkers suffering from liver steatosis were found to have a positive correlation between AN concentrations, laboratory markers of liver disease and TNF-alpha. Such correlation was absent in non-drinkers suffering from liver steatosis. This suggests that alcohol may modulate the inhibitory effect of TNF-alpha on AN production, and thus, increase its plasma concentrations.
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PMID:High adiponectin and TNF-alpha levels in moderate drinkers suffering from liver steatosis: comparison with non drinkers suffering from similar hepatopathy. 1617 Mar 95

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