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)

Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a "western" diet. To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild-type C57BL/6 (B6) mice were fed either a standard chow or western diet and assessed for several inflammatory markers. Western-fed B6 mice showed expected reductions in glucose and insulin tolerance compared with chow-fed mice. In contrast, western-fed 12-LOKO mice maintained glucose and insulin tolerance similar to chow-fed mice. Circulating proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, were increased in western B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in western B6 mice. 12-LO activity was significantly elevated by western diet in islets from B6 mice. Islets from 12-LOKO mice did not show western-diet-induced islet hyperplasia or increases in caspase-3 apoptotic staining observed in western-fed B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from western-fed B6 mice. In visceral fat, macrophage numbers and monocyte chemoattractant protein-1 expression were elevated in western B6 mice but not 12-LOKO mice. These data suggest that 12-LO activation plays a role in western-diet-induced damage in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake.
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PMID:12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. 1878 Jul 76

Lee et al. report that an angiotensin II type 1 receptor blocker (ARB) improved glucose intolerance in OLETF rats, an experimental model of type 2 diabetes. ARB treatment resulted in modulation of the adipose tissue, leading to an increased number of small, differentiated adipocytes able to produce more adiponectin and less monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1. This supports the relevance of the functional interplay between adipose tissue and the renin-angiotensin system in states of insulin resistance.
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PMID:Renin-angiotensin system blockade and diabetes: moving the adipose organ from the periphery to the center. 1859 25

We previously reported an association between the activating protein (AP)-2beta transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2beta showed stronger AP-2beta expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2beta leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes accelerated the promoter activity of monocyte chemoattractant protein-1 (MCP-1) and subsequently increased both mRNA and protein expression and protein secretion. Furthermore, knockdown of endogenous AP-2beta by RNA interference reduced the mRNA and the protein expression of MCP-1. EMSAs and chromatin immunoprecipitation assays revealed specific binding of AP-2beta to MCP-1 promoter regions, in vitro and in vivo. Additionally, site-directed mutagenesis of the AP-2 binding site located at -137 to -129 relative to the transcription start site markedly diminished MCP-1 promoter activity, whereas other putative AP-2 binding sites did not. Our results clearly show that AP-2beta directly enhanced MCP-1 secretion by binding to its promoter. Thus, we propose that AP-2beta positively regulates MCP-1 expression; subsequently contributes to the infiltration of macrophages to adipose tissue; and leads to insulin resistance, type 2 diabetes, and cardiovascular diseases.
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PMID:Transcription factor activating protein-2beta: a positive regulator of monocyte chemoattractant protein-1 gene expression. 1902 87

The cat has recently been proposed as a valuable model for type 2 diabetes mellitus (T2DM), because feline diabetes shares several similarities with the disease in humans. Impaired beta-cell function, decreased beta-cell mass, insulin resistance that is often related to obesity, and pancreatic amyloid deposition, are among these common features. In this study, and to further develop the cat as a model of T2DM, feline pancreatic islets were isolated and real-time PCR quantification of mRNA transcripts of genes central to beta-cell function and survival established. In particular, mRNA quantification systems were determined for insulin, the insulin enhancer pancreatic duodenal homeobox-1 (PDX-1), the insulin suppressor CCAAT/enhancer binding protein-beta (C/EBPbeta), glucose transporter isoform 2 (GLUT2), Fas receptor, the caspase-8 inhibitor FLIP (FLICE [caspase-8]-inhibitory protein) and two chemokines, interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1). Pancreatic islets were isolated by collagenase digestion from healthy cat donors. Partial feline mRNA sequences were determined for PDX-1, C/EBPbeta, GLUT2 and FLIP using primers identified from conserved regions of human, dog and rat mRNA. These novel and the previously available sequences (insulin, Fas receptor, IL-8 and MCP-1) were used to design feline-specific primers suitable for real-time PCR in isolated pancreatic islets. The adopted protocol of collagenase digestion yielded pancreatic islets that were frequently surrounded by acinar cells. Quantification of mRNA transcripts was simple and reproducible in healthy cats. Characterisation of genes related to insulin signalling in cats will prove useful to better understand the pathogenesis of feline diabetes and possibly of human T2DM.
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PMID:Quantitative real-time PCR detection of insulin signalling-related genes in pancreatic islets isolated from healthy cats. 2200 67

Adiponectin and adiponectin receptors (AdipoRs) have been found to play significant roles in the etiology of obesity-related chronic disease. Their discovery has been a long and complicated path, with many challenges. Developing methods to unravel the molecular secrets has been an informative process in itself. However, with both functional and genetic studies confirming adiponectin as a therapeutic target adipokine, many roles and interactions with certain other biomolecules have been clearly defined. We have found that decreased high molecular weight (HMW) adiponectin plays a crucial and causal role in obesity-linked insulin resistance and metabolic syndrome; that AdipoR1 and AdipoR2 serve as the major AdipoRs in vivo; and that AdipoR1 activates the AMP kinase (AMPK) pathway and AdipoR2, the peroxisome proliferator-activated receptor alpha (PPARalpha) pathway in the liver, to increase insulin sensitivity and decrease inflammation. Further conclusions are that decreased adiponectin action and increased monocyte chemoattractant protein-1 (MCP-1) form a vicious adipokine network causing obesity-linked insulin resistance and metabolic syndrome; PPARgamma upregulates HMW adiponectin and PPARalpha upregulates AdipoRs; that dietary osmotin can serve as a naturally occurring adiponectin receptor agonist; and finally, that under starvation conditions, MMW adiponectin activates AMPK in hypothalamus, and promotes food intake, and at the same time HMW adiponectin activates AMPK in peripheral tissues, such as skeletal muscle, and stimulates fatty-acids combustion. Importantly, under pathophysiological conditions, such as obesity and diabetes, only HMW adiponectin was decreased; therefore, strategies to increase only HMW adiponectin may be a logical approach to provide a novel treatment modality for obesity-linked diseases, such as insulin resistance and type 2 diabetes. It is hoped that these data will be helpful in developing treatments to counteract the destructive, expensive and painful effects of obesity.
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PMID:Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. 1913 82

Berberine (BBR) has been shown to improve several metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, by stimulating AMP-activated protein kinase (AMPK). However, the effects of BBR on proinflammatory responses in macrophages are poorly understood. Here we show that BBR represses proinflammatory responses through AMPK activation in macrophages. In adipose tissue of obese db/db mice, BBR treatment significantly downregulated the expression of proinflammatory genes such as TNF-alpha, IL-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1beta, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. Moreover, these inhibitory effects of BBR on proinflammatory responses were abolished by AMPK inhibition via either compound C, an AMPK inhibitor, or dominant-negative AMPK, implying that BBR would downregulate proinflammatory responses in macrophages via AMPK stimulation.
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PMID:Berberine suppresses proinflammatory responses through AMPK activation in macrophages. 1920 54

Obesity is associated with chronic inflammation in adipose tissue. Proinflammatory cytokines including tumor necrosis factor-alpha and interleukin-6 secreted by adipose tissue during the metabolic syndrome are proposed to cause local and general insulin resistance and promote development of type 2 diabetes. We have used a compound mutant mouse, Apoe(-/-)xCD4dnTGFbR, with dysregulation of T-cell activation, excessive production of proinflammatory cytokines, hyperlipidemia, and atherosclerosis, to dissect the role of inflammation in adipose tissue metabolism. These mice are lean, which avoids confounding effects of concomitant obesity. Expression and secretion of a set of proinflammatory factors including tumor necrosis factor-alpha, interferon-gamma, and monocyte chemoattractant protein-1 was increased in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice, as was the enzyme 11beta-hydroxysteroid dehydrogenase type 1, which converts cortisone to bioactive cortisol. Interleukin-6, which has an inhibitory glucocorticoid response element in its promoter, was not upregulated. In spite of intense local inflammation, insulin sensitivity was not impaired in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice unless exogenous interleukin-6 was administered. In conclusion, T-cell activation causes inflammation in adipose tissue but does not lead to insulin resistance in this tissue in the absence of interleukin-6.
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PMID:T cell-mediated inflammation in adipose tissue does not cause insulin resistance in hyperlipidemic mice. 1960 85

OBJECTIVE Subclinical inflammation is an important risk factor for type 2 diabetes and diabetes complications. However, data on the association between inflammation and acute diabetic foot syndrome are scarce. The aim of this study was to compare systemic immune mediators in diabetic patients with and without an ulcer and to identify modulating factors. RESEARCH DESIGN AND METHODS Circulating levels of acute-phase proteins, cytokines, and chemokines were measured in diabetic patients with an ulcer (n = 170) and without an ulcer (n = 140). Of the patients, 88% had type 2 diabetes. RESULTS Patients with an acute foot ulcer had higher levels of C-reactive protein (CRP), fibrinogen, interleukin (IL)-6, macrophage migration inhibitory factor, macrophage inflammatory protein-1alpha, and interferon-gamma-inducible protein-10 as well as lower levels of RANTES (regulated on activation normal T-cell expressed and secreted) (all P < 0.01). No differences were found for IL-8, IL-18, and monocyte chemoattractant protein-1. Most of these associations persisted after adjustment for demographic and anthropometric data, metabolic confounders, and diabetes complications. In multivariate models, size of ulcer according to the University of Texas classification but not the grade of infection was independently associated with three markers of subclinical inflammation (CRP, IL-6, and fibrinogen). CONCLUSIONS We demonstrate in our cross-sectional study that acute foot ulcers and their severity are associated with a marked upregulation of acute-phase proteins, cytokines, and chemokines independently of the concomitant infection. Further studies should investigate whether an activation of the immune system precedes the development of foot ulcer and whether anti-inflammatory therapies might be effective.
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PMID:Immune mediators in patients with acute diabetic foot syndrome. 1950 15

It is known that L-arginine treatment can ameliorate endothelial dysfunction and insulin sensitivity in type 2 diabetes mellitus patients, but little is known on L-arginine effects on these variables in nondiabetic patients with stable cardiovascular disease (coronary artery disease). We evaluated the effects of long-term oral L-arginine treatment on endothelial dysfunction, inflammation, adipokine levels, glucose tolerance, and insulin sensitivity in these patients. Sixty-four patients with cardiovascular disease previously submitted to an aortocoronary bypass and not known for type 2 diabetes mellitus had an oral glucose load to define their glucose tolerance. Thirty-two patients with nondiabetic response were eligible to receive, in a double-blind randomized parallel order, L-arginine (6.4 g/d) or placebo for 6 months. An evaluation of insulin sensitivity index during the oral glucose load, markers of systemic nitric oxide bioavailability and inflammation, and blood flow was performed before and at the end of the treatment in both groups. Compared with placebo, L-arginine decreased asymmetric dimethylarginine levels (P < .01), indices of endothelial dysfunction, and increased cyclic guanosine monophosphate (P < .01), L-arginine to asymmetric dimethylarginine ratio (P < .0001), and reactive hyperemia (P < .05). Finally, L-arginine increased insulin sensitivity index (P < .05) and adiponectin (P < .01) and decreased interleukin-6 and monocyte chemoattractant protein-1 levels. In conclusion, insulin resistance, endothelial dysfunction, and inflammation are important cardiovascular risk factors in coronary artery disease patients; and L-arginine seems to have anti-inflammatory and metabolic advantages in these patients.
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PMID:Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass. 1959 54

Tumor necrosis factor-alpha (TNF-alpha) upregulates the expression of monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules in type 2 diabetes. We hypothesized that TNF-alpha and MCP-1 may interact to contribute to the evolution of vascular inflammation and endothelial dysfunction in coronary arterioles in type 2 diabetes. To test this hypothesis, we administered anti-MCP-1 to block MCP-1 signaling in genetically modified mice with type 2 diabetes (Lepr(db)) and in heterozygote (m Lepr(db)) lean control. Anti-MCP-1 partially restored vasodilation to the endothelium-dependent vasodilator acetylcholine in isolated, cannulated, and pressurized coronary arterioles in Lepr(db) mice but did not affect vasodilation in m Lepr(db) mice. Anti-MCP-1 attenuated superoxide production and the protein expression of nitrotyrosine, which is an indicator of peroxynitrite production, in isolated coronary arterioles of Lepr(db) mice. Immunostaining results showed that the expression of MCP-1 and vascular cellular adhesion molecule-1 is colocalized with endothelial cells and macrophages. Anti-TNF-alpha or anti-MCP-1 markedly reduced macrophage infiltration and the number of MCP-1-positive endothelium in Lepr(db) mice. The neutralization of TNF-alpha or anti-MCP-1 reduced the expression of adhesion molecules, suggesting that proinflammatory cytokines interact to amplify the signaling process that leads to vascular dysfunction. These findings demonstrate that the endothelial dysfunction occurring in type 2 diabetes is the result of the effects of the inflammatory cytokine TNF-alpha and TNF-alpha-related signaling, including the expression of MCP-1 and adhesion molecules, which further exacerbates vessel inflammation and oxidative stress.
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PMID:Role of MCP-1 in tumor necrosis factor-alpha-induced endothelial dysfunction in type 2 diabetic mice. 1966 44


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