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Query: UMLS:C0011860 (type 2 diabetes)
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The renin-angiotensin system is a major regulatory system of cardiovascular and renal function. Basic research has revealed exciting new aspects, which could lead to novel or modified therapeutic approaches. Renin-angiotensin system blockade exerts potent antiatherosclerotic effects, which are mediated by their antihypertensive, anti-inflammatory, antiproliferative, and oxidative stress lowering properties. Inhibitors of the system-ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now first-line treatments for hypertensive target organ damage and progressive renal disease. Their effects are greater than expected by their ability to lower blood pressure alone. Angiotensin receptor blockers reduce the frequency of atrial fibrillation and stroke. Renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients. Thus, blockade of this system will remain a cornerstone of our strategies to reduce cardiovascular risk.
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PMID:Renin-angiotensin system and cardiovascular risk. 1761 59

Hypertension is more prevalent and more difficult to control and is associated with a higher mortality rate in patients with diabetes than in nondiabetic patients. Elevated blood pressure contributes importantly to the development of albuminuria and progression of renal damage in diabetic nephropathy. Strong evidence indicates that the presence of albuminuria and overt nephropathy in patients with type 1 and type 2 diabetes is associated with a marked increase in the rate of fatal and nonfatal cardiovascular events. Blockade of the renin-angiotensin system in patients with type 2 diabetes with or without chronic kidney disease is associated with a significant reduction in risk for cardiovascular events. Renin-angiotensin system-blocking agents should be considered first-step pharmacologic therapy for hypertension in diabetic patients, with addition of other agents, if needed, to meet the recommended blood pressure goal of <130/80 mm Hg. In most instances, a diuretic is also needed to reduce blood pressure.
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PMID:Reducing cardiovascular events in high-risk patients: the challenge of managing hypertension in patients with diabetic renal disease. 1808 Mar 58

Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise. The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment. The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.
J Renin Angiotensin Aldosterone Syst 2008 Jun
PMID:Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis. 1858 83

TREATMENT OF ARTERIAL HYPERTENSION - Blood pressure (BP) should be regularly measured in all patients with CKD (Strength of Recommendation C). - BP control and proteinuria reduction delay progression of CKD (Strength of Recommendation A) and reduce cardiovascular risk (Strength of Recommendation C). Thus, control of both factors should be the treatment objective. - The BP target in patients with CKD should be < 130/80 mmHg, and 125/75 mmHg if proteinuria is > 1 g/24 hours (Strength of Recommendation A). - Lifestyle changes should be made: low-sodium diet (less than 100 mEq/day of sodium or 2.4 g/day of salt); weight reduction if patient is overweight (body mass index 20-25 kg/m2); regular aerobic physical exercise and moderate alcohol intake for BP control and prevention of cardiovascular risk (Strength of Recommendation A). - The choice of the antihypertensive drug in patients with CKD depends on the etiology of CKD, cardiovascular risk, or presence of clinical or subclinical cardiovascular disease (Strength of Recommendation A). - Two or more antihypertensive drugs are usually required to control blood pressure in patients with CKD (Strength of Recommendation B), and will frequently include a diuretic, which in stages 4-5 should be a loop diuretic (Strength of Recommendation B). - Renin-angiotensin-aldosterone system (RAAS) inhibitors are first choice drugs in patients with diabetic nephropathy, patients with non-diabetic nephropathy with a protein/creatinine ratio higher than 200 mg/g, and patients with heart failure (Strength of Recommendation A). The combination of ACEIs and ARBs is indicated for reducing proteinuria that remains high despite treatment with a RAAS inhibitor, provided potassium levels do not exceed 5.5 mEq/L (Strength of Recommendation B). - When RAAS blockers are started or their dose is changed in patients with advanced CKD, kidney function and serum potassium levels should be monitored at least after 1-2 weeks. DIAGNOSIS AND TREATMENT OF DYSLIPIDEMIA - A complete evaluation of the lipid profile including total cholesterol, LDL-C, HDL-C, and triglycerides should be performed in any patient with CKD at baseline and at least annually (Strength of Recommendation B). - In patients with stage 4-5 CKD and LDL-C >or= 100 mg/dL, treatment to decrease levels to < 100 mg/dL should be considered because of their high CV risk. This reduction is recommended in secondary prevention and in primary prevention in diabetic patients. Lipid-lowering treatment is recommended in all other patients, although no evidence showing its benefits is available yet (Strength of Recommendation C). - In patients with stage 4-5 CKD and triglyceride levels >or= 500 mg/dL which are not corrected by treating the underlying cases, treatment with triglyceride-lowering drugs may be considered to reduce the risk of pancreatitis. However, treatment with fibrates should be used with caution, and these drugs should not be associated to statins due to the risk of rhabdomyolysis (Strength of Recommendation C). There is little experience on the efficacy and safety of omega-3 fatty acids for the treatment of hypertriglyceridemia in patients with grade 4-5 CRF, but they may be considered a possibly safer alternative to fibrates (Strength of Recommendation C). SMOKING - Smoking is a cardiovascular risk factor and a risk factor for progression of kidney disease in patients with CRF (Strength of Recommendation B). - Use of active measures to achieve smoking cessation is recommended in patients with CRF (Strength of Recommendation C). HOMOCYSTEINE - Hyperhomocysteinemia has been postulated as a cardiovascular risk factor in the general population and in kidney patients, but the available evidence is not consistent. - There is no evidence that vitamin therapy decreases cardiovascular risk in patients with CRF, and recommendation of routine vitamin measurement and start of vitamin therapy to reduce cardiovascular risk in these patients is therefore questionable (Strength of Recommendation B). LEFT VENTRICULAR HYPERTROPHY - Left ventricular hypertrophy (LVH) is a cardiovascular risk factor in patients with CRF (Strength of Recommendation B). - It is advisable to perform an echocardiogram at baseline and every 12-24 months and to consider treatments allowing for LVH regression (Strength of Recommendation C). The approach to LVH should be early and multifactorial because its reversibility is limited once established (Strength of Recommendation C). - RAAS blockade with ACEIs or ARBs partially reverts LVH in patients with CRF (Strength of Recommendation B). ANTI-PLATELET AGGREGATION - Because of the high cardiovascular risk in patients with CKD, anti-platelet aggregant therapy, especially low-dose aspirin, would be indicated in patients with type 2 diabetes as primary prevention, and in all patients with CKD as secondary prevention. There is however no evidence of the benefits of anti-platelet aggregant therapy in primary prevention in patients with CKD, particularly in stages 4-5; indication for treatment in this situation should therefore be individualised because of its greater risk of bleeding. - Adequate good blood pressure control should previously be achieved to minimise the risk of haemorrhagic stroke (Strength of Recommendation C).
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PMID:[Arterial hypertension and dyslipidemia in patients with chronic kidney disease (CKD). Anti-platelet aggregation. Goal oriented treatment]. 1901 37

Aliskiren is the first direct renin inhibitor for the treatment of hypertension. Clinical experience from studies in over 14,000 patients has shown that aliskiren, alone or in combination with other antihypertensive therapies, provides effective blood pressure lowering with a good safety and tolerability profile.The ultimate aim of antihypertensive therapy, however, is to reduce the risk of adverse cardiovascular and renal outcomes.The effect of aliskiren on surrogate markers of organ damage and clinical outcomes is being assessed in the ongoing ASPIRE HIGHER programme, the largest clinical trials programme in the cardio-renal disease area. Results from the ALOFT, AVOID and ALLAY studies suggest that aliskiren has positive effects on markers of cardiovascular and renal damage in patients with type 2 diabetes and nephropathy, heart failure and left ventricular hypertrophy.ASPIRE HIGHER also includes four large-scale studies assessing the potential outcome benefits of aliskiren, and the results of these trials will help define the clinical utility of aliskiren in the treatment of cardiovascular and renal diseases. In this article, we review the antihypertensive efficacy of aliskiren and explore its potential in the management of cardiovascular and renal risk.
J Renin Angiotensin Aldosterone Syst 2009 Jun
PMID:Managing cardiovascular and renal risk: the potential of direct renin inhibition. 1950 53

Interruption of the Renin-Angiotensin-Aldosterone System (RAAS) with Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin-Receptor Blockers (ARBs), alone or in combination, has become a leading therapeutic strategy to slow down the progression of chronic kidney disease. Nevertheless, a considerable proportion of patients progress despite this therapy. New alternative arms are available today to treat hypertension in uncontrolled patients that might have a role in renoprotection. The role of aliskiren, the recently available renin inhibitor may be assumed, based on the pathophysiology of RAAS related renal damage and from data derived on experimental and clinical studies in-patient with type 2 diabetes related nephropathy. The review focuses on the potential consequences of (pro)renin blockade in glomerular hypertension and renal scarring along with some patented treatment methods. The benefit of this additional therapy is still only hypothetical. Ad hoc clinical trials have been conducted to confirm the expected results. Finding that prolonged inhibition of renin vasoconstrictor effect, suppression of plasma renin activity and a more effective RAAS blockade, in patients with chronic RAAS inhibition may help to achieve a sustained reduction of proteinuria, would suggest that renin inhibitors may represent a new weapon to fight progressive nephropathies.
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PMID:Direct Renin inhibition: promising treatment in renoprotection? 2043 46

The renin-angiotensin system plays a central role in the pathological mechanisms of diabetic nephropathy and is regulated by renal expression of cyclooxygenase-2 (COX-2). In the present study, the kidneys of diabetic KK-A(y) mice, a model of human type 2 diabetes, were investigated histologically and immunohistochemically at 8, 12, 16, and 20 weeks of age, and changes in renal lesions and expression of COX-2 and renin were evaluated quantitatively. Glomerular damage, characterized by expansion of mesangial matrices and nodular lesions, was observed in the kidneys of these mice. The glomerular sclerosis score gradually increased with age and was significantly higher than those of age-matched control C57BL/6 mice at 12, 16, and 20 weeks of age. Although mild tubulointerstitial damage was observed, there was no significant change in the interstitial fibrosis score. These findings were considered early diabetic nephropathy changes. COX-2-positive signals were consistently detected in the macula densa cells of the thick ascending limbs in all KK-A(y) mice, with a slightly higher score observed at 8 weeks of age. No COX-2-positive signals were detected in C57BL/6 mice. Renin-positive signals were commonly detected in the juxtaglomerular arterioles, and the scores in KK-A(y) mice increased at 16 weeks and decreased at 20 weeks of age. The present study demonstrated activation of renal COX-2 and renin expression in diabetic KK-A(y) mice at different stages. This finding suggests that these two enzymes contribute to the development and progression of diabetic nephropathy via different mechanisms.
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PMID:Immunohistochemical examination of cyclooxygenase-2 and renin in a KK-A(y) mouse model of diabetic nephropathy. 2066 Sep 94

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease (CVD) morbidity and mortality worldwide. Renin-angiotensin system (RAS) blockers have been indispensable in diminishing the macrovascular and microvascular complications of diabetes. In addition, cumulative evidence from retrospective studies pointed toward a beneficial effect of RAS agents in preventing the development and progression of T2DM. This disease-modifying potential of RAS blockers has been substantiated by recent prospective trials. Contemporary concepts regarding the natural history of T2DM and the pathophysiologic processes involved have increased our understanding of the mechanisms underlying the therapeutic potential of these agents in diabetes management. In addition to their established roles in the primary prevention of CVD in patients with diabetes, RAS blockers might be considered a suitable therapeutic choice for preventing the development of frank diabetes in high-risk patients.
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PMID:The role of renin-angiotensin agents in altering the natural history of type 2 diabetes mellitus. 2080 36

Renin-angiotensin system (RAS) activation and abnormalities of ambulatory blood pressure (ABP) are present in obesity, but relationships between components of the RAS and ABP have not been defined in the young. Anthropometric measurements and 24-h ABP were obtained on 30 obese adolescents with and without type 2 diabetes mellitus. Plasma renin activity (PRA), aldosterone, and other cardiovascular risk factors were measured. Median PRA levels were 2.5 [interquartile range (IQR), 1.7-4.1] ng/mL/h and were higher in the diabetic subjects compared with the nondiabetics. Females had significantly higher PRA than males 3.2 (IQR, 2-4.8) versus 1.8 (IQR, 1.1-2.9) ng/mL/h (p = 0.04) and were more obese. BMI Z score and PRA were significantly correlated (rho = 0.46, p < 0.001). PRA inversely correlated with 24-h systolic ABP (rho = -0.46, p = 0.02) and strongly with 24-h pulse pressure (rho = -0.61, p = 0.001). Aldosterone levels were also correlated with 24-h pulse pressure (rho = -0.46, p = 0.02). In multivariate models, lower PRA was independently associated with 24-h systolic blood pressure. In this study, PRA was positively correlated with BMI, but the relationships between components of the RAS and ABP were inverse. Further studies are needed to define the pathophysiologic relationship between RAS components and blood pressure regulation in obese youth.
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PMID:Relationships between renin, aldosterone, and 24-hour ambulatory blood pressure in obese adolescents. 2117 17

The aim was to determine whether serum prorenin levels affect the development of diabetic retinopathy (DR) in type 2 diabetes. Baseline serum prorenin levels were measured in 196 patients (85 males, 111 females) with type 2 diabetes without DR using the antibody-activating direct prorenin assay. The fundi were checked regularly. The participants were divided into two groups based on the serum prorenin levels (high and low). We used Kaplan-Meyer analysis to detect differences in the development of DR between the two groups within the same gender. Kaplan-Meyer analysis showed that males with a high serum prorenin level tended to develop DR earlier and more frequently than males with a low prorenin level ( p = 0.004 by the log rank test). However, there was no difference in the development of DR between high and low groups in females (p = 0.58). Serum prorenin levels in males with type 2 diabetes could be a new prognostic indicator of the development of DR.
J Renin Angiotensin Aldosterone Syst 2011 Sep
PMID:Higher levels of prorenin predict development of diabetic retinopathy in patients with type 2 diabetes. 2133 Apr 19


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