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)

1. Calcium/calmodulin-dependent protein kinase II (CaMKII) has an important function in mediating insulin release but its role in the development of diabetes-induced cardiovascular complications is not known. 2. We investigated the ability of a chronic administration of KN-93 (5 mg kg(-1) alt diem for 4 weeks), an inhibitor of CaMKII, to modulate the altered vasoreactivity of the perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes. 3. The vasoconstrictor responses induced by noradrenaline (NE), endothelin-1 (ET-1), and angiotensin II (Ang II), were significantly increased whereas, vasodilator responses to carbachol and histamine were significantly reduced in the perfused mesenteric bed of the STZ-diabetic rats as compared with non-diabetic controls. 4. Inhibition of CaMKII by KN-93 treatment did not affect blood glucose levels but produced a significant normalization of the altered agonist-induced vasoconstrictor and vasodilator responses. KN-93 did not affect agonist-induced responses in control animals. In addition, KN-93 significantly reduced weight loss in diabetic rats. 5. The present data suggest that CaMKII is an essential mediator in the development of diabetic vascular dysfunction and may also play an important role in signalling pathways leading to weight loss during diabetes.
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PMID:Inhibition of calcium/calmodulin-dependent protein kinase II normalizes diabetes-induced abnormal vascular reactivity in the rat perfused mesenteric vascular bed. 1456 35

Our initial studies on renal cyclooxygenase (COX)-2 expression and activity addressed the critical role of angiotensin II (Ang II) in increasing tumor necrosis factor alpha (TNF) that eventuated in expression of COX-2 in the medullary thick ascending limb (mTAL) of the nephron. COX-2 supplanted the dominant oxygenase, the cytochrome P450 (CYP) enzyme, omega-hydroxylase, that synthesized 20-hydroxyeicosatetraenoic acid (20-HETE). These findings served as the basis for additional studies on: 1) the role of glucocorticoids in regulating COX-2 expression and activity in the mTAL; and 2) the utilization of the same signaling pathways in response to stimulation of the mTAL calcium receptor (CaR). These studies of mTAL COX-2 expression which are addressed in the first part of this chapter are followed by explorations of the expression of COX-2 in preglomerular microvessels (PGMV) and the relationship of COX-2 to 20-HETE, the principal eicosanoid of PGMV. The third and last component of this chapter explores the signaling events, focusing on COX-2, which are set in motion by diabetes.
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PMID:Renal COX-2, cytokines and 20-HETE: tubular and vascular mechanisms. 1496 24

Recent evidence points to the renin-angiotensin system (RAS) as one of the systems involved in the etiology of micro- and macrovascular disease in diabetic patients. To help elucidate this possibility, the effect of daily treatment with enalapril (25 mg/kg/d) was evaluated in streptozotocin (STZ)-diabetic rats at 2 weeks following the induction of diabetes. Untreated diabetic rats and non-diabetic rats that were age-matched were used for comparison. Vascular studies included the determination of aortic ring responses to norepinephrine (NE), angiotensin II (Ang II) and acetylcholine (Ach). Systolic blood pressure (SBP), cardiac output (CO) indices, plasmatic and vascular angiotensin-converting enzyme (ACE) activity and thickness of the aortic wall were also assessed. Enalapril improved Ach-induced relaxation by increasing the maximal relaxation from 54.3 +/- 4.3% in untreated diabetic rats to 89.8 +/- 6.2% (n=9, p<0.05) and by decreasing the EC50 value from 32.6 +/- 9.9 nmol/l in untreated diabetic animals to 17.9 +/- 5.1 nmol/l (n=8, p<0.05). In addition, enalapril normalized the high responses to NE found in diabetic rats without inducing changes in the EC50 value. A significant reduction in SBP (from 158 +/- 4 mm Hg to 123 +/- 1 mm Hg, p<0.05), combined with an improved CO index (from 40 +/- 2 ml/min x 100 g BW to 50 +/- 1 ml/min x 100 g BW), was observed in the enalapril-treated diabetic group. A significant regression of the media thickness was also observed in the aorta of diabetic rats after treatment. ACE activity in the aorta of diabetic rats, that was doubled compared to controls (p<0.05), decreased after enalapril treatment. These results point to the vascular RAS as one of the key systems in the etiology of vascular alterations at early stages of diabetes. Therefore, ACE inhibitors, as well as other pharmacological approaches targeting the vascular RAS, should be considered in the treatment of diabetic patients from the very early stages of the condition.
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PMID:Enalapril improves vascular and cardiac function in streptozotocin-diabetic rats. 1498 3

Recent data indicate that the oxidative stress plays an important role in the pathogenesis of diabetes and its complications such as retinopathy, nephropathy and accelerated atherosclerosis. In diabetic retinopathy, it was demonstrated a selective loss of pericytes accompanied by capillary basement membrane thickening, increased permeability and neovascularization. This study was designed to investigate the role of diabetic conditions such as high glucose, AGE-Lysine, and angiotensin II in the modulation of antioxidant enzymes activities, glutathione level and reactive oxygen species (ROS) production in pericytes. The activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) was measured spectrophotometrically. The production of ROS was detected by spectrofluorimetry and fluorescence microscopy after loading the cells with 2'-7' dichlorofluoresceine diacetate; as positive control H2O2 was used. Intracellular calcium was determined using Fura 2 AM assay. The results showed that the cells cultured in high glucose alone, do not exhibit major changes in the antioxidant enzyme activities. The presence of AGE-Lys or Ang II induced the increase of SOD activity. Their combination decreased significantly GPx activity and GSH level. A three times increase in ROS production and a significant impairment of intracellular calcium homeostasis was detected in cells cultured in the presence of the three pro-diabetic agents used. In conclusion, our data indicate that diabetic conditions induce in pericytes: (i) an increase of ROS and SOD activity, (ii) a decrease in GPx activity and GSH level, (iii) a major perturbation of the intracellular calcium homeostasis. The data may explain the structural and functional abnormalities of pericytes characteristic for diabetic retinopathy.
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PMID:Changes in oxidative balance in rat pericytes exposed to diabetic conditions. 1509 Feb 67

Although the importance of protein tyrosine phosphorylation by tyrosine kinases in mitogenic signaling is well-accepted, recent studies also suggest that tyrosine dephosphorylation by protein tyrosine phosphatases (PTPases) play an equally important role. For example, both angiotensin II (Ang II) and insulin are known to mediate protein tyrosine phosphorylation and dephosphorylation events. These apparently paradoxical effects of Ang II and insulin suggest that both convergent and divergent intracellular signaling cascades are stimulated downstream of their respective receptors, producing diverse cellular responses. In this review, we discuss the hypothesis that the protein tyrosine phosphatase (PTPase), PTP-1B, plays a central role in Ang II-induced insulin resistance by inhibiting activation of the insulin receptor. We hypothesize that Ang II-induced PTP-1B activation leads to dephosphorylation of the insulin receptor and that this signaling pathway underlies the maladaptive responses observed in diabetic vascular and renal tissue during type II diabetes.
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PMID:Angiotensin II-induced insulin resistance and protein tyrosine phosphatases. 1527 87

Diseases such as hypertension, atherosclerosis, hyperlipidemia, and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many factors influence cellular changes, of which angiotensin II (Ang II) appears to be amongst the most important. The physiological and pathophysiological actions of Ang II are mediated primarily via the Ang II type 1 receptor. Growing evidence indicates that Ang II induces its pleiotropic vascular effects through NADPH-driven generation of reactive oxygen species (ROS). ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, regulation of endothelial function, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca2+ concentration ([Ca2+]i), a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, these events play an important role in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review focuses on the biology of ROS in Ang II signaling in vascular cells and discusses how oxidative stress contributes to vascular damage in cardiovascular disease.
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PMID:Reactive oxygen species and angiotensin II signaling in vascular cells -- implications in cardiovascular disease. 1527 29

Obesity and insulin resistance confer increased risk for accelerated coronary disease and cardiomyopathic phenomena. We have previously shown that inhibition of angiotensin-converting enzyme (ACE) prevents coronary perimicrovascular fibrosis in genetically obese mice that develop insulin resistance. This study was performed to elucidate mechanism(s) implicated and to determine the effects of attenuation of angiotensin II (Ang) II. Genetically obese ob/ob mice were given ACE inhibitor (temocapril) or Ang II type 1 (AT(1)) receptor blocker (olmesartan) from 10 to 20 weeks. Cardiac expressions of plasminogen activator inhibitor (PAI)-1, the major physiologic inhibitor of fibrinolysis, and transforming growth factor (TGF)-beta(1), a prototypic profibrotic molecule, were determined and extent of perivascular coronary fibrosis was measured. Twenty-week-old obese mice exhibited increased plasma levels of PAI-1 and TGF-beta(1) compared with the values in lean counterpart. Perivascular coronary fibrosis in arterioles and small arteries was evident in obese mice that also showed increased left ventricular collagen as measured by hydroxyproline assay. Immunohistochemistry confirmed the deposition of perivascular type 1 collagen. Markedly increased PAI-1 and TGF-beta were seen immunohistochemically in coronary vascular wall and confirmed by western blotting. When obese mice were treated with temocapril or olmesartan from 10 to 20 weeks, both were equally effective and prevented increases in perivascular fibrosis, plasma PAI-1 and TGF-beta(1), left ventricular collagen and mural immunoreactivity for PAI-1, TGF-beta and collagen type 1. The c-Jun NH(2)-terminal kinase (JNK) activity was elevated in the left ventricle of obese mice (western) and blocked by temocapril and olmesartan. Ang II-mediated upregulation of PAI-1 and TGF-beta(1) with collagen deposition may explain the mechanism of perivascular fibrosis in obese mice. ACE inhibition and blockade of AT(1) receptor may prevent coronary perivascular fibrosis and collagen deposition even before development of overt diabetes. JNK activation may be a mediator of obesity-related cardiac dysfunction and a potential therapeutic target.
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PMID:Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. 1527 22

Hyperglycemia was reported to enhance angiotensin (Ang) II generation in rat cardiomyocytes, and Ang II inhibition reduces cardiovascular morbidity and mortality in diabetic patients. In diabetic patients, the enhanced activation of intracellular pathways related with myocyte hypertrophy and gene expression might enhance the progression of cardiac damage. Therefore, we investigated the effects of glucose on Ang II-mediated activation of Janus-activated kinase (JAK)-2, a tyrosine kinase related with myocyte hypertrophy and cytokine and fibrogenetic growth factor overexpression, in ventricular myocytes isolated from nonfailing human hearts (n = 5) and failing human hearts (n = 8). In nonfailing myocytes, JAK2 phosphorylation was enhanced by Ang II only in the presence of high glucose (25 mmol/l) via Ang II type I (AT1) receptors (+79% vs. normal glucose, P < 0.05). JAK2 activation was prevented by inhibitors of reactive oxygen species (ROS) generation (diphenyleneiodonium [DPI], tiron, and apocynin). In myocytes isolated from failing hearts, JAK2 phosphorylation was enhanced by high glucose alone (+107%, P < 0.05). High glucose-induced JAK2 activation was blunted by both ACE inhibition (100 nmol/l ramipril) and AT1 antagonism (1 mumol/l valsartan), thus revealing that the effects are mediated by autocrine Ang II production. Inhibition of ROS generation also prevented high glucose-induced JAK2 phosphorylation. In conclusion, in human nonfailing myocytes, high glucose allows Ang II to activate JAK2 signaling, whereas in failing myocytes, hyperglycemia alone is able to induce Ang II generation, which in turn activates JAK2 via enhanced oxidative stress.
Diabetes 2005 Feb
PMID:Hyperglycemia activates JAK2 signaling pathway in human failing myocytes via angiotensin II-mediated oxidative stress. 1567 97

1 G-protein-coupled receptor signalling, including transactivation of receptor tyrosine kinases (RTKs), has been implicated in vascular pathology. However, the role of specific RTKs in the development of diabetes-induced cardiovascular complications is not known. 2 We investigated the ability of a chronic administration of genistein, a broad-spectrum inhibitor of tyrosine kinases (TKs), AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) TK activity, and AG825, a specific inhibitor of Erb2, to modulate the altered vasoreactivity of isolated carotid artery ring segments to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes. 3 In diabetic carotid artery, the vasoconstrictor responses induced by noradrenaline (NE), endothelin-1 (ET-1), and angiotensin II (Ang II), were significantly increased whereas vasodilator responses to carbachol and histamine were significantly reduced. Inhibition of TKs, EGFR or Erb2 pathway did not affect the body weight or agonist-induced vasoconstrictor and vasodilator responses in the non-diabetic control animals. However, inhibition of TKs by genistein, EGFR TK by AG1478 or Erb2 by AG825 treatment produced a significant normalization of the altered agonist-induced vasoconstrictor responses without affecting blood glucose levels. Treatment with diadzein, an inactive analogue of genistein, did not affect the vasoconstrictor and vasodilator responses in the diabetic animals. 4 Treatment with genistein, AG1478 or AG825 resulted in a significant improvement in diabetes-induced impairment in endothelium-dependent relaxation to carbachol and histamine. 5 These data suggest that activation of TK-mediated pathways, including EGFR TK signalling and Erb2 pathway, are involved in the development of diabetic vascular dysfunction in the carotid artery.
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PMID:The role of tyrosine kinase-mediated pathways in diabetes-induced alterations in responsiveness of rat carotid artery. 1575 6

The renin-angiotensin system with its active metabolite angiotensin (Ang) II has been related not only to hypertension but also to obesity and insulin resistance. Recent evidence obtained in vitro suggests that the type 2 Ang II receptor (AT2R) mediates the trophic action of Ang II on adipocyte differentiation and lipogenesis. We used AT2R(y/-) mice to delineate a potential role of AT2R in adipose tissue development and metabolism. AT2R(y/-) mice had a normal adiposity but displayed a striking adipose tissue phenotype characterized by small adipocytes and an increase in cell number. In muscle, the expression of several genes involved in lipid metabolism, including fatty acid translocase, uncoupling protein-3, peroxisome proliferator-activated receptors (alpha, delta), and carnitine palmitoyl transferase-1, was increased in AT2R-deficient mice. In response to high-fat feeding, these mice were protected against obesity and obesity-related glucose intolerance, as assessed by glucose tolerance tests. Moreover, lipid oxidation assessed by indirect calorimetry was higher in AT2R-deficient mice than in wild-type mice, irrespective of the diet. This suggests that AT2R-dependent signaling exerts a direct or indirect negative control on lipid utilization in muscles. These data support the idea that AT2R-dependent Ang II signaling increases adipose cell mass and glucose intolerance and thus could participate to the deleterious effects of a high-fat diet.
Diabetes 2005 Apr
PMID:Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance. 1579 37


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