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

The metabolic syndrome (MS) is a common risk factor for cardiovascular disease and type-2 diabetes. Recently, telmisartan, an angiotensin II receptor antagonist that has an antihypertensive effect, has been reported to be a partial peroxisome proliferator-activated receptor gamma (PPARgamma) agonist. The anti-diabetic hormone adiponectin has been recognized as a marker of in vivo PPARgamma activation. Therefore, we studied telmisartan's effect on the metabolic profile and adiponectin levels in a fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rat model. Twenty-four male Sprague-Dawley rats were divided into three groups (eight in each). One group of control rats was fed standard chow for 5 weeks while a second was fed a fructose-enriched diet. A third group was fed a fructose-enriched diet for 5 weeks and treated with telmisartan 5 mg/kg/day during the last 2 weeks. Fructose feeding increased systolic blood pressure (mean+/-SEM), from 130+/-1 to 148+/-2 mmHg, insulin from 0.26+/-0.03 to 0.68+/-0.08 ng/mL, and triglycerides from 102+/-6 to 285+/-23 mg/dL (p<0.05 for all variables). Telmisartan treatment reversed these effects and reduced blood pressure to 125+/-2 mmHg, insulin levels to 0.41+/-0.07 ng/mL, and triglycerides to 146+/-18 mg/dL (p<0.05 for all variables), while attenuating the increase in body weight during weeks 3 to 5. In contrast, telmisartan did not affect plasma adiponectin levels. In conclusion, although telmisartan is considered a partial PPARgamma agonist, its beneficial effect in the fructose-induced hypertension, hypertriglyceridemia, and hyperinsulinemia rat model is apparently not mediated by adiponectin elevation but rather by direct inhibition of AT1 receptor.
 ...
PMID:Effect of telmisartan, angiotensin II receptor antagonist, on metabolic profile in fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rats. 1836 28

Several enzymatic sources of reactive oxygen species (ROS) were described as potential reasons of eNOS uncoupling in diabetes mellitus. In the present study, we investigated the effects of AT1-receptor blockade with chronic telmisartan (25 mg/kg/day, 6.5 weeks) therapy on expression of the BH4-synthesizing enzyme GTP-cyclohydrolase I (GCH-I), eNOS uncoupling, and endothelial dysfunction in streptozotocin (STZ, 60 mg/kg iv, 7 weeks)-induced diabetes mellitus (type I). Telmisartan therapy did not modify blood glucose and body weight. Aortas from diabetic animals had vascular dysfunction as revealed by isometric tension studies (acetylcholine and nitroglycerin potency). Vascular and cardiac ROS produced by NADPH oxidase, mitochondria, eNOS, and xanthine oxidase were increased in the diabetic group as was the expression of NADPH oxidase subunits at the protein level. The expression of GCH-I and the phosphorylation of eNOS at Ser1177 was decreased by STZ treatment. Therapy with telmisartan normalized these parameters. The present study demonstrates for the first time that AT1-receptor blockade by telmisartan prevents downregulation of the BH4 synthase GCH-I and thereby eNOS uncoupling in experimental diabetes. In addition, telmisartan inhibits activation of superoxide sources like NADPH oxidase, mitochondria, and xanthine oxidase. These effects may explain the beneficial effects of telmisartan on endothelial dysfunction in diabetes.
 ...
PMID:AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. 1853 57

The blockade of the renin-angiotensin-aldosterone system (RAAS) has been shown to be useful, or even mandatory, in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and nephropathy with albuminuria, due to diabetes or not. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors and/or recently a direct inhibitor of renin such as aliskiren. Various studies have demonstrated the advantage of optimising RAAS blockade in order to benefit of the best cardiorenal protection. The present article describes the various modalities to optimize the RAAS blockade, either by using a maximal dosage of a monotherapy, or by choosing a double inhibition of RAAS. New prospects for the RAAS blockade will be also briefly considered.
 ...
PMID:[How I treat... by optimizing the blockade of the renin-angiotensin-aldosterone system]. 1857 70

Reactive oxygen species have emerged as important molecules in cardiovascular dysfunction such as diabetes and hypertension. Recent work has shown that oxidative stress and angiotensin II signaling mutually regulate each other by multiple mechanisms and contribute to the development of hypertension. Most of the known biological actions of angiotensin II can be attributed to AT1 receptors. The present study was carried out to investigate the role of renal AT1 receptor signaling in oxidative stress-mediated hypertension. Male Sprague-Dawley rats received tap water (control) or 30 mM L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mM tempol (an antioxidant) for 2 wk. Compared with control rats, BSO-treated rats exhibited increased oxidative stress and reduced antioxidant levels and developed hypertension. BSO treatment also caused increased renal proximal tubular AT1 receptor protein abundance, message levels, and ligand binding. In these rats, angiotensin II caused significantly higher accumulation of inositol trisphosphate (IP3) and phospholipase C (PLC) activation which was sensitive to blockade by AT1 but not to AT2 antagonist. Also, angiotensin II-mediated, AT1-dependent MAP kinase, Na-K-ATPase, and Na/H exchanger 3 activation was higher in BSO-treated rats than in control rats. Tempol supplementation of BSO-treated rats restored redox status, normalized AT1 receptor expression, and decreased blood pressure. Tempol also normalized the angiotensin II-mediated, AT1-dependent IP3 accumulation and PLC, MAP kinase, Na-K-ATPase, and Na/H exchanger 3 stimulation. These data suggest that oxidative stress leads to AT1 receptor upregulation, which in turn causes overstimulation of sodium transporters and subsequently contributes to sodium retention and hypertension. Tempol, while reducing oxidative stress, normalizes AT1 receptor signaling and decreases blood pressure.
 ...
PMID:Oxidative stress-induced renal angiotensin AT1 receptor upregulation causes increased stimulation of sodium transporters and hypertension. 1861 17

The correlations co-exist among diabetes mellitus, hypertension and the kidney. Renal injury will develop in 35% type 1 and type 2 diabetes mellitus patients. Diabetic nephropathy is the key factor for the occurence of hypertension in type 1 diabetes mellitus. In case of type 2 diabetes mellitus with prevalent essencial hypertension the diabetic nephropathy is supporting factor for the development of hypertension. Untreated or inadequately treated hypertension accelerates the progression of diabetic renal impairment. The presence of diabetes mellitus as well as hypertension or proteinuria is significant cardiovascular risk factor. The goal of treatment with angiotensin converting enzyme inhibitors or AT1 receptor of angiotensin II blockers is both slowing-down of renal injury progression and reduction in risk of cardiovascular complications.
 ...
PMID:[Diabetes mellitus, hypertension and kidney]. 1863 Jun 36

The renin-angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We have shown that vitamin D exerts renoprotective actions by transcriptionally suppressing renin. Here we demonstrated that combination therapy with an AT1 receptor blocker and a vitamin D analog markedly ameliorated renal injury in the streptozotocin (STZ)-induced diabetes model due to the blockade of the compensatory renin rise by the vitamin D analog, leading to more effective RAS inhibition. STZ-treated diabetic DBA/2J mice developed progressive albuminuria and glomerulosclerosis within 13 weeks, accompanied by increased intrarenal production of angiotensin (Ang) II, fibronection, TGF-beta, and MCP-1 and decreased expression of slit diaphragm proteins. Treatment of the diabetic mice with losartan or paricalcitol (19-nor-1,25-dihydroxyvitamin D(2), an activated vitamin D analog) alone moderately ameliorated kidney injury; however, combined treatment with losartan and paricalcitol completely prevented albuminuria, restored glomerular filtration barrier structure, and markedly reduced glomerulosclerosis. The combined treatment suppressed the induction of fibronection, TGF-beta, and MCP-1 and reversed the decline of slit diaphragm proteins nephrin, Neph-1, ZO-1, and alpha-actinin-4. These were accompanied by blockade of intrarenal renin and Ang II accumulation induced by hyperglycemia and losartan. These data demonstrate that inhibition of the RAS with combination of vitamin D analogs and RAS inhibitors effectively prevents renal injury in diabetic nephropathy.
 ...
PMID:Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. 1883 78

Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulin-induced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin II-aldosterone systems and their role in glucose metabolism and diabetes prevention.
 ...
PMID:The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. 1885 18

The aim of this study was designed to investigate the possible beneficial effects of the angiotensin-converting enzyme (ACE) inhibitor, Quinapril (Q) and, the angiotensin (ang) II T(1) (AT1) receptor blocker, irbesartan (Irb), in streptozotocin (STZ)-induced diabetes in rats. The rats were randomly allotted into one of five experimental groups: A (control), B (diabetic untreated), C (diabetic treated with Q), D (diabetic treated with Irb), and E (diabetic treated with Q&Irb), each group containing 10 animals. Groups B-E received STZ. Diabetes was induced in four groups by a single intraperitoneal (i.p) injection of STZ (50 mg/kg, freshly dissolved in 5 mmol/L citrate buffer, pH 4.5). Two days after STZ treatment, development of diabetes in four experimental groups was confirmed by measuring blood glucose levels in a tail vein blood samples. Rats with blood glucose levels of 250 mg/dL or higher were considered to be diabetic. The rats in Q-, Irb-, and Q&Irb-treated groups were given Q (in a dose of 3 mg/kg body weight), Irb (5 mg/kg body weight), and Q&Irb (in a dose of 1.5 mg/kg + 2.5 mg/kg body weight) once a day orally by using intra-gastric intubation for 12 weeks starting two days after STZ injection. Treatment of Q and especially Irb reduced the glomerular size and thickening of capsular, glomerular, and tubular basement membranes; and increased amounts of mesangial matrix and tubular dilatation and renal function as compared with diabetics untreated. Notably, the better effects were obtained when Q and Irb given together. We conclude that Q, Irb, and especially Q+Irb therapy causes renal morphologic and functional improvement after STZ-induced diabetes in rats. We believe that further preclinical research into the utility of Q and Irb treatment, alone or its combination, may indicate its usefulness as a potential treatment in diabetic nephropathy (DNp).
 ...
PMID:Effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on streptozotocin-induced diabetic nephropathy. 1901 56

The phylogenetically old renin-angiotensin-system (RAS) was originally described as a circulating hormonal system and a main cardiovascular regulator. However, there also exist 'local RASs' which are situated in cardiovascular as well as non-cardiovascular tissues where they are involved in physiological and patho-physiological processes such as inflammation, fibrosis, proliferation or apoptosis. Local RASs are activated in diabetes, preferentially in organs affected by hyperglycaemic injury such as the kidney or the retina. Increased renal or retinal Ang II levels may contribute to diabetic tissue injury in two ways: (i) by stimulating the angiotensin AT1-receptor and downstream pathological chains of events and (ii) by bidirectional interaction with the 'classical' hyperglycaemia-induced pathobiochemical pathways (oxidative stress, generation of advanced glycation end products, increased polyol pathway flux, activation of protein kinase C, increased hexosamine pathway flux). The involvement of the RAS in the pathomechanisms underlying diabetic end organ damage suggests pharmacological RAS inhibition as a therapeutic approach in these disorders. This assumption has been supported by numerous animal studies. Clinically, RAS inhibition is currently the first line, guideline-approved treatment in diabetic nephropathy. The recently published DIRECT, RASS and AdRem studies provided evidence that RAS inhibition may also be beneficial in diabetic retinopathy; however, evidence for RAS-inhibition in retinopathy is still much weaker than for nephropathy. The present article reviews the emerging knowledge about cardiovascular and non-cardiovascular effects of the RAS with an emphasis on the mechanisms of RAS involvement and pharmacological RAS inhibition in diabetic end organ damage.
 ...
PMID:The evolving story of the RAAS in hypertension, diabetes and CV disease: moving from macrovascular to microvascular targets. 1981 70

Diabetic retinopathy is the most common microvascular complication caused by diabetes mellitus and is a leading cause of vision loss among working-age adults in developed countries. Understanding the effects of diabetes on the retinal proteome may provide insights into factors and mechanisms responsible for this disease. We have performed a comprehensive proteomic analysis and comparison of retina from C57BL/6 mice with 2 months of streptozotocin-induced diabetes and age-matched nondiabetic control mice. To explore the role of the angiotensin AT1 receptor in the retinal proteome in diabetes, a subgroup of mice were treated with the AT1 antagonist candesartan. We identified 1792 proteins from retinal lysates, of which 65 proteins were differentially changed more than 2-fold in diabetic mice compared with nondiabetic mice. A majority (72%) of these protein changes were normalized by candesartan treatment. Most of the significantly changed proteins were associated with metabolism, oxidative phosphorylation, and apoptotic pathways. An analysis of the proteomics data revealed metabolic and apoptotic abnormalities in the retina from diabetic mice that were ameliorated with candesartan treatment. These results provide insight into the effects of diabetes on the retina and the role of the AT1 receptor in modulating this response.
 ...
PMID:Angiotensin AT1 receptor antagonism ameliorates murine retinal proteome changes induced by diabetes. 1984 1


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