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

Neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (COX-2) regulate the tubuloglomerular feedback (TGF) and renin-angiotensin system (RAS) in the kidney. In type 1 diabetic rats, renal overproduction of these enzymes and their relationship to the pathogenesis of diabetic nephropathy has been demonstrated. In the present study, we histologically and immunohistochemically investigated the kidneys of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, as a model of type 2 diabetes, at 62 weeks of age (chronic phase of diabetes). The kidneys of OLETF rats showed typical diabetic nephropathy. Quantitative scores for glomerulosclerosis and interstitial fibrosis in OLETF rats were significantly higher than those of age-matched control Long-Evans Tokushima Otsuka (LETO) rats. nNOS- and COX-2-positive immunoreactions were observed in the distal tubules and collecting ducts. These reactions appeared to be more widely distributed in OLETF, and the number of nNOS-and COX-2-positive sites in the OLETF were significantly more than those in LETO rats. Expression of renin, angiotensin II, and inducible nitric oxide synthase (iNOS) were also examined immunohistochemically, and no differences between OLETF and LETO rats were observed in the distributions and the number of immunoreactive-sites. In conclusion, the overproduction of nNOS and COX-2 in the kidney of OLETF rats was confirmed, suggesting that the overproduction of nNOS and/or COX-2 does not affect the intrarenal RAS or iNOS production but does affect TGF.
 ...
PMID:Neuronal nitric oxide synthase and cyclooxygenase-2 in diabetic nephropathy of type 2 diabetic OLETF rats. 1650 8

Currently, in Japan, approximately 95% of patients with diabetes mellitus have non-insulin-dependent (type 2) diabetes mellitus (NIDDM), and diabetic nephropathy is a major cause of patients requiring chronic haemodialysis. A previous study showed that Hachimi-jio-gan has a protective effect in rats subjected to subtotal nephrectomy plus streptozotocin injection, a model of insulin-dependent (type 1) diabetic nephropathy. In this study, we used the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of human NIDDM, to investigate whether long-term administration of Hachimi-jio-gan affects glycaemic control and renal function in NIDDM. Male OLETF rats, aged 22 weeks, were divided into 4 groups of 10 and given Hachimi-jio-gan (50, 100 or 200 mg kg(-1) daily) orally or no treatment for 32 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats (n = 6) were used as non-diabetic normal controls. Hachimi-jio-gan reduced hyperglycaemia dose-dependently from 16 weeks of the administration period. Urinary protein excretion decreased significantly from an early stage, and creatinine clearance levels improved at 32 weeks. In addition, the levels of serum glycosylated protein and renal advanced glycation end-products were effectively reduced. Hachimi-jio-gan also significantly reduced the levels of thiobarbituric acid-reactive substances in renal mitochondria, although it showed only a tendency to reduce these in serum. Furthermore, long-term administration of Hachimi-jio-gan reduced renal cortical expression of proteins, such as transforming growth factor-beta1 (TGF-beta1), fibronectin, inducible nitric oxide synthase and cyclooxygenase-2. The 100- and 200-mg kg(-1) daily doses of Hachimi-jio-gan significantly reduced TGF-beta1 and fibronectin protein expression to levels below those of LETO rats. These data suggest that Hachimi-jio-gan may have a beneficial effect on the progression of diabetic nephropathy in OLETF rats by attenuating glucose toxicity and renal damage.
 ...
PMID:Activity of the Chinese prescription Hachimi-jio-gan against renal damage in the Otsuka Long-Evans Tokushima fatty rat: a model of human type 2 diabetes mellitus. 1659 72

In adipocytes, oxidative stress and chronic inflammation are closely associated with metabolic disorders, including insulin resistance, obesity, cardiovascular disease, and type 2 diabetes. However, the molecular mechanisms underlying these metabolic disorders have not been thoroughly elucidated. In this report, we demonstrate that overexpression of glucose-6-phosphate dehydrogenase (G6PD) in adipocytes stimulates oxidative stress and inflammatory responses, thus affecting the neighboring macrophages. Adipogenic G6PD overexpression promotes the expression of pro-oxidative enzymes, including inducible nitric oxide synthase and NADPH oxidase, and the activation of nuclear factor-kappaB (NF-kappaB) signaling, which eventually leads to the dysregulation of adipocytokines and inflammatory signals. Furthermore, secretory factors from G6PD-overexpressing adipocytes stimulate macrophages to express more proinflammatory cytokines and to be recruited to the adipocytes; this would cause chronic inflammatory conditions in the adipose tissue of obesity. These effects of G6PD overexpression in adipocytes were abolished by pretreatment with NF-kappaB inhibitors or antioxidant drugs. Thus, we propose that a high level of G6PD in adipocytes may mediate the onset of metabolic disorders in obesity by increasing the oxidative stress and inflammatory signals.
 ...
PMID:Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals. 1706 29

Previous epidemiologic studies have suggested that periodontal disease is closely related to obesity and glucose tolerance. As the level of adiponectin, an adipocyte-derived cytokine, in plasma had been reported to decrease in obese and type 2 diabetes patients, we explored the role of adiponectin in the etiology of periodontitis using the D clone of RAW264, a clone that exhibits highly efficient osteoclast formation, to determine whether adiponectin acts as a regulatory molecule in osteoclast formation stimulated by lipopolysaccharide of periodontopathic bacteria. We observed that adiponectin acted as a potent inhibitor of osteoclast formation stimulated by Toll-like receptor 4 (TLR4) ligand and receptor activator of NF-kappaB ligand (RANKL). Because NF-kappaB is an important transcription factor in osteoclast formation, we examined the effect of adiponectin on its transcriptional activity. A luciferase assay showed that adiponectin was able to inhibit the TLR4-mediated NF-kappaB activity in RAW264 cells. In addition, we observed that the cytokine was actually able to inhibit TLR4-mediated expression of the gene for inducible nitric oxide synthase and production of nitric oxide in the cells. These observations strongly suggest that adiponectin may function as a negative regulator of lipopolysaccharide/RANKL-mediated osteoclast formation in periodontal disease.
 ...
PMID:Adiponectin inhibits osteoclast formation stimulated by lipopolysaccharide from Actinobacillus actinomycetemcomitans. 1709 90

Hyperglycemia is one of the main causes of oxidative stress in type 2 diabetes mellitus. During hyperglycemia, the increased level of various reducing sugars in the blood enhances the production of reactive oxygen species (ROS) and triggers tissue damage, especially in pancreatic beta-cells. Streptozotocin (STZ) is a diabetogen that causes diabetes mellitus via ROS-induced apoptosis in beta-cells. In this study, SR10, an herbal formulation consisting of the aqueous extracts of Radix Astragali, Radix Codonopsis and Cortex Lycii was examined for its antidiabetic effects in vitro. SR10 treatment resulted in significant enhancement of survival rate of rat pancreatic beta-cells which were treated by streptozotocin. SR10 apparently reduced apoptosis of streptozotocin-treated beta-cells by decreasing DNA fragmentation, sub-G(1) peak area and percentage of apoptotic cells. Nitric oxide (NO) production in streptozotocin-treated cells was inhibited by SR10 via the suppression of the expression of inducible nitric oxide synthase (iNOS). The implication of SR10 in treating type 2 diabetes mellitus was discussed.
 ...
PMID:Protective effects of an herbal formulation of Radix Astragali, Radix Codonopsis and Cortex Lycii on streptozotocin-induced apoptosis in pancreatic beta-cells: an implication for its treatment of diabetes mellitus. 1772 33

Skeletal muscle inducible nitric oxide synthase (NOS) protein is greatly elevated in people with type 2 diabetes mellitus, whereas endothelial NOS is at normal levels. Diabetic rat studies suggest that skeletal muscle neuronal NOS (nNOS) micro protein expression may be reduced in human insulin resistance. The aim of this study was to determine whether skeletal muscle nNOSmicro protein expression is reduced in people with impaired glucose homeostasis and whether exercise training increases nNOSmicro protein expression in these individuals because exercise training increases skeletal muscle nNOSmicro protein in rats. Seven people with type 2 diabetes mellitus or prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and 7 matched (sex, age, fitness, body mass index, blood pressure, lipid profile) healthy controls aged 36 to 60 years participated in this study. Vastus lateralis muscle biopsies for nNOSmicro protein determination were obtained, aerobic fitness was measured (peak pulmonary oxygen uptake [Vo(2) peak]), and glucose tolerance and insulin homeostasis were assessed before and after 1 and 4 weeks of cycling exercise training (60% Vo(2) peak, 50 minutes x 5 d wk(-1)). Skeletal muscle nNOSmicro protein was significantly lower (by 32%) in subjects with type 2 diabetes mellitus or prediabetes compared with that in controls before training (17.7 +/- 1.2 vs 26.2 +/- 3.4 arbitrary units, P < .05). The Vo(2) peak and indicators of insulin sensitivity improved with exercise training in both groups (P < .05), but there was no effect of exercise training on skeletal muscle nNOSmicro protein in either group. In conclusion, individuals with impaired glucose homeostasis have reduced skeletal muscle nNOSmicro protein content. However, because exercise training improves insulin sensitivity without influencing skeletal muscle nNOSmicro protein expression, it seems that changes in skeletal muscle nNOSmicro protein are not central to the control of insulin sensitivity in humans and therefore may be a consequence rather than a cause of diabetes.
 ...
PMID:Skeletal muscle neuronal nitric oxide synthase micro protein is reduced in people with impaired glucose homeostasis and is not normalized by exercise training. 1788 53

The adipocyte metabolism has been shown to change during the fat enlargement process associated to obesity. Several procoagulant proteins such as plasminogen activator inhibitor type 1, tissue factor or factor VII and also inducible nitric oxide synthase show higher expression in adipose tissue of obese people in comparison to lean. This overexpression could explain at least a part of the atherogenic and cardiovascular risk associated with obesity. In addition to cytokine secretion, many other features have been observed to be common to adipocyte and monocyte/macrophage lines: for example, phagocytic and microbicidal activities, and possibly a cellular plasticity of adipose precursors. Overweight and obesity are associated with an increased risk of such metabolic abnormalities as dyslipidemia, hypertension or type 2 diabetes mellitus and cardiovascular diseases, common features of the metabolic syndrome. Initially, insulin resistance or hyperinsulinemia was suggested as the origin of these abnormalities. More recent studies indicate that adipokynes have an important role in obesity-associated metabolic complications, and suggest that chronically elevated local or systemic concentrations of adipokynes contribute to the development of complications associated with obesity and metabolic syndrome. Considering all the evidence relating to diet and inflammation, the best diet for protecting against the metabolic derangements associated with obesity and metabolic syndrome would be high in fibre-rich cereals, fruit, vegetables, fish, virgin olive oil and nuts; moderate in wine; and low in meat, processed meat foods and trans-fatty acids.
 ...
PMID:Inflammation, obesity and comorbidities: the role of diet. 1790 26

N-acetylaspartic acid (NAA) is converted into aspartate and acetate by aspartoacylase. Abnormal levels of the enzyme leads to accumulation of NAA and these changes have been observed in Canavan disease and type 2 diabetes. How upregulation of NAA affect the gastrointestine protein levels and the function is not known. Incubation of rat stomach tissue with NAA 1.5 mM, 1.5 microM and 1.5 nM induced inflammatory agents TNFalpha, p38MAPK, iNOS, PKC, COX2 and ICAM3; transcription factors phospho-NF-kBp65, cjun and cfos; contractile proteins MLCK and phospho MLC; and calcium channel alpha1C and calcium channel, voltage-dependent, beta 3 subunit compared to their respective control. Incubation of circular smooth muscle cells with the above doses of NAA induced contractility compared to the control. These studies suggest that NAA alters proteins levels and smooth muscle contractility and these changes likely to contribute to gastrointestinal disorder seen in these diseases.
 ...
PMID:Upregulation of N-acetylaspartic acid alters inflammation, transcription and contractile associated protein levels in the stomach and smooth muscle contractility. 1794 58

Cardiac contractile dysfunction is a common occurrence in type 2 diabetes. The aim was to examine if inducible nitric oxide synthase (iNOS) causes cardiac dysfunction in Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. ZDF and Zucker lean control rats (20 week old) were studied at 6 h after recovery from halothane anaesthesia and surgery that involved insertions of catheters into the iliac arteries, iliac veins and the left ventricle via the right carotid artery. Protein expression and activity of iNOS in the hearts were measured by immunostaining and arginine-citrulline conversion assay, respectively. Both groups had similar baseline left ventricular developed pressure and maximum rate of rise of left ventricular pressure (+dP/dt), but heart rate and rate pressure product were lower in the ZDF than control rats. Dobutamine dose-dependently increased left ventricular developed pressure, +dP/dt, heart rate and rate pressure product in both groups, but the responses were less in the diabetic than control rats. The activity and protein expression of iNOS and nitrotyrosine were higher in the hearts of the diabetic than control rats. Selective inhibition of iNOS by 1400 W (N-3-aminomethyl-benzyl-acetamidine) did not alter responses to dobutamine in the control rats, but augmented the effects of dobutamine on left ventricular developed pressure and rate pressure product in the diabetic rats. The results indicate that activation of iNOS contributed to left ventricular contractile dysfunction in the ZDF rats, and this was partially reversed by selective inhibition of the activity of iNOS.
 ...
PMID:Inducible nitric oxide synthase depresses cardiac contractile function in Zucker diabetic fatty rats. 1797 76

Diabetes and insulin resistance are associated with an increased risk of hypertension and cardiovascular disease. Recent evidence demonstrates that AT2 receptors (AT2R) play an important role in the hemodynamic control of hypertension by vasodilation. The quantitative significance of AT2R in the establishment of diabetic vascular dysfunction, however, is not well defined and needs further investigation. Goto-Kakizaki (GK) rats, a polygenic model of spontaneous normotensive type 2 diabetes, were used to examine any abnormalities in cardiovascular function associated with AT2R at the early stage of the disease without endothelium influence. Using a myograph to measure the isometric force, we observed that ANG II-induced contraction was impaired in denuded GK aorta compared with control Wistar-Kyoto (WKY) aorta and exhibited a retarded AT1R antagonist response and enhanced Rho kinase signaling. When AT1R were blocked, ANG II induced a significant vasodilation of precontracted GK aorta via AT2R. The protein and mRNA of AT2R were increased in diabetic GK denuded aorta. Blocking AT2R restored the ANG II-induced contraction in the GK vasculature to control levels, demonstrating a counteractive role for AT2R in AT1R-induced contraction. Inhibition of inducible nitric oxide synthase (iNOS) by NG-monomethyl-L-arginine mimicked AT2R inhibition in denuded GK aorta, suggesting that AT2R-induced vasodilation was dependent on iNOS/NO generation. The protein and mRNA of iNOS were also increased in GK aorta. In conclusion, these results clearly demonstrate that enhanced AT2R and iNOS-induced, NO-mediated vasodilation impair ANG II-induced contraction in an endothelium-independent manner at the early stage of type 2 diabetes.
 ...
PMID:Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats. 1846 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>