Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin resistance and beta-cell degranulation as well as diabetes, indicating that globular adiponectin and leptin appeared to have both distinct and overlapping functions. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation such as acyl-CoA oxidase, and molecules involved in energy dissipation such as uncoupling proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE-deficient background, gAd Tg apoE-deficient mice showed amelioration of atherosclerosis, which was associated with decreased expression of class A scavenger receptor and tumor necrosis factor alpha. This is the first demonstration that globular adiponectin can protect against atherosclerosis in vivo. In conclusion, replenishment of globular adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis.
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PMID:Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. 1243 86

Adiponectin is a novel polypeptide that is highly specific to adipose tissue. In contrast to other adipocytokines, adiponectin levels are decreased in obesity and associated comorbidities, such as type 2 diabetes. Decreased expression of adiponectin is correlated with insulin resistance. It has been suggested that several agents, such as tumor necrosis factor alpha, could mediate their effects on insulin metabolism through modulating adiponectin secretion from adipocytes. The mechanisms for the development of atherosclerotic vascular disease in obese individuals are largely unknown. Several findings support the interesting hypothesis that adiponectin could be a link between obesity and related atherosclerosis. First, adiponectin levels are lower in patients with coronary artery disease. Second, adiponectin modulates endothelial function and has an inhibitory effect on vascular smooth muscle cell proliferation. Moreover, adiponectin is accumulated more preferably to the injured vascular wall than intact vessels and has been shown to suppress macrophage-to-foam cell transformation. Adiponectin may also be involved in the modulation of inflammation. Thiazolidinediones, antiatherogenic and other effects have been explained by their direct enhancing effect on adiponectin. In conclusion, adiponectin has anti-inflammatory and antiatherogeneic effects as well as multiple beneficial effects on metabolism. Therefore it is not a surprise that adiponectin therapy has been tested in animal models of obesity, and it has been shown to ameliorate hyperglycemia and hyperinsulinemia without inducing weight gain or even inducing weight loss in some studies. Unlike agents that exert their effects centrally, adiponectin's effects seem to be peripherally mediated. The evidence of an association between adiponectin and the metabolic and cardiovascular complications of obesity is growing all the time.
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PMID:Adiponectin: a link between excess adiposity and associated comorbidities? 1243 46

Accumulating evidence suggests that the pathophysiology of diabetes is analogous to chronic inflammatory states. Circulating levels of inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNFalpha) are increased in both type 1 and type 2 diabetes. TNFalpha plays an important role in the pathogenesis of insulin resistance in type 2 diabetes. However, the reason for this increase remains unclear. Levels of the dicarbonyl methylglyoxal (MGO) are elevated in diabetic plasma and MGO-modified bovine serum albumin (MGO-BSA) can trigger cellular uptake of TNF. Therefore we tested the hypothesis that MGO-modified proteins may cause TNFalpha secretion in macrophage-like RAW 264.7 cells. Treatment of cells with MGO-BSA induced TNFalpha release in a dose-dependent manner. MGO-modified ribonuclease A and chicken egg ovalbumin had similar effects. Cotreatment of cells with antioxidant reagent N-acetylcysteine (NAC) inhibited MGO-BSA-induced TNFalpha secretion. MGO-BSA stimulated the simultaneous activation of p44/42 and p38 mitogen-activated protein kinase. PD98059, a selective MEK inhibitor, inhibited MGO-BSA-induced TNFalpha release as well as ERK phosphorylation. Pretreatment of cells with NAC also resulted in inhibition of MGO-BSA-induced ERK phosphorylation. MGO-BSA induced dose-dependent NFkappaB activation as shown by electrophoresis mobility shift assay. The MGO-BSA-induced NFkappaB activation was prevented in the presence of PD98059, NAC, and parthenolide, a selective inhibitor of NFkappaB. Furthermore, the NFkappaB inhibitor parthenolide suppressed MGO-BSA-induced TNFalpha secretion. Confocal microscopy using dichlorofluorescein to demonstrate intracellular reactive oxygen species (ROS) showed that MGO-BSA produced more ROS compared with native BSA. MGO-BSA could also stimulate protein kinase C (PKC) translocation to the cell membrane, considered a key signaling pathway in diabetes. However, there was no evidence that PKC was involved in TNFalpha release based on inhibition by calphostin C and staurosporine. Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes.
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PMID:Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. 1250 94

The relationship between basal serum tumor necrosis factor alpha (TNFalpha) levels and peripheral tissue (muscle) sensitivity to insulin was examined in 63 subjects with normal glucose tolerance (NGT), 18 subjects with impaired glucose tolerance (IGT), and 123 patients with type 2 diabetes mellitus (T2DM). The BMI was similar in NGT (28.8+/-0.7 kg/m(2)), IGT (31.1+/-1.0), and T2DM (30.0+/-0.4) groups. The fasting serum TNFalpha concentration in T2DM (4.4+/-0.2 pg/ml) was significantly higher than in NGT (3.1+/-0.2) and IGT (3.4+/-0.2; both P<0.05). In T2DM the fasting plasma glucose (FPG=183+/-5 mg/dl) and insulin (FPI=17+/-1 micro U/ml) concentrations were significantly higher than in NGT (FPG=95+/-1; FPI=10+/-1) and IGT (FPG=100+/-2; FPI=13+/-1; all P<0.01). The rate of total body insulin-mediated glucose disposal (Rd; 40 mU/m(2) min euglycemic insulin clamp in combination with (3)H-glucose) was reduced in T2DM (102+/-3 mg/m(2) min) compared with NGT (177+/-10) and IGT (151+/-14; both P<0.01). The serum TNFalpha concentration was inversely correlated with Rd (r=-0.47, P<0.0001) and positively correlated with both FPG (r=0.32, P=0.004) and FPI (r=0.32, P=0.004) in NGT plus IGT. No correlation was observed between serum TNFalpha and Rd (r=-0.02), FPG (r=0.15), or FPI (r=0.15) in T2DM. In stepwise multiple regression analysis using age, sex, BMI, FPG, FPI and serum TNFalpha concentration as independent variables, only BMI and serum TNFalpha concentration were significant and independent predictors of Rd (r(2)=0.29, P<0.0001) in the NGT plus IGT group, while FPG and FPI were significant and independent predictors of Rd (r(2)=0.13, P<0.0001) in T2DM. These results suggest that: (i) an increase in circulating TNFalpha concentration is associated with peripheral insulin resistance and increased plasma glucose and insulin levels prior to the onset of type 2 diabetes; and (ii) the further deterioration in peripheral insulin resistance in T2DM (compared with NGT and IGT) is unrelated to the increase in serum TNFalpha concentration.
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PMID:Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients. 1253 59

Type 2 diabetic mellitus (type 2 DM) comprises more than 95% of all Taiwanese patients with DM. Tumor necrosis factor-alpha (TNF-alpha) expression is linked with insulin resistance, and is under strong genetic control. The correlation between TNF promoter genotypes and type 2 DM is still controversial, because discrepancies among different studies exist. Ethnic differences play certain roles in these conflicting results, because the distribution of TNF promoter polymorphisms is different among study subjects with different racial origins. Therefore, we examined the relationship between the incidence of type 2 diabetes in Taiwanese and two polymorphisms of the TNF-alpha promoter region (positions -238 and -308) as well as the correlation between these polymorphisms and the patients' biochemical manifestations. Genomic DNA was extracted from peripheral blood cells of 261 Taiwanese patients with type 2 DM and 189 non-diabetic control study subjects, and their TNF promoter G-238A and G-308A polymorphisms were analyzed by PCR-RFLP analysis. No significant association between TNF-alpha G-238A and G-308A polymorphisms with type 2 diabetic incidence was observed. However, associations between TNF-alpha G-238A and low-density lipoprotein-cholesterol and between G-308A promoter polymorphism and high-fasting plasma glucose levels, using multiple linear regression analysis with adjustment for the subjects' age, sex, body mass index and diabetic status, were found. Our results suggested that though TNF-alpha G-238A and G-308A polymorphisms were not involved in the pathogenesis of type 2 DM, type 2 diabetic patients carrying TNFA-A or TNF-308*2 genotype might be more susceptible to diabetic complications such as atherosclerosis.
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PMID:TNF-alpha polymorphisms and type 2 diabetes mellitus in Taiwanese patients. 1275 58

Plasma inflammatory cytokines are elevated in obese subjects as well as in those with type 2 diabetes. This presumably results in systemic insulin resistance, characterized by a pro-atherogenic plasma lipid profile and reduced apolipoprotein AI (apoAI) protein levels. To determine how cytokine-mediated insulin resistance suppresses apoAI gene expression, we investigated the effect of tumor necrosis factor alpha (TNF alpha) and interleukin-1beta (IL-1beta) on apoAI protein, mRNA, and transcriptional activity in the human hepatoma cell line HepG2. ApoAI secretion was suppressed in a dose-dependent manner in HepG2 cells treated with both cytokines. ApoAI protein levels were 2892+/-22.0, 2263+/-117, 2458+/-25.0, 3401+/-152, 2333+/-248, 1520+/-41.5 and 956.0+/-11.0 arbitrary units (AU) in cells treated with 0, 0.3, 1.0, 3.0, 10, 30, and 100 ng/ml TNF alpha, achieving statistical significance in the 30 and 100 ng/ml range (P<0.0009). ApoAI protein levels were 4055+/-360, 3697+/-101, 3347+/-327, 1561+/-33.0, 1581+/-182, 810.0+/-59.5, and 1766+/-717 AU in cells treated with similar doses of IL-1beta, achieving statistical significance within the range of 3-100 ng/ml (P<0.02). ApoAI mRNA levels were suppressed 50.8% in HepG2 cells treated with 30 ng/ml TNF alpha for 24 h (P<0.05), and remained suppressed for up to 96 h. Similarly, treatment of cells with 30 ng/ml IL-1beta for 24 h, resulted in 42.9% reduction in apoAI mRNA levels (P<0.05) and remained suppressed for up to 96 h. In order to determine if the effect of TNF alpha and IL-1beta occurs at the transcriptional level, HepG2 cells were transfected with a chloramphenicol acetyltransferase (CAT) reporter gene plasmid containing the full-length apoAI promoter, and after 24 h, treated with TNF alpha (30 ng/ml), IL-1beta (30 ng/ml), or both cytokines. CAT activity was suppressed by both cytokines (24.0+/-1.9% acetylation in control cells vs. 5.6+/-1.2% (P<0.0004), 10.2+/-1.5% (P<0.0006), and 3.9+/-0.9% acetylation (P<0.0002) in cells treated with TNF alpha, IL-1beta, and the combination of both cytokines, respectively) suggesting that cytokine-mediated suppression occurs at the transcriptional level. Using a series of apoAI deletion constructs, the cytokine response element was mapped between nucleotides -325 and -186 (relative to the transcriptional start site). This region contains a previously identified and characterized cis-element, site A, which binds several different transcription factors. Finally, electrophoretic mobility shift assays (EMSA) showed that TNF alpha treatment of HepG2 cells is associated with reduced nuclear factor binding to site A. These studies suggest that inflammatory cytokines down-regulate apoAI expression at least partly through inhibition of binding of the nuclear factors to site A of the apoAI promoter.
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PMID:Suppression of apolipoprotein AI gene expression in HepG2 cells by TNF alpha and IL-1beta. 1457 9

Diabetic neuropathy develops as a result of hyperglycemia-induced local metabolic and microvascular changes in both type I and type II diabetes mellitus. Diabetic neuropathy shows slower impulse conduction, axonal degeneration, and impaired regeneration. Diabetic neuropathy affects peripheral, central, and visceral sensorimotor and motor nerves, causing improper locomotor and visceral organ dysfunctions. The pathogenesis of diabetic neuropathy is complex and involves multiple pathways. Lack of success in preventing neuropathy, even with successful treatment of hyperglycemia, suggests the presence of early mediators between hyperglycemia-induced metabolic and enzymatic changes and functional and structural properties of Schwann cells (SCs) and axons. It is feasible that once activated, such mediators can act independently of the initial metabolic stimulus to modulate SC-axonal communication. Neuropoietic cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), tumor necrosis factor alpha (TNF-alpha), and transforming growth factor beta (TGF-beta), exhibit pleiotrophic effects on homeostasis of glia and neurons in central, peripheral, and autonomic nervous system. These cytokines are produced locally by resident and infiltrating macrophages, lymphocytes, mast cells, SCs, fibroblasts, and sensory neurons. Metabolic changes induced by hyperglycemia lead to dysregulation of cytokine control. Moreover, their regulatory roles in nerve degeneration and regeneration may potentially be utilized for the prevention and/or therapy of diabetic neuropathy.
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PMID:Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. 1466 51

Genome-wide scanning is a powerful tool to identify susceptible chromosome loci, however, individual chromosomal regions still have many candidate genes. Although cDNA microarray analysis provides valuable information for identifying genes involved in pathogenesis, expression levels of many genes are changed. A novel approach for identification of therapeutic targets is the combination of genome-wide scanning and the use of DNA chips, as shown in Fig. (1). Using DNA chips, we screened for secreted molecules, the expressions of which were changed in adipose tissues from mice rendered insulin resistance. Decreased expression of one of these molecules, adiponectin/Acrp30, correlates strongly with insulin resistance. Interestingly, recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where adiponectin gene is located. Decreasing serum adiponectin levels are associated with increased risk for type 2 diabetes. Interestingly, adiponectin was decreased in insulin resistant rodent models both of obesity and lipoatrophy, and replenishment of adiponectin ameliorated their insulin resistance. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes Adiponectin knockout mice showed insulin resistance and glucose intolerance. In muscle and liver, adiponectin activated AMP kinase and PPARalpha pathways thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated insulin resistance under a high-fat diet. Despite similar plasma glucose and lipid levels on an apoE deficient background, adiponectin transgenic apoE deficient mice showed amelioration of atherosclerosis, which was associated with decreased expressions of class A scavenger receptor and tumor necrosis factor alpha. Finally, cDNA encoding adiponectin receptors (AdipoR1 and R2) have been identified by expression cloning, which facilitates the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and the designing of novel antidiabetic and anti-atherogenic drugs with AdipoR1 and R2 as molecular targets.
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PMID:Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. 1468 55

Obesity and type 2 diabetes are associated with a state of abnormal inflammatory response. While this correlation has also been recognized in the clinical setting, its molecular basis and physiological significance are not yet fully understood. Studies in recent years have provided important insights into this curious phenomenon. The state of chronic inflammation typical of obesity and type 2 diabetes occurs at metabolically relevant sites, such as the liver, muscle, and most interestingly, adipose tissues. The biological relevance of the activation of inflammatory pathways became evident upon the demonstration that interference with these pathways improve or alleviate insulin resistance. The abnormal production of tumor necrosis factor alpha (TNF-alpha) in obesity is a paradigm for the metabolic significance of this inflammatory response. When TNF-alpha activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. Studies have since focused on the identification of additional inflammatory mediators critical in metabolic control and on understanding the molecular mechanisms by which inflammatory pathways are coupled to metabolic control. Recent years have seen a critical progress in this respect by the identification of several downstream mediators and signaling pathways, which provide the crosstalk between inflammatory and metabolic signaling. These include the discovery of c-Jun N-terminal kinase (JNK) and I kappa beta kinase (I kappa K) as critical regulators of insulin action activated by TNF-alpha and other inflammatory and stress signals, and the identification of potential targets. Here, the role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms underlying JNK-induced insulin resistance will be discussed.
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PMID:Inflammatory pathways and insulin action. 1470 46

This study was performed to compare concentrations of pro-inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) as well as acute-phase protein, such as C-reactive protein (CRP) between subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). The purpose of this study was to verify whether the pro-inflammatory cytokine-induced acute-phase response is a pathogenic mechanism in type 2 diabetes in elderly Korean women. A total of 1737 elderly subjects aged over 60 years participated in a population based study in Seoul, Korea (SWS Study 1999). Amongst them, a total of 232 non-smoking and non-diabetic female subjects aged 60-89 years was randomly selected and compared with each other. Higher serum high-sensitivity CRP (hs-CRP) concentrations were shown in subjects with IGT than those with normal glucose tolerance (median 1.2 versus 0.9, P < 0.05). Moreover, a relationship between serum hs-CRP concentrations and many components of the metabolic syndrome were detected. Serum pro-inflammatory cytokine IL-6 or TNF-alpha concentrations, however, were neither increased in subjects with IGT nor closely correlated with the components of the metabolic syndrome. In multiple regression analysis with stepwise selection method using hs-CRP as a dependent variable, it was found that white blood cell (WBC) counts, body mass index (BMI), fasting insulin, post-load 2h glucose, hematocrit and LDL cholesterol were significant independent variables. Our study confirms that increased acute-phase reaction is associated with impaired glucose tolerance and the metabolic syndrome in elderly Korean women. However, the hypothesis that pro-inflammatory cytokine-induced systemic inflammation is an early metabolic defect prior to onset of type 2 diabetes, is not supported in our study of elderly Korean women.
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PMID:Comparison of serum concentrations of C-reactive protein, TNF-alpha, and interleukin 6 between elderly Korean women with normal and impaired glucose tolerance. 1506 2


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