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)

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of inflammation.
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PMID:Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. 1470 29

C-reactive protein (CRP) is a liver-derived pattern recognition molecule that is increased in inflammatory states. It rapidly increases within hours after tissue injury, and it is suggested that it is part of the innate immune system and contributes to host defense. Since cardiovascular disease is at least in part an inflammatory process, CRP has been investigated in the context of arteriosclerosis and subsequent vascular disorders. Based on multiple epidemiological and intervention studies, minor CRP elevation [high-sensitivity CRP (hsCRP)] has been shown to be associated with future major cardiovascular risk (hsCRP:<1 mg/L=low risk; 1-3 mg/L=intermediate risk; 3-10 mg/L=high risk; >10 mg/L=unspecific elevation). It is recommended by the American Heart Association that patients at intermediate or high risk of coronary heart disease may benefit from measurement of hsCRP with regard to their individual risk prediction. Elevation of hsCRP is associated with increased risk of type 2 diabetes development in patients with all levels of metabolic syndrome. In type 1 and type 2 diabetes mellitus, hemoglobin A1c significantly correlates with hsCRP levels and future cardiovascular risk. Also, hsCRP levels increase with the stage of beta-cell dysfunction and insulin resistance. Non-diabetes drugs that have been shown to reduce hsCRP concentrations include aspirin, statins, cyclooxygenase-2 inhibitors, and fibrates. Recent intervention studies have also demonstrated the distinct efficacy of different anti-diabetes treatments on a variety of cardiovascular risk markers. Intensive insulin therapy may reduce inflammation, but this effect may be influenced by the degree of weight gain. Treatment with peroxisome proliferator-activated receptor gamma has lead to substantial reduction of hsCRP and other cardiovascular risk markers in several comparator studies. Since this effect was shown to be independent of the degree of glycemic improvement, it can be regarded as a classspecific effect. Whether these findings translate into a reduction of overall cardiovascular mortality will soon be shown by the currently running thiazolidinedione outcome studies. Positive results in these trials will further strengthen the value and acceptance of hsCRP, which is recommended as a predictive laboratory marker for cardiovascular disease risk also in patients with diabetes mellitus.
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PMID:High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. 1647 48

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.
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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.
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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

Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic beta-cells. Furthermore, the number of pancreatic beta-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E(2) (PGE(2)). To investigate whether high glucose-induced PGE(2) has an adverse effect on pancreatic beta-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their beta-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of beta-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because beta-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE(2) signaling thus contributes to the reduction of the pancreatic beta-cell mass through inhibition of proliferation, thereby aggravating diabetes further.
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PMID:Destruction of pancreatic beta-cells by transgenic induction of prostaglandin E2 in the islets. 1687 78

In our previous study, the polyherbal drug Hachimi-jio-gan was reported to possess a protective effect against the progression of diabetic nephropathy by attenuating glucose toxicity and renal damage with a type 2 diabetic model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Based on these findings, this study was undertaken to reveal the effect of Hachimi-jio-gan on pancreatic damage focusing on fibrosis and oxidative stress in type 2 diabetes. OLETF rats were orally administered Hachimi-jio-gan for 32 weeks, and we assessed the changes in the serum glucose level every 8 weeks, as well as those of body weight, and food and water consumption every 4 weeks. In addition, pancreatic wet weight, insulin content, and Western blot analyses of transforming growth factor-beta(1), fibronectin, and nuclear factor-kappaB-related inflammatory enzymes, such as inducible nitric oxide synthesis and cyclooxygenase-2, were also performed in the pancreas. As a consequence, long-term treatment with Hachimi-jio-gan had a hypoglycemic effect, reducing pancreatic atrophy and fibrosis, and ameliorating the oxidative status. Therefore, this may provide evidence that Hachimi-jio-gan is a therapeutic target for preventing the development of pancreatic damage concomitant with hyperglycemia in type 2 diabetes.
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PMID:Protective effect of Hachimi-jio-gan against the development of pancreatic fibrosis and oxidative damage in Otsuka Long-Evans Tokushima Fatty rats. 1760 44

We investigated the preventive effects of ferulic acid (FA) and alpha-tocopherol (AT) on the progression of diabetic nephropathy. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as type 2 diabetes and non-diabetes models, respectively. Two-thirds of the OLETF rats were fed 0.2% FA-containing or 0.5% AT-containing chow. Diabetic nephropathy was assessed based on urinary protein excretion and pathological changes which were scored based on the percentages of extracellular matrix area in the glomerular area. Furthermore, renal messenger RNA (mRNA) expression of intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and transforming growth factor-beta1 (TGF-beta1) was quantified by real-time polymerase chain reaction. After 12 weeks of FA- or AT-supplementation, urinary protein in untreated-OLETF group was significantly higher than that in LETO group, thus FA-supplementation significantly decreased urinary protein excretion. Pathological scores in FA-supplemented group were significantly lower than those in untreated OLETF group. Supplementation with either FA or AT significantly prevented the elevation of TGF-beta1 mRNA expression caused by diabetes. Treatment with neither FA nor AT had a significant effect on COX-2 or ICAM-1 mRNA expressions. We have demonstrated the preventative effects of FA on diabetic nephropathy via suppression of TGF-beta1 upregulation, furthermore FA may be more potent than AT.
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PMID:Ferulic acid prevents pathological and functional abnormalities of the kidney in Otsuka Long-Evans Tokushima Fatty diabetic rats. 1789 50

The protective effect of proanthocyanidins from persimmon peel, using both oligomers and polymers, was investigated in a db/db type 2 diabetes model. Male db/db mice were divided into three groups: control (vehicle), polymer-, or oligomer- (10 mg/(kg body weight x day x p.o.)) administered mice. Age-matched nondiabetic m/m mice were used as a normal group. The administration of proanthocyanidins reduced hyperglycemia in db/db mice through a decline in the serum level of glucose and glycosylated protein. In addition, it had a strong effect on hyperlipidemia through lowering levels of triglyceride, total cholesterol, and nonesterified fatty acids. The protective effect against hyperglycemia and hyperlipidemia was greater in the groups administered the oligomeric rather than polymeric form. The increased oxidative stress in db/db mice was attenuated by the administration of oligomers through inhibiting the generation of reactive oxygen species and lipid peroxidation and elevating the reduced glutathione/oxidized glutathione ratio. On the other hand, polymers did not show such an effect. Moreover, expressions in the liver of sterol regulatory element binding protein (SREBP)-1 and SREBP-2 were downregulated by the administration of proanthocyanidins, especially the oligomeric form. Oligomers caused a slight elevation in the expression of peroxisome proliferator-activated receptors alpha. Furthermore, oligomeric proanthocyanidin regulated the expression of nuclear factor kappaB in db/db type 2 diabetes via the activation of inhibitor protein kappaB-alpha. It also attenuated the protein expressions of cyclooxygenase-2 and inducible nitric oxide synthase. This suggests that oligomers would act as a regulator in inflammatory reactions associated with oxidative stress in type 2 diabetes. The present study results suggest that proanthocyanidin administration, especially the oligomeric form, may improve oxidative stress via the regulation of hyperlipidemia than hyperglycemia in type 2 diabetes.
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PMID:Effects of proanthocyanidin preparations on hyperlipidemia and other biomarkers in mouse model of type 2 diabetes. 1869 Jun 94

The purpose of this study was to determine whether cyclooxygenase expression in arteries is affected by diabetes. Streptozotocin-injected rats and Goto-Kakizaki rats were used as animal models for type 1 and type 2 diabetes, respectively. Cyclooxygenase-2 expression was induced by lipopolysaccharide. Lipopolysaccharide-induced cyclooxygenase-2 expression was significantly lower in aortas isolated from streptozotocin-injected rats and Goto-Kakizaki rats than in aortas of control rats, while expression level of cyclooxygenase-1 was not affected by lipopolysaccharide and was not different in aortas of the three groups of rats. The level of 6-keto-prostaglandin F(1alpha) that accumulated in the presence of lipopolysaccharide as well as the basal accumulation level in the absence of lipopolysaccharide was significantly lower in aortas of streptozotocin-injected rats and Goto-Kakizaki rats than in aortas of control rats. The net increase in 6-keto-prostaglandin F(1alpha) level in response to stimulation with lipopolysaccharide, which was calculated by subtracting the basal accumulation level from the total accumulation level, was also significantly lower in aortas of streptozotocin-injected rats and Goto-Kakizaki rats than in aortas of control rats. There were no significant differences in the accumulated 6-keto-prostaglandin F(1alpha) levels in the absence or presence of lipopolysaccharide and the levels of basal and lipopolysaccharide-induced cyclooxygenase-2 expression in control or Goto-Kakizaki rat aortas under the conditions of different glucose concentrations in the medium. These results suggest that lipopolysaccharide-induced cyclooxygenase-2 expression and subsequent prostacyclin production are decreased in aortas isolated from both type 1 and type 2 diabetes rats.
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PMID:Depression of cyclooxygenase-2 induction in aortas of rats with type 1 and type 2 diabetes mellitus. 1870 4

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists of the thiazolidinedione class are widely used for the treatment of type 2 diabetes subjects due to their ability to improve insulin resistance. Troglitazone and ciglitazone belong to the PPARgamma agonists of thiazolidinediones. We report here that troglitazone but not ciglitazone increased IL-1beta induced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in vascular smooth muscle cell (VSMC) from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Potentiated expression of COX-2 and iNOS by troglitazone was inhibited by MG-132, a specific inhibitor of inhibitory factor kappaB (IkappaB) activation. Troglitazone treatment of these cells also resulted in a dose-dependent increase in IL-1beta induced IkappaBalpha phosphorylation. These data suggest that troglitazone is capable of increasing IL-1beta induced COX-2 and iNOS expression through an IkappaBalpha dependent mechanism in VSMC from WKY and SHR.
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PMID:Troglitazone increases IL-1beta induced cyclooxygenase-2 and inducible nitric oxide synthase expression via enhanced phosphorylation of IkappaBalpha in vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats. 1882 62


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