Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC)-induced changes in glomerular mesangial cell (MC) phenotypic behavior has been implicated in diabetes. The activity of diacylglycerol-sensitive PKC isoforms in MCs is altered by ambient changes in glucose, but the regulation of PKC activity and subsequent intracellular signaling events are not yet clearly defined. Small GTP-binding proteins of the ADP-ribosylation factor (Arfs) family, may regulate protein kinase membrane recruitment and hence its activity in signaling events of non-polarized cells. Members of the ARF family may coordinate membrane dynamics and other cellular functions through their interaction with PKC. We studied the activation of Arf, PKC betaI and phospholipase D (PLD) in MCs cultured under normal or high glucose conditions. MCs cultured in high glucose medium exhibited predominantly cytosolic localization of PKC betaI, Arf3 and Arf6. However, phorbol ester (PMA) stimulation of cells cultured in high glucose significantly enhanced membrane association of PKC betaI and Arf6, but not Arf3. Using [3H]choline chloride to prelabel MCs and measuring [3H]choline-containing metabolite release as PLD activity, PMA stimulated a significant increase of PLD activity under high glucose condition. Our data suggest that Arf6 plays a specific role in activation of PKC betaI and PLD under high glucose condition, and may be a significant intracellular event in the change of the mesangial cell phenotype associated with diabetic nephropathy.
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PMID:High glucose-induced membrane translocation of PKC betaI is associated with Arf6 in glomerular mesangial cells. 1503 Jan 77

Acute and chronic effects of the insulinotropic drug nateglinide upon insulin release were examined in the BRIN-BD11 cell line. Nateglinide (10-400 microm) stimulated a concentration-dependent increase (P<0.05-P<0.001) in insulin release at a non-stimulatory (1.1 mm) glucose concentration. The insulinotropic response to 200 microm nateglinide was increased at 30 mm (P<0.01), but not 5.6-16.7 mm glucose concentrations. In depolarized cells, nateglinide (50-200 microm) evoked K(ATP) channel-independent insulin secretion (P<0.05-P<0.001) in the absence and presence of 5.6-30.0 mm glucose (P<0.001). Exposure for 18 h to 100 microm nateglinide abolished the acute insulinotropic effects of 200 microm nateglinide, tolbutamide or glibenclamide, but had no effect upon the insulinotropic effect of 200 microm efaroxan. While 18 h exposure to 100 microm nateglinide did not affect basal insulin release or insulin release in the presence of 16.7 mm glucose, 25 microm forskolin or 10 nm PMA, significant inhibition of the insulinotropic effects of 20 mm leucine and 20 mm arginine were observed. These data show that nateglinide stimulates both K(ATP) channel-dependent and-independent insulin secretion. The maintained insulinotropic effects of this drug with increasing glucose concentrations support the antihyperglycaemic actions of nateglinide in Type II diabetes. Studies of the long-term effects of nateglinide indicate that nateglinide shares signalling pathways with sulphonylureas, but not the imidazoline efaroxan. This may be significant when considering a nateglinide treatment regimen, particularly in patients previously treated with sulphonylurea.
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PMID:Acute and long-term effects of nateglinide on insulin secretory pathways. 1515 41

Mesangial cells (MG) are an important source of renal PGE2 and PGI2. The purpose of this study was to examine the effects of cicaprost (CCP; PGI2 analog) on MG function and the expression of IP receptors in streptozotocin (STZ)-diabetic rats and glucose-treated MG cells. CCP increased cellular cAMP in immortalized rat MG cells. Both glucose and anisomycin attenuated CCP-cAMP, but not PMA, angiotensin II, or transforming growth factor-beta. Also, IP receptor protein was reduced in response to glucose. While CCP decreased the levels of the cell cycle inhibitor p27, it did not alter thymidine or leucine incorporation. However, CCP reduced fibronectin levels by 40% and increased matrix metalloproteinase-2 levels threefold, a key enzyme in matrix degradation. Finally, IP receptors were significantly reduced in the outer medulla of 4- and 12-wk STZ-diabetic rats and in the cortex, outer, and inner medullary regions in 6-mo uninephrectomized STZ-diabetic rats. The changes in the CCP/IP system observed in this study suggest that IP may serve as an alternate therapeutic target in diabetes.
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PMID:Reduced IP receptors in STZ-induced diabetic rat kidneys and high-glucose-treated mesangial cells. 1516 1

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and inhibits food intake, gastric emptying, and glucagon secretion, actions that promote reduction of fasting and postprandial glycemia in subjects with type 2 diabetes. The rapid degradation of native GLP-1 has engendered interest in more stable longer-acting GLP-1 receptor agonists such as exendin-4 (Ex-4); however, the potential consequences of sustained GLP-1 receptor activation leading to receptor desensitization has not been extensively studied. We have now examined a range of GLP-1 receptor-dependent responses following treatment with Ex-4 using INS-1 cells in vitro and both wild-type control and MT-Ex-4 transgenic mice in vivo. Although both GLP-1 and Ex-4 acutely desensitized GLP-1 receptor-dependent cAMP accumulation in INS-1 cells, Ex-4 produced more sustained receptor desensitization, relative to GLP-1, in both acute (5-120 min) and chronic (24-72 h) experiments. PMA (4-phorbol 12-myristate 13-acetate) but not glucagon, glucose-dependent insulinotropic polypeptide (GIP), or epinephrine produced heterologous desensitization in vitro. MT-Ex-4 transgenic mice exhibited a reduced glycemic response to oral but not intraperitoneal glucose challenge following acute Ex-4 administration. In contrast, no differences in glycemic excursion or plasma insulin were observed after 1 week of twice-daily Ex-4 administration to wild-type versus MT-Ex-4 mice. Similarly, the levels of insulin, pdx-1, and GLP-1 receptor mRNA transcripts were comparable in wild-type and MT-Ex-4 transgenic mice after 1 week of Ex-4 administration. However, repeated Ex-4 administration significantly reduced food intake in MT-Ex-4 but not in wild-type mice. These findings illustrate that although Ex-4 is more potent than native GLP-1 in producing GLP-1 receptor desensitization in vitro, chronic exposure to Ex-4 in normal or transgenic mice is not associated with significant downregulation of GLP-1 receptor-dependent responses coupled to glucose homeostasis in vivo.
Diabetes 2004 Dec
PMID:Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo. 1556 12

Obese people are at high risk for developing diabetes, dyslipidemia, hypertension, and cardiovascular diseases, which lead to an increased risk of mortality. Activated polymorphonuclear neutrophils (PMN) generate extremely high amounts of reactive oxygen species (ROS), but these are normally targeted at pathogens inside intracellular phagosomes. These same beneficial antimicrobial functions can cause significant local tissue injury and lead to the development of pathologic systemic inflammatory conditions. PMN apoptosis is a major mechanism associated with the resolution of inflammatory reactions. The goals of the present study were: 1) to evaluate the level of reactive oxygen species production in PMN from obese people before and during body mass reduction, 2) to investigate the in vitro effect of flavonoids: quercetin and rutin on oxidative metabolism and apoptosis of stimulated neutrophils in obese patient. We tested 30 obese patients (women) before body mass reduction and 20 patients during low calories diet. The inclusion criteria were based on physical examination, BMI, WHR, the body composition examination based on bioimpedance method and biochemical assessment. PMN were isolated and oxidant production, in response to 1 microg/ml PMA, was characterised by the production of hydrogen peroxide, nitric oxide and chemiluminescence intensity. Caspase-3 activation was assayed by the method of DEVD-AMC cleavage in PMN cultured up to 24 hours. The results of our study showed: 1) the decrease in PMN oxidant production in patient during the mass reduction, 2) the strong antioxidant activity of quercetin and rutin in obese patients before and during the body mass reduction, these effects were dose dependent and rutin was less potent than quercetin, 3) acceleration of PMN apoptosis by rutin is associated with an increase in caspase 3 activity.
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PMID:[Oxidative metabolism of neutrophils in obese patients before and during body mass reduction: the in vitro effect of quercetin and rutin]. 1612 80

Dopamine, via activation of D1-like receptors, inhibits Na,K-ATPase and Na,H-exchanger in renal proximal tubules and promotes sodium excretion. This effect of dopamine is not seen in conditions associated with oxidative stress such as hypertension, diabetes, and aging due to uncoupling of D1-like receptors from G proteins. To identify the role of oxidative stress in uncoupling of the D1-like receptors, we utilized primary cultures from rat renal proximal tubules. Hydrogen peroxide (H2O2), an oxidant, treatment to the cell cultures increased the level of malondialdehyde, a marker of oxidative damage. Further, H2O2 decreased membranous D1-like receptor numbers and proteins, D1-like agonist (SKF 38393)-mediated [35S]GTPgammaS binding and SKF 38393-mediated inhibition of Na,K-ATPase. Moreover, H2O2 treatment to the cultures caused membranous translocation of G-protein-coupled receptor kinase 2 (GRK 2) and increased serine phosphorylation of D1A receptors accompanied by an increase in protein kinase C (PKC) activity. Interestingly, PKC inhibitors blocked the H2O2-mediated stimulation of GRK 2 and serine phosphorylation of D1A receptors. Further, GRK 2 antisense but not scrambled oligonucleotides attenuated the effect of H2O2 on membranous expression of GRK 2. Moreover, direct activation of PKC with phorbol ester (PMA) resulted in reduction of SKF 38393-mediated [35S]GTPgammaS binding. We conclude that H2O2 stimulates PKC leading to the activation of GRK 2, which causes serine phopshorylation of D1A receptors and receptor G-protein uncoupling in these cells, resulting in impairment in D1-like receptor function.
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PMID:Hydrogen peroxide causes uncoupling of dopamine D1-like receptors from G proteins via a mechanism involving protein kinase C and G-protein-coupled receptor kinase 2. 1633 75

Oxidative stress plays a major role in the pathogenesis and in the onset of macrovascular complications of diabetes. We previously reported that the antihyperglycaemic drug metformin was able to decrease significantly intracellular reactive oxygen species (ROS) production of bovine aortic endothelial cells (BAEC) activated by high levels of glucose and angiotensin II (ANG). The aim of the present study was to investigate whether the antioxidant effect of metformin on BAEC could be mediated through a modulation of protein kinase C (PKC) activity, which plays a key role in the pathophysiology of diabetes. The effects of metformin on intracellular ROS production, PKC translocation and activity were studied on endothelial cells stimulated by PMA (a direct PKC activator), ANG or high levels of glucose as pathophysiological stimuli of endothelial dysfunction in diabetes. We showed that metformin decreased ROS production on PMA-, ANG- and glucose-stimulated BAEC in a similar manner to that obtained by PKC specific inhibitors (calphostin C, chelerythrine) alone. On the other hand, metformin reduced both PKC membrane translocation and kinase activity in ANG-stimulated cells. In PMA-activated cells, metformin reduced membrane PKC activity but we did not observe any alteration of PKC membrane translocation. Finally, in vitro incubation with purified PKC indicated that metformin had no direct effect on PKC activity. Taken together, our results suggest that metformin exerted intracellular antioxidant properties by decreasing ROS production through the inhibition of PKC activity.
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PMID:Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase C. 1673 Jun 66

The predisposition to infection and chronic inflammation in diabetes may in part be related to the effects of hyperglycemia or other metabolic abnormality on polymorphonuclear leukocytes (PMN). We evaluated oxidative respiratory burst activity (superoxide production) in non-stimulated and stimulated PMN from 70 stable type 2 Hispanic diabetic patients, as compared to 70 healthy Hispanic individuals without diabetes. The influences of protein kinase C (PKC) inhibitors and certain antibiotics on superoxide production were examined. Both resting and stimulated (PMA, zymosan) PMN from diabetic individuals produced more superoxide than PMN from controls. Inhibitors of PKC, a possible mediator of the augmented respiratory burst activity, decreased superoxide production in all (resting and stimulated) diabetic and control PMN. Azithromycin, which is markedly concentrated by PMN, profoundly inhibited superoxide generation in all groups of diabetic and control cells. PMN from Hispanic diabetic patients produced greater quantities of superoxide than non-diabetic controls. This increased oxidative respiratory burst activity may predispose to infection and chronic inflammation in diabetes. PKC inhibitors and azithromycin inhibited this respiratory burst response. The possible role of PKC (especially PKC beta) as the mediator of this augmented respiratory burst response requires further evaluation, and may lead to therapeutic studies with appropriate inhibitors.
Diabetes Res Clin Pract 2007 Apr
PMID:Increased polymorphonuclear leukocyte respiratory burst function in type 2 diabetes. 1695 66

Vanadium(IV) oxo-bis(maltolato) (BMOV), an organovanadium compound, is a potent insulinomimetic agent and improves glucose homeostasis in various models of diabetes. We have shown previously that BMOV stimulates the phosphorylation of PKB which may contribute as one of the mechanisms for the insulinomimetic effect of this compound. However, the upstream mechanism of BMOV-induced PKB phosphorylation remains elusive. Therefore, in this study, we examine the upstream events leading to BMOV-induced PKB phosphorylation in HepG2 cells. Since BMOV is an inhibitor of protein tyrosine phosphatases and through enhanced tyrosine phosphorylation may activate various protein tyrosine kinases (PTK), we have investigated the potential role of different receptor or nonreceptor PTK in mediating BMOV-induced PKB phosphorylation. Among several pharmacological inhibitors that were tested, only AG1024, a selective inhibitor of IGF-1R-PTK, almost completely blocked BMOV-stimulated phosphorylation of PKB. In contrast, AG1295 and AG1478, specific inhibitors of PDGFR and EGFR, respectively, were unable to block the BMOV response. Moreover, efficient reduction of the level of IGF-1R protein expression by antisense oligonucleotides (ASO) attenuated BMOV-induced PKB phosphorylation. BMOV-induced PKB phosphorylation was associated with an increased level of tyrosine phosphorylation of the IRbeta subunit, IGF-1Rbeta subunit, IRS-1, and p85alpha subunit of PI3-kinase. However, this response was independent of IR-PTK activity because in cells overexpressing a PTK-inactive form of IR, insulin response was attenuated while the effect of BMOV remained intact. A role of PKC in BMOV-induced response was also tested. Pharmacological inhibition with chelerythrine, a nonselective PKC inhibitor, or rottlerin, a PKCdelta inhibitor, as well as chronic treatment with PMA attenuated BMOV-induced PKB phosphorylation. In contrast, GO6976 and RO31-8220 PKCalpha/beta selective inhibitors failed to alter the BMOV effect. Taken together, these data suggest that IGF-1R and PKCdelta are required to stimulate PKB phosphorylation in response to BMOV in HepG2 cells and provide new insights into the molecular mechanism by which this compound exerts its insulinomimetic effects.
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PMID:Involvement of insulin-like growth factor type 1 receptor and protein kinase Cdelta in bis(maltolato)oxovanadium(IV)-induced phosphorylation of protein kinase B in HepG2 cells. 1698 20

We evaluated the role of oxidative stress in diabetic nephropathy by measuring intracellular reactive oxygen species (ROS) and redox-sensitive transcription factors in isolated peripheral mononuclear cells (PBMC) in 66 diabetic patients with or without diabetic nephropathy (Groups III and II, respectively) and 49 normal controls (Group I). Stimulated ROS was significantly higher in Group III compared to Group II (increment of H(2)O(2)-induced ROS production: 21.8+/-2.2% vs. 11.1+/-2.0%; increment of PMA-induced ROS production 23.5+/-4.5% vs. 21.6+/-2.2%; both respectively), and the activity of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1), but not specificity protein 1 (Sp1) was significantly higher in Group III than in Group II (2.53-fold vs. 2.0-fold vs. 1.43-fold, respectively). Both PBMC- and urinary TGF-beta1 levels were higher in Group III than Group II (3.23+/-0.39 ng/g vs. 1.99+/-0.68 ng/g in PBMCs, 16.88+/-6.84 (ng/g Cr) vs. 5.61+/-1.57 (ng/g Cr) in urine, both respectively), and they correlated with the activity of NF-kappaB and AP-1 and 24-h urine albumin excretion (UAE). Increased intracellular ROS generation in PBMCs of diabetic patients is involved in the pathogenesis of diabetic nephropathy via activation NF-kappaB and AP-1 and an increased expression of TGF-beta1.
Diabetes Res Clin Pract 2008 Jul
PMID:The activation of NF-kappaB and AP-1 in peripheral blood mononuclear cells isolated from patients with diabetic nephropathy. 1848 15


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