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)

More than 80% of patients with type 2 diabetes mellitus develop hypertension, and approx. 20% of patients with hypertension develop diabetes. This combination of cardiovascular risk factors will account for a large proportion of cardiovascular morbidity and mortality. Lowering elevated blood pressure in diabetic hypertensive individuals decreases cardiovascular events. In patients with hypertension and diabetes, the pathophysiology of cardiovascular disease is multifactorial, but recent evidence points toward the presence of an important component dependent on a low-grade inflammatory process. Angiotensin II may be to a large degree responsible for triggering vascular inflammation by inducing oxidative stress, resulting in up-regulation of pro-inflammatory transcription factors such as NF-kappaB (nuclear factor kappaB). These, in turn, regulate the generation of inflammatory mediators that lead to endothelial dysfunction and vascular injury. Inflammatory markers (e.g. C-reactive protein, chemokines and adhesion molecules) are increased in patients with hypertension and metabolic disorders, and predict the development of cardiovascular disease. Lifestyle modification and pharmacological approaches (such as drugs that target the renin-angiotensin system) may reduce blood pressure and inflammation in patients with hypertension and metabolic disorders, which will reduce cardiovascular risk, development of diabetes and cardiovascular morbidity and mortality.
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PMID:Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. 1732 19

Blockade of the renin-angiotensin system reduces cardiovascular morbidity and mortality in diabetic patients. Angiotensin II (Ang II) plays an important role in the structural and functional abnormalities of the diabetic heart. We investigated whether or not Ang II type 1 receptor blocker (ARB) could attenuate left ventricular (LV) remodeling in male mice with diabetes mellitus (DM) induced by the injection of streptozotocin (200 mg/kg, i.p.). Diabetic mice were treated with candesartan (1 mg/kg/day; DM+Candesartan, n=7) or vehicle (DM+Vehicle, n=7) for 8 weeks. Heart rate and aortic blood pressure were comparable between the groups. Normal systolic function was preserved in diabetic mice. In contrast, diastolic function was impaired in DM+Vehicle and was improved in DM+Candesartan, as assessed by the deceleration time of the peak velocity of transmitral diastolic flow (40.3+/-0.3 vs. 37.3+/-0.5 ms, p<0.01) and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 10.6+/-0.7 vs. 8.7+/-0.6 ms, p<0.05) without significant changes in heart rate and aortic blood pressure. Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis and apoptosis in association with the expression of connective tissue growth factor (CTGF) and myocardial oxidative stress. Moreover, candesartan directly inhibited Ang II-mediated induction of CTGF in cultured cardiac fibroblasts. ARB might be beneficial to prevent cardiac abnormalities in DM.
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PMID:Angiotensin II type 1 receptor blocker attenuates myocardial remodeling and preserves diastolic function in diabetic heart. 1758 56

Angiotensin II (Ang II), a circulating hormone that can be synthesized locally in the vasculature, has been implicated in diabetes-associated vascular complications. This study was conducted to determine whether high glucose (HG) (approximately 23.1 mmol/L), a diabetic-like condition, stimulates Ang II generation and the underlying mechanism of its production in rat vascular smooth muscle cells. The contribution of various enzymes involved in Ang II generation was investigated by silencing their expression with small interfering RNA in cells exposed to normal glucose (approximately 4.1 mmol/L) and HG. Angiotensin I (Ang I) was generated from angiotensinogen by cathepsin D in the presence of normal glucose or HG. Although HG did not affect the rate of angiotensinogen conversion, it decreased expression of angiotensin-converting enzyme (ACE), downregulated ACE-dependent Ang II generation, and upregulated rat vascular chymase-dependent Ang II generation. The ACE inhibitor captopril reduced Ang II levels in the media by 90% in the presence of normal glucose and 19% in HG, whereas rat vascular chymase silencing reduced Ang II production in cells exposed to HG but not normal glucose. The glucose transporter inhibitor cytochalasin B, the aldose reductase inhibitor alrestatin, and the advanced glycation end product formation inhibitor aminoguanidine attenuated HG-induced Ang II generation. HG caused a transient increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and ERK1/2 inhibitors reduced Ang II accumulation by HG. These data suggest that polyol pathway metabolites and AGE can stimulate rat vascular chymase activity via ERK1/2 activation and increase Ang II production. In addition, decreased Ang II degradation, which, in part, could be attributable to a decrease in angiotensin-converting enzyme 2 expression observed in HG, contributes to increased accumulation of Ang II in vascular smooth muscle cells by HG.
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PMID:Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells. 1762 97

Glucose is a key fuel and an important metabolic substrate in mammals. Renal proximal tubular cells (PTCs) not only reabsorb filtered glucose but are also believed to play a role in the glucotoxicity associated with renal pathogenesis, such as in diabetes. The proximal tubule environment is where 90% of the filtered glucose is reabsorbed by the low-affinity/high-capacity Na(+)/glucose cotransporter 2 (SGLT2) and facilitated diffusion glucose transporter 2 (GLUT2). Both active and facilitative glucose transporters have distinct distribution profiles along the proximal tubule related to their particular kinetic characteristics. A number of mechanisms contribute to the changes in the cellular functions, which occur in response to exposure to various endogenous factors. Hyperglycemia was reported to regulate the renal SGLT activities through the reactive oxygen species-nuclear factor-kappaB pathways, which suggests that the transcellular glucose uptake within the PTCs contribute to the development of diabetic-like nephropathy. Angiotensin II (ANG II) plays an important role in its development through epidermal growth factor receptor (EGFR) transactivation. Therefore, a combination of high glucose, ANG II, and EGF are involved in diabetic-like nephropathy by regulating the SGLT activity. In addition, endogenously enhanced SGLTs have a cytoprotective function. The renal proximal tubules play a major role in regulating the plasma glucose levels, and there is increasing interest in the renal glucose transporters on account of their potential implications in the treatment of various conditions including diabetes mellitus.
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PMID:Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. 1819 99

Angiotensin II Receptor blockers (ARBs) are an important addition to the current range of medications available for treating a wide spectrum of diseases including cardiovascular diseases. Coronary heart disease (CHD) is the most common cause of death in the United Kingdom and worldwide. More importantly, the presence of the metabolic syndrome and the likelihood of diabetes mellitus taking on epidemic proportions in the years to come all threaten to maintain the mortality rate due to CHD. This review article focuses on the clinical studies that have helped define the trends in the usage of these agents in the prevention and treatment of diabetes mellitus and its complications and also explores possible mechanisms of action and future developments.
Diabetes Obes Metab 2007 Sep
PMID:The role of angiotensin II type 1 receptor blockers in the prevention and management of diabetes mellitus. 1769 55

Abdominal obesity is a risk factor for cardiovascular disease worldwide, and it is becoming a dramatic issue for national health systems. Overweight and obesity are highly associated with multiple comorbidities, elevated blood pressure values, dyslipidaemia, reduced insulin sensitivity and alterations of large and minor vessels. Activation of the renin-angiotensin system (RAS) in adipose tissue may represent an important link between obesity and hypertension. Angiotensin II has been shown to play a role in adipocyte growth and differentiation. Adipocytes also secrete adiponectin, enhancing insulin sensitivity and preventing atherosclerosis. Blockade of the RAS with either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker results in a substantial increase in adiponectin levels and improved insulin sensitivity. Obesity-related hypertension needs a comprehensive approach to treatment including both weight loss and pharmacological therapies. Antihypertensive drugs prescription should be based on guidelines recommendations for management of hypertension, taking into account the growing evidences about the relationship between some antihypertensive drugs and the development of new-onset diabetes. This review discusses the role of RAS in the relationship between obesity, essential hypertension and insulin resistance.
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PMID:Obesity, essential hypertension and renin-angiotensin system. 1790 24

Angiotensin II type-1 receptor blockers are widely used with the expectation of prevention of stroke, potential effects to ameliorate of type-2 diabetes, which seems to be closely associated with the impairment of cognitive function in humans. Recently, we have reported that an angiotensin II type-1 receptor blocker prevented cognitive impairment in mice after focal cerebral ischemia, at least partly through an angiotensin II type-2 receptor-mediated increase in a neuroprotective factor, methyl methanesulfonate sensitive-2. Here, we examined the possibility that an angiotensin II type-1 receptor blocker could improve cognitive function in a type-2 diabetic mouse model, KK-A(y). KK-A(y) mice subjected to 20 trials of a passive avoidance task every week from 8 weeks exhibited a significantly impaired avoidance rate, and moreover, its age-dependent decline, especially after 14 weeks of age, compared with age-matched C57BL6 mice. Oral administration of candesartan at a nonhypotensive dose (0.005% in laboratory chow) in KK-A(y) mice improved cognitive function and inhibited the impairment of cognitive decline. Methyl methanesulfonate sensitive-2 expression in the brain was lower in KK-A(y) mice than in C57BL6 mice. Treatment with candesartan markedly increased mRNA expression of angiotensin II type-2 receptor and methyl methanesulfonate sensitive-2 in the brain in KK-A(y) mice, determined by quantitative RT-PCR. In KK-A(y) mice treated with candesartan, age-dependent increases in blood glucose and insulin were significantly suppressed. Our results suggest that candesartan ameliorates the impaired cognitive function in type-2 diabetes mice, at least because of an increased expression of methyl methanesulfonate sensitive-2, a neuroprotective factor, in addition to improvement of glucose intolerance.
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PMID:Amelioration of cognitive impairment in the type-2 diabetic mouse by the angiotensin II type-1 receptor blocker candesartan. 1796

The Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study is a nationwide, prospective, multicenter observational study that was designed to enroll hypertensive Japanese patients (>30,000 subjects). The patients in this study received treatment with open-label losartan, an angiotensin II receptor antagonist, for a maximum of 5 years. This report summarizes the study protocol and the baseline characteristics of the patients. Between June 2000 and May 2002, patients were screened in all 47 prefectures around Japan. Among the 31,515 patients screened, 31,048 patients were enrolled in this study and treated with losartan at a daily dose of 25-50 mg. These patients were 62.4 +/- 12.1 years old (mean +/- SD) and the mean clinic systolic/diastolic blood pressure (BP) values were 165.3 +/- 17.3/94.3 +/- 11.7 mmHg (mean +/- SD). The complications of hyperlipidemia, diabetes mellitus, cardiovascular disease, and cerebrovascular disease were also present in 38.5%, 13.1%, 8.0%, and 4.4% of patients, respectively. Regarding the World Health Organization classification, grade 2 hypertension was most frequent in this patient cohort. Nearly 10,000 patients agreed to perform home BP monitoring and report details regarding their lifestyles at baseline. Among the patients, 4.2% had white coat hypertension at the baseline. The J-HEALTH study is expected to provide valuable information about the significance of clinic and home BP control and home BP monitoring for the management of hypertension in Japanese patients.
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PMID:Design and baseline characteristics of an observational study in Japanese patients with hypertension: Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH). 1803 73

Renal pathology and dyslipidemia commonly coexist. Treatments that lower albuminuria/proteinuria may lower lipids, but it is not known whether lipid lowering independent of lessening albuminuria/proteinuria slows progression of kidney disease. We examined the association between LDL cholesterol levels and treatment with losartan on end-stage renal disease (ESRD). Lipid levels and albuminuria measurements were obtained at baseline and at year 1 in a post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, which compared the effects of losartan- versus placebo-based antihypertensive therapy in patients with type 2 diabetes and nephropathy. LDL cholesterol lowering was associated with a lower risk of ESRD; however, this seemed to be largely an association with the reduction in albuminuria.
Diabetes Care 2008 Mar
PMID:Effect of LDL cholesterol and treatment with losartan on end-stage renal disease in the RENAAL study. 1807 Sep 95

Moderate elevations in blood pressure translate to significant increases in cardiovascular and cerebro vascular risk. Beneficially, this relationship allows small decreases in blood pressure to be associated with risk reduction. Both the renin-angiotensin system and the sympathetic nervous system are involved in hypertension, hence targeting these systems is likely to be of benefit in the treatment of hypertension. Angiotensin II type 1 receptor blockers (ARBs) are used for controlling blood pressure and treating heart failure in a broad range of patients, including those with diabetes and the elderly. Not only have ARBs shown good efficacy and tolerability, they also appear to have a protective effect that goes beyond that expected from the reduction of blood pressure. The ARB eprosartan is a nonbiphenyl nontetrazole angiotensin II type 1 receptor (AT1) antagonist, which acts to decrease total peripheral resistance. Eprosartan acts at vascular AT1 receptors (postsynaptically) and at presynaptic AT1 receptors, where it inhibits noradrenaline release. In clinical studies, eprosartan has been shown to significantly reduce cardiovascular and cerebrovascular events, whilst avoiding the persistent cough that commonly occurs with the use of angiotensin-converting enzyme inhibitors. Eprosartan can also be differentiated from other ARBs due to its noradrenergic effects, which other ARBs used at therapeutic doses do not possess. Eprosartan, therefore, represents a useful therapeutic option in the management of patients with hypertension, including those with a history of stroke or with co-morbid type 2 diabetes mellitus.
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PMID:Introduction: The pharmacological profile of eprosartan--implications for cerebrovascular and cardiovascular risk reduction. 1809 7


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