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 incidence of obesity (especially childhood obesity) and its associated health-related problems have reached epidemic proportions in the United States. Recent investigations suggest that the causes of obesity involve a complex interplay of genetic, environmental, psychobehavioral, endocrine, metabolic, cultural, and socioeconomic factors. Several genes and their protein products, such as leptin, may be particularly important in appetite and metabolic control, although the genetics of human obesity appear to involve multiple genes and metabolic pathways that require further elucidation. Severe obesity is frequently associated with significant comorbid medical conditions, including coronary artery disease, hypertension, type II diabetes mellitus, gallstones, nonalcoholic steatohepatitis, pulmonary hypertension, and sleep apnea. Long-term reduction of significant excess weight in these patients may improve or resolve many of these obesity-related health problems, although convincing evidence of long-term benefit is lacking. Available treatments of obesity range from diet, exercise, behavioral modification, and pharmacotherapy to surgery, with varying risks and efficacy. Nonsurgical modalities, although less invasive, achieve only relatively short-term and limited weight loss in most patients. Currently, surgical therapy is the most effective modality in terms of extent and duration of weight reduction in selected patients with acceptable operative risks. The most widely performed surgical procedure, Roux-en-Y gastric bypass, achieves permanent (followed up for more than 14 years) and significant weight loss (more than 50% of excess body weight) in more than 90% of patients.
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PMID:Current status of medical and surgical therapy for obesity. 1117 43

The epithelial polymeric immunoglobulin receptor/transmembrane secretory component (pIgR/SC) transports into secretions polymeric immunoglobulin A (pIgA), which is considered the first line of defense of the respiratory tract. The present study, done with quantitative immunohistochemistry, evaluated epithelial expression of secretory component (SC) and Clara cell protein (CC16) and neutrophil infiltration into the airways of eight patients with severe chronic obstructive pulmonary disease (COPD) who were undergoing lung transplantation, as compared with these processes in six nonsmoking patients with pulmonary hypertension who were used as controls and in lung specimens from five smokers without chronic bronchitis. Staining for SC was significantly decreased in the COPD patients as compared with the controls, both in large (mean optical density [MOD]: 23.4 [range: 21.1 to 27.8] versus 42.2 [range: 28.2 to 49.3], p = 0.003) and in small airways (MOD: 30.8 [range: 20.3 to 39.4] versus 41.5 [range: 39.2 to 46.2], p = 0.003). SC expression in small airways correlated strongly with functional parameters such as FEV1 (Kendall's tau (K) = 0.76, p = 0.008), FVC (K = 0.64, p = 0.03), and midexpiratory flow at 50% of VC (MEF50) (K = 0.74, p = 0.01). The reduced expression of SC in large airways correlated with neutrophil infiltration in submucosal glands (K = -0.47, p = 0.03). Expression of CC16 in the bronchial epithelium of COPD patients was also significantly decreased as compared with that of controls, especially in small airways (MOD: 28.3 [range: 26.8 to 32.4] versus 45.8 [range: 40.7 to 56.0], p = 0.002), but no correlation was observed with lung function tests. In conclusion, this study shows that reduced expression of SC in airway epithelium is associated with airflow obstruction and neutrophil infiltration in severe COPD.
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PMID:Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease. 1120 45

The peroxisome proliferator-activated receptor (PPAR) gamma is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Thiazolidinediones, pharmacological ligands for PPARgamma, are currently used in the management of type 2 diabetes. Peroxisome proliferator-activated receptor gamma is expressed in the lung and pulmonary vasculature, and its expression is reduced in the vascular lesions of patients with pulmonary hypertension. Furthermore, thiazolidinedione PPARgamma ligands reduced pulmonary hypertension and vascular remodeling in several experimental models of pulmonary hypertension. This report reviews current evidence that PPARgamma may represent a novel therapeutic target in pulmonary hypertension and examines studies that have begun to elucidate mechanisms that underlie these potential therapeutic effects.
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PMID:The Role of PPARgamma in pulmonary vascular disease. 1831 34

Obesity is a worldwide epidemic and is known to increase the risk of cardiovascular disease, type 2 diabetes, and certain forms of cancer. In addition, obesity is now recognized as an important risk factor in the development of several respiratory diseases. Of these respiratory diseases, it has already been well established that obesity can lead to obstructive sleep apnea (OSA) and obesity-hypoventilation syndrome (OHS). More recent data suggest that the prevalence of wheezing and bronchial hyper-responsiveness, two symptoms often associated with asthma, are increased in overweight and obese individual. Indeed, epidemiological studies have reported that obesity is a risk factor for the development of asthma. Furthermore, a number of studies indicate that obesity is also associated with a higher risk of developing deep vein thrombi, pulmonary emboli, pulmonary hypertension, and pneumonia. Finally, weight reduction has been shown to be effective in improving the symptoms and severity of several respiratory diseases, including OSA and asthma. Thus, overweight and obese patients should be encouraged to lose weight to reduce their risk of developing respiratory diseases or improve the course of pre-existing conditions.
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PMID:Obesity and respiratory diseases. 1902 35

Human urotensin II (U-II), the most potent vasoconstrictor undecapeptide identified to date, and its receptor (UT) are involved in the pathogenesis of systemic and pulmonary hypertension. Here, we review recent advances in our understanding of the pathophysiology of U-II with particular reference to its role in atherosclerotic cardiovascular diseases. Single-nucleotide polymorphisms of U-II gene (S89N) are associated with onset of essential hypertension, type II diabetes mellitus, and insulin resistance in the Asian population. Plasma U-II levels are elevated in patients with vascular endothelial dysfunction-related diseases such as essential hypertension, diabetes mellitus, atherosclerosis, ischemic heart disease, and heart failure. Chronic infusion of U-II enhances atherosclerotic lesions in the aorta in apolipoprotein E-knockout mice. In human atherosclerotic plaques from the aorta and coronary and carotid arteries, U-II is expressed at high levels in endothelial cells (ECs) and lymphocytes, whereas UT is expressed at high levels in vascular smooth muscle cells (VSMCs), ECs, monocytes, and macrophages. U-II stimulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in human ECs as chemoattractant for monocytes, and accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages. U-II produces reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate oxidase activation in human VSMCs, and stimulates VSMC proliferation with synergistic effects when combined with ROS, oxidized LDL, and serotonin. Clinical studies demonstrated increased plasma U-II levels in accordance with the severity of carotid atherosclerosis in patients with essential hypertension and that of coronary artery lesions in patients with ischemic heart disease. Here, we summarize the key roles of U-II in progression of hypertension and atherosclerotic cardiovascular diseases.
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PMID:Human urotensin II promotes hypertension and atherosclerotic cardiovascular diseases. 1919 21

Heterocyclic indazole derivatives are claimed in patent WO2008138448 as inhibitors of the serum- and glucocorticoid-inducible-kinase 1 (SGK1) and drugs for the pharmacological treatment of SGK1-related diseases, such as diabetes, obesity, metabolic syndrome, systemic and pulmonary hypertension, cardiac fibrosis, hypertrophy and insufficiency, arteriosclerosis, glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, deranged electrolyte excretion, fibrosing and inflammatory disease (e.g., liver cirrhosis, lung fibrosis, rheumatism, arthrosis, Crohn s disease, chronic bronchitis, radiation fibrosis, sclerodermia, cystic fibrosis, scar formation and Alzheimer' disease), tumor growth, peptic ulcers and some disorders hitherto not conclusively shown to involve SGK1. Most of the claims are supported by the literature. SGK1 is ubiquitously expressed and its expression is stimulated by hyperglycemia, cell shrinkage, ischemia, glucocorticoids, mineralocorticoids and several inflammatory mediators including TGF-ss. SGK1 is activated by insulin and growth factors via the phosphatidylinositol-3-kinase pathway. SGK1 regulates ion channels (including ENaC, KCNE1/KCNQ1), carriers (including NCC, NHE3, SGLT1), Na(+)/K(+)-ATPase, enzymes (including glycogen-synthase-kinase-3) and transcription factors (including FOXO3a, ss-catenin, NF-kappaB). A gain-of-function SGK1 gene variant, carried by approximately 3 - 5% of Caucasians and approximately 10% of Africans, is associated with increased blood pressure, obesity and type 2 diabetes. In vitro and in vivo experiments suggested a critical role of SGK1 in renal fluid retention and hypertension, glucose-induced obesity, coagulation and increased matrix protein formation.
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PMID:Heterocyclic indazole derivatives as SGK1 inhibitors, WO2008138448. 2002 Dec 89

Activation of peroxisome proliferator-activated receptor (PPAR)-gamma suppresses proliferation of rat pulmonary artery smooth muscle cells (PASMCs), and therefore ameliorates the development of pulmonary hypertension in animal models. However, the molecular mechanisms underlying this effect remain largely unknown. This study addressed this issue. The PPARgamma agonist rosiglitazone dose-dependently stimulated heme oxygenase (HO)-1 expression in PASMCs, 5 microm rosiglitazone inducing a 12.1-fold increase in the HO-1 protein level. Cells pre-exposed to rosiglitazone showed a dose-dependent reduction in proliferation in response to serotonin; this was abolished by pretransfection of cells with sequence-specific small interfering RNA against HO-1. In addition, rosiglitazone stimulated p21(WAF1) expression in PASMCs, a 2.34-fold increase in the p21(WAF1) protein level being achieved with 5 microm rosiglitazone; again, this effect was blocked by knockdown of HO-1. Like loss of HO-1, loss of p21(WAF1) through siRNA transfection also reversed the inhibitory effect of rosiglitazone on PASMC proliferation triggered by serotonin. Taken together, our findings suggest that activation of PPARgamma induces HO-1 expression, and that this in turn stimulates p21(WAF1) expression to suppress PASMC proliferation. Our study also indicates that rosiglitazone, a medicine widely used in the treatment of type 2 diabetes mellitus, has potential benefits for patients with pulmonary hypertension.
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PMID:Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor-gamma signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. 2016 60

Fenfluramine has been associated with an increased risk of pulmonary hypertension and valvular disease. Benfluorex is a fenfluramine derivative approved for the treatment of metabolic syndrome and type 2 diabetes mellitus. To date, only three isolated clinical cases of valvular disease and two recent case-control studies have been reported in patients exposed to benfluorex. Herein, the case is described of a patient with mitral and aortic valvular disease, with both echocardiographic and histopathological findings, who had been receiving benfluorex for several years, without any other etiology of valvular disease. The case is suggestive of toxic valvular lesions, similar to those observed previously during treatment with fenfluramine, pergolide, and cabergolide.
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PMID:Mitral and aortic valvular disease associated with benfluorex use. 2171 28

Although type 1 and type 2 diabetes are strongly associated with systemic cardiovascular morbidity, the relationship with pulmonary vascular disease had been almost disregarded until recent epidemiological data revealed that diabetes might be a risk factor for pulmonary hypertension. Recent experimental studies suggest that diabetes induces changes in lung function insufficient to elevate pulmonary pressure. The aim of this study was to assess the effects of diabetes on the sensitivity to other risk factors for pulmonary hypertension. We therefore analysed the effects of the combination of diabetes with exposure to moderate hypoxia on classical markers of pulmonary hypertension. Control (saline-treated) and diabetic (70 mg kg(-1) streptozotocin-treated) male Wistar-Kyoto rats were followed for 4 weeks and exposed to normoxia or moderate normobaric hypoxia (14%) for another 2 weeks. Hypoxia, but not diabetes, strongly reduced voltage-gated potassium currents, whereas diabetes, but not hypoxia, induced pulmonary artery endothelial dysfunction. Both factors independently induced pulmonary vascular remodelling and downregulated the lung bone morphogenetic protein receptor type 2. However, diabetes, but not hypoxia, induced pulmonary infiltration of macrophages, which was markedly increased when both factors were combined. Diabetes plus hypoxia induced a modest increase in diastolic and mean pulmonary artery pressure and right ventricular weight, while each of the two factors alone had no significant effect. The pattern of changes in markers of pulmonary hypertension was different for moderate hypoxia and diabetes, with no synergic effect except for macrophage recruitment, and the combination of both factors was required to induce a moderate elevation in pulmonary arterial pressure.
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PMID:Different patterns of pulmonary vascular disease induced by type 1 diabetes and moderate hypoxia in rats. 2224 83

Nitric oxide (NO) has long been known as endothelium-derived relaxing factor. It is a vasodilator, modulating vascular tone, blood pressure and hemodynamics, a role exploited by nitrate donor therapy for angina, heart failure, pulmonary hypertension and erectile dysfunction. In addition, its powerful antioxidant, anti-inflammatory and antithrombotic actions are antiatherogenic with antiatherothrombotic impact. NO signaling modulates skeletal muscle and myocardial contractility and metabolism and is intimately linked with insulin signaling. Vascular and muscle NO signaling coordinate skeletal muscle and myocardial energy demand with supply and are critical for both carbohydrate and fatty acid total-body homeostasis. NO signaling in mitochondria underlies much of NO's metabolic effect, which, at low physiologic levels, links cellular energy demand with mitochondrial energy supply, while beneficially affecting mitochondrial oxidative stress and calcium handling. Mitochondria are also the site for the life-threatening deleterious effects arising from inflammation-related excessive NO levels. NO-deficient states are characterized by cell senescence, oxidative stress, inflammation, endothelial dysfunction, vascular disease, insulin resistance and type 2 diabetes mellitus. NO-enriching therapy would be expected to be of benefit not only for its hemodynamic but also for its metabolic impact. In contrast, strategies are needed to curtail excessive NO in states such as septic shock.
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PMID:Characterization of the role of nitric oxide and its clinical applications. 2272 23


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