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)

Arterial wall stiffness, an important independent risk factor for cardiovascular disease in patients with hypertension, is worsened by the coexistence of diabetes mellitus. This randomised, prospective, double-blind, crossover trial assessed the effects of telmisartan on arterial stiffness in patients with Type 2 diabetes with essential hypertension. After a two-week placebo wash out period, 28 ambulatory patients received telmisartan (40 mg) or placebo for three weeks. Following a second two-week placebo wash out period, patients received the alternate treatment for a further three weeks. Augmentation index and central blood pressure (BP) were determined using the SphygmoCor device and pulse wave velocity (PWV) was measured using an automatic device, the Complior trade mark, at the beginning and the end of each period. Telmisartan significantly reduced the carotid femoral PWV compared with placebo (mean adjusted treatment difference 0.95 m/s; 95% CI: 1.67, 0.23 m/s; p=0.013). Peripheral and central diastolic, systolic and pulse pressures were also significantly reduced with telmisartan compared with placebo. In conclusion, telmisartan reduces arterial stiffness and peripheral and central BPs as assessed by PWV and pulse contour analysis in hypertensive patients with Type 2 diabetes. These properties of telmisartan suggest that it may improve cardiovascular outcome in this patient population.
J Renin Angiotensin Aldosterone Syst 2002 Sep
PMID:Effects of telmisartan on arterial stiffness in Type 2 diabetes patients with essential hypertension. 1256 68

Although angiotensin II has long been considered to represent the end product of the renin-angiotensin system (RAS), there is accumulating evidence that it encompasses additional effector peptides with diverse functions. In this respect, angiotensin IV (Ang IV) formed by deletion of the two N terminal amino acids, has sparked great interest because of its wide range of physiological effects. Among those, its facilitatory role in memory acquisition and retrieval is of special therapeutic relevance. High affinity binding sites for this peptide have been denoted as AT(4)- receptors and, very recently, they have been proposed to correspond to the membrane-associated OTase/ IRAP aminopeptidase. This offers new opportunities for examining physiological roles of Ang IV in the fields of cognition, cardiovascular and renal metabolism and pathophysiological conditions like diabetes and hypertension. Still new recognition sites may be unveiled for this and other angiotensin fragments. Recognition sites for Ang-(1-7) (deletion of the C terminal amino acid) are still elusive and some of the actions of angiotensin III (deletion of the N terminal amino acid) in the CNS are hard to explain on the basis of their interaction with AT(1)-receptors only. A more thorough cross-talk between in vitro investigations on native and transfected cell lines and in vivo investigations on healthy, diseased and transgenic animals may prove to be essential to further unravel the molecular basis of the physiological actions of these small endogenous angiotensin fragments.
J Renin Angiotensin Aldosterone Syst 2002 Dec
PMID:Cellular targets for angiotensin II fragments: pharmacological and molecular evidence. 1258 63

The cumulative incidence of diabetic nephropathy in Type 1 diabetes mellitus is in the order of 25 30%. The recognition that elevated blood pressure (BP) is a major factor in the progression of these patients to end-stage renal failure has led to the widespread use of antihypertensive therapy in order to preserve glomerular filtration rate and ultimately to reduce mortality. The routine measurement of microalbuminuria allows early identification of the subgroup of patients at increased risk of developing clinical nephropathy. Microalbuminuric Type 1 diabetic patients show a number of characteristic pathological abnormalities. In addition to elevated BP and abnormal circadian rhythm, there are also associated abnormalities of vagal function, lipid profile and endothelial function, as well as an increased prevalence of retinopathy. The first section of this two-part review focusses on the early changes associated with renal involvement in Type 1 diabetes. It addresses the associations between urinary albumin excretion, glycaemic control, smoking, BP, circadian BP variation, QT interval abnormalities and autonomic function in three groups of patients; those with normoalbuminuria, those progressing towards microalbuminuria and those with established low-grade microalbuminuria.
J Renin Angiotensin Aldosterone Syst 2002 Dec
PMID:Blood pressure and cardiac autonomic function in relation to risk factors and treatment perspectives in Type 1 diabetes. 1258 66

Diabetic retinopathy is the leading cause of blindness in the under 65s, and with the burden of disease case load expected to exceed 200 million worldwide within 10 years, much effort is being spent on prophylactic interventions. Early work focused on improving glycaemic control; however, with the publication of EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) and United Kingdom Prospective Diabetes Study (UKPDS), the focus has recently moved to control of blood pressure and specifically the renin-angiotensin system (RAS). There is a large body of evidence for a local RAS within the eye that is activated in diabetes. This appears to be directly responsible, as well as indirectly through other mediators, for an increase in concentration of vascular endothelial growth factor (VEGF), a selective angiogenic and vasopermeability factor that is implicated in the pathogenesis of diabetic retinopathy. Inhibition of angiotensin-converting enzyme appears to reduce concentrations of VEGF, with a concurrent anti-proliferative effect independent of systemic VEGF levels or blood pressure. Angiotensin II (Ang II) Type 1 (AT(1)) receptor blockade has been shown to reduce neovascularisation independent of VEGF levels in animal models. This may be due to antagonism of activation of mitogen-activated protein kinase, which is a potent cellular proliferation stimulator, by Ang II, although this needs further evaluation.
J Renin Angiotensin Aldosterone Syst 2002 Dec
PMID:The renin-angiotensin-aldosterone system and the eye in diabetes. 1258 67

The DIabetic Retinopathy Candesartan Trials (DIRECT) Programme consists of three randomised, double-masked, parallel, placebo-controlled studies to determine the impact of treatment with candesartan on diabetic retinopathy. In Type 1 diabetes, 1,700 patients without retinopathy will be randomised into a primary prevention study, and 1,200 with non-proliferative retinopathy into a secondary prevention study. In Type 2 diabetes, 1,600 patients with non-proliferative retinopathy will be randomised. Patients will be followed for at least three years. Eligible patients must be normotensive (systolic blood pressure [SBP] 130 mmHg and diastolic blood pressure [DBP] 85 mmHg) without antihypertensive medication in Type 1 diabetes, and either normotensive or treated hypertensive (SBP 160 mmHg and SBP 90 mmHg) and not taking angiotensin-converting enzyme inhibitors or AT(1)-receptor blockers in Type 2 diabetes. All patients will be normoalbuminuric, based on two overnight urine collections. The primary endpoint is based upon retinal photographs, graded to the Early Treatment of Diabetic Retinopathy Study scale. A two-step increase on this scale defines incidence, and a three-step increase defines progression of retinopathy. The main secondary endpoint for each study is change in urinary albumin excretion rate. A positive outcome of the DIRECT Programme would be an important step forward in the clinical management of patients with diabetes.
J Renin Angiotensin Aldosterone Syst 2002 Dec
PMID:The DIabetic Retinopathy Candesartan Trials (DIRECT) Programme, rationale and study design. 1258 69

Since renin catalyses the first and rate-limiting step of the renin-angiotensin system (RAS) cascade, interruption of the generation of angiotensin II (Ang II) by renin inhibitors at this highly specific initial step of the cascade has long been a therapeutic goal. The early development of renin inhibitors was hampered by problems with bioavailability and high costs of synthesis. However, more recently a potent non-peptidic inhibitor of renin, aliskiren, with acceptable oral bioavailability, has been synthesised. Aliskiren effectively reduces Ang II levels in normal volunteers and has been shown to lower blood pressure (BP) in patients with mild-to-moderate hypertension. Renin inhibitors would be expected to have similar, but not identical effects to those of the established RAS antagonists. Due to the lack of effective alternative enzyme pathways, blockade of Ang II production may be more effective with renin inhibition than with angiotensin-converting enzyme (ACE) inhibition. Furthermore, because renin has high specificity for only one substrate, angiotensinogen, side-effects would be expected to be less frequent. It is currently unclear whether blockade of Ang II type 1 (AT1) receptors, leaving other Ang II receptors (AT2, AT3 and AT4) unblocked, is preferable to the reduction in plasma and tissue Ang II levels achieved with either ACE or renin inhibition. Pharmacological suppression of the RAS, through ACE inhibition, or blockade of AT1, beta-adrenoceptor or mineralocorticoid receptors, has been proven to reduce morbidity and mortality in patients with hypertension, diabetes mellitus, atherosclerosis, heart failure and nephropathy. While, to date, aliskiren has only been shown to reduce BP, it appears likely that orally-active renin inhibitors could prove useful in the management of a wide range of cardiovascular pathologies.
J Renin Angiotensin Aldosterone Syst 2003 Mar
PMID:Potential of renin inhibition in cardiovascular disease. 1269 47

Several clinical trials have consistently shown that antihypertensive treatment, particularly with angiotensin-converting enzyme inhibitors (ACE-I) reduces albuminuria in Type 1 diabetic patients. More recently, data on the beneficial effects of ACE-I on the preservation of glomerular filtration rate and renal ultrastructure have emerged. However, in general, these trials have recruited a wide spectrum of diabetics, including some patients with severe albuminuria. Thus, the question of the ideal stage at which to instigate what is likely to be lifelong therapy in young people still remains unanswered. Exercise is known to significantly increase both blood pressure (BP) and urinary albumin excretion (UAE), both of which are important determinants of progression of nephropathy in diabetes. Thus, it is possible that exercise may have an adverse effect on diabetic renal disease. The effects of ACE-I on exercise-BP and exercise-UAE in microalbuminuric Type 1 diabetic patients has not been examined in long-term placebo-controlled studies. In the second part of this two-part review, we examine the effects of the ACE-I, lisinopril, 20 mg o.d. for two years, in comparison with placebo, on UAE, 24-hour ambulatory BP, exercise-BP, exercise-UAE and renal haemodynamics in 22 patients with Type 1 diabetes and low-grade microalbuminuria. We further discuss the effects of ACE-I on nephropathy and other complications of diabetes.
J Renin Angiotensin Aldosterone Syst 2003 Mar
PMID:ACE inhibitor intervention in Type 1 diabetes with low grade microalbuminuria. 1269 49

An elevation in angiotensin II (Ang II) levels is a common occurrence in a diverse number of cardiovascular diseases including hypertension, hypercholesterolaemia, atherosclerotic coronary artery disease, left ventricular hypertrophy (LVH), heart failure and diabetes. An important effect of Ang II is activation of the NAD(P)H oxidase, a major source of reactive oxygen species (ROS) production by vascular cells. This increase in cellular ROS contributes to the pathogenesis of vascular disease by altering endothelial cell function, enhancing smooth muscle cell growth and proliferation, stimulating inflammatory proteins, including macrophage chemoattractant agents, growth factors and cytokines, and modulating matrix remodelling. Studies of genetically-altered mice have unequivocally shown that activation of the NAD(P)H oxidase by Ang II contributes to hypertension, LVH and atherosclerosis. Furthermore, increasing evidence suggest that the NAD(P)H oxidase contributes to human disease, suggesting that it is a potential target for future therapeutic intervention.
J Renin Angiotensin Aldosterone Syst 2003 Jun
PMID:Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease. 1280 86

The ability of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) to lower blood pressure (BP) is well established. ACE inhibitors (ACE-Is) have also been shown to improve the prognosis of a broad range of patients at high cardiovascular risk, including those with heart failure, post-myocardial infarction (MI), and nephropathy. These benefits suggest that interrupting the renin-angiotensin-aldosterone system (RAAS) with ACE-Is has a widespread vasculoprotective effect, provided that BP is also adequately controlled. Evidence that RAAS blockade by ARBs also improves long-term clinical outcomes in patients with cardiovascular disease has started to accumulate, and will be tested further during the coming years as a number of large-scale, prospective trials are completed. These trials are investigating the long-term protective effects of ARBs on morbidity and mortality in patients with hypertension, heart failure, diabetes mellitus, acute MI, or established vascular disease. The results should establish the extent to which ARBs exhibit the vasculoprotective properties demonstrated by ACE-Is in patients at high cardiovascular risk. If ARBs are found to provide benefits that are similar to, or even greater than ACE-Is, it may have important implications for drug selection, given the excellent tolerability of ARBs. Some studies are also investigating whether more extensive RAAS blockade using a combination of an ARB and an ACE-I will offer even greater protection than either agent alone.
J Renin Angiotensin Aldosterone Syst 2003 Jun
PMID:Angiotensin II receptor blockers and cardiovascular outcomes: what does the future hold? 1280 87

Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-beta (TGF-beta) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-beta and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human (CAT-192) anti-TGF-beta monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-beta antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-beta antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition.
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PMID:Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. 1281 41


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