Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.
 ...
PMID:ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy. 1819 98

An insertion (I)/deletion (D) polymorphism of the angiotensin-converting-enzyme (ACE) gene influences the circulating and renal activity of the renin-angiotensin-aldosterone system. This Practice Point commentary discusses a 2008 paper by Parving et al. that analyzed the interaction between losartan and the I/D polymorphism in patients in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. The investigators found that patients with type 2 diabetes and proteinuria who have the D allele have an unfavorable renal prognosis, which is improved by losartan treatment (vs placebo) when given together with conventional antihypertensive treatment. No significant improvement in outcomes was observed in losartan-treated patients with the II genotype. Previous observational studies had suggested a decreased beneficial effect of ACE inhibitors in patients with type 1 diabetic nephropathy who have the DD genotype. Prospective studies in this area are needed before I/D genotype characterization can be used to guide the choice of therapy in patients with diabetes and proteinuria.
 ...
PMID:ACE gene polymorphism and the prognosis and treatment of overt diabetic nephropathy. 880 48

Elevated blood pressure levels are highly prevalent and are a major reason for cardiovascular events and thus place a significant financial burden on healthcare systems worldwide. Guidelines recommend five first-line anti-hypertensive drug classes, but compelling indications may indicate favoring one drug class over another. Angiotensin receptor blockers (ARBs) have demonstrated a blood pressure lowering efficacy which is at least comparable with other drug classes, including ACE inhibitors (ACE-I), beta-blockers, calcium channel blockers and diuretics. They have, in addition, a lower side effect profile than other drug classes and patients on ARBs are more persistent with therapy. Compelling indications for the use of ARBs are heart failure, post-myocardial infarction, diabetic nephropathy, proteinuria/microalbuminuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and ACE-I induced cough. The ARB irbesartan has demonstrated a high efficacy in lowering blood pressure, which has been shown to be at least comparable with ACE-Is and superior to other ARBs such as losartan and valsartan. This translated into a better cost-effectiveness for irbesartan than for valsartan and losartan in the treatment of hypertension. In addition, irbesartan has been shown to be effective in both early and late stage diabetic nephropathy. It has further demonstrated considerable cost savings over standard therapy including beta-blockers, diuretics and non-dihydropyridine calcium channel blockers at all stages of kidney disease. Based on efficacy data from the Irbesartan Diabetic Nephropathy Trial and Reduction of Endpoints in NIDDM (non insulin dependant diabetes melitis) with the Angiotensin II Antagonist Losartan Study, it has also demonstrated cost savings over losartan in late stage renal disease. While both losartan and irbesartan are registered for the treatment of late stage diabetic nephropathy, irbesartan is also registered for early stage diabetic nephropathy in the EU. In summary, the data from randomized clinical trials on the efficacy of antihypertensive drugs provides an indication of their real value to patients. In addition observational data from clinical practice and proven end-organ protection in diabetic nephropathy provides further evidence of the true value of irbesartan compared to other ARBs in the treatment of hypertension.
 ...
PMID:The value of irbesartan in the management of hypertension. 1960

Hypertension is a major risk factor for the development of cardiovascular disease. Numerous placebo-controlled trials have demonstrated that treatment of hypertension results in substantial reduction of hypertension-related vascular events. The benefit of specific therapies beyond their effect on blood pressure is well established. Losartan is an orally-active, selective, nonpeptide, angiotensin II type 1-receptor antagonist (ARB), and it was the first in this class to be marketed. Several large-scale clinical trials have demonstrated that losartan and other ARBs have benefits in preventing cardiovascular disease. The Losartan Intervention For End point reduction in hypertension (LIFE) study demonstrated improved outcomes with losartan as compared with atenolol-based therapies in hypertensive patients with left ventricular hypertrophy, mainly because of stroke prevention. The Reduction of End points in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated that losartan prevented the progression of diabetic nephropathy. In this review, evidence from these and other clinical trials with losartan shall be discussed. The pharmacodynamic and pharmacokinetic properties of losartan are described to explain its mechanisms of action. Among the ARB class, losartan possesses certain unique properties, which may enhance its cardiovascular protective effects. These include an increase of urinary uric acid excretion and antiatherothrombotic properties. Potential future roles for losartan and other ARBs shall be discussed, in addition to emphasizing areas in which evidence is currently lacking or indecisive, including head-to-head comparisons of ARBs and the effects of combining an ARB with angiotensin-converting-enzyme inhibitors.
 ...
PMID:Losartan in cardiovascular disease. 1980 43

The mechanisms underlying the effect of the renin-angiotensin-aldosterone system (RAAS) inhibition on endothelial dysfunction in type 2 diabetes are incompletely understood. This study explored a causal relationship between RAAS activation and oxidative stress involved in diabetes-associated endothelial dysfunction. Daily oral administration of valsartan or enalapril at 10 mg/kg/day to db/db mice for 6 weeks reversed the blunted acetylcholine-induced endothelium-dependent dilatations, suppressed the upregulated expression of angiotensin II type 1 receptor (AT(1)R) and NAD(P)H oxidase subunits (p22(phox) and p47(phox)), and reduced reactive oxygen species (ROS) production. Acute exposure to AT(1)R blocker losartan restored the impaired endothelium-dependent dilatations in aortas of db/db mice and also in renal arteries of diabetic patients (fasting plasma glucose level > or =7.0 mmol/l). Similar observations were also made with apocynin, diphenyliodonium, or tempol treatment in db/db mouse aortas. DHE fluorescence revealed an overproduction of ROS in db/db aortas which was sensitive to inhibition by losartan or ROS scavengers. Losartan also prevented the impairment of endothelium-dependent dilatations under hyperglycemic conditions that were accompanied by high ROS production. The present study has identified an initiative role of AT(1)R activation in mediating endothelial dysfunction of arteries from db/db mice and diabetic patients.
 ...
PMID:Angiotensin II type 1 receptor-dependent oxidative stress mediates endothelial dysfunction in type 2 diabetic mice. 2013 8

We recently showed that losartan and paricalcitol are synergistic in the treatment of diabetic nephropathy in a model of type 1 diabetes. To test this strategy in a model of type 2 diabetes, we treated 2-month-old diabetic Lprdb/db mice with losartan, paricalcitol, or a combination of losartan and paricalcitol for 3 months. Vehicle-treated diabetic mice developed progressive albuminuria and glomerular abnormalities with mesangial expansion and glomerulosclerosis compared to their non-diabetic littermate control mice. Accompanying damage of the glomerular filtration barrier was a marked reduction in podocyte number as well as reduced expression of slit diaphragm proteins. Further, there was increased glomerular expression of extracellular matrix proteins, monocyte chemoattractant protein-1 and transforming growth factor-beta. Losartan or paricalcitol each alone moderately ameliorated albuminuria and glomerular damage. However, their combined use showed a dramatic therapeutic synergism, manifested by prevention of progressive albuminuria, restoration of the glomerular filtration barrier, reversal of the decline in slit diaphragm proteins, reduced synthesis of extracellular matrix proteins, and reduction of glomerulosclerosis. These effects were accompanied by blockade of the compensatory increase of renin production and angiotensin I/II accumulation in the kidney. Thus, our study further shows that vitamin D analogs can increase the efficacy of AT1 receptor blockade, leading to a more effective prevention of kidney disease in type 2 diabetes.
 ...
PMID:Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes. 2046 30

It is well known that type 2 diabetes mellitus is frequently associated with vascular dysfunction and an elevated systemic blood pressure, yet the underlying mechanisms are not completely understood. We previously reported that in mesenteric arteries from established type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats, which exhibit endothelial dysfunction, there is an imbalance between endothelium-derived vasodilators [namely, nitric oxide (NO) and hyperpolarizing factor (EDHF)] and vasoconstrictors [contracting factors (EDCFs) such as cyclooxygenase (COX)-derived prostanoids]. Here, we investigated whether the angiotensin II receptor antagonist losartan might improve endothelial dysfunction in OLETF rats at the established stage of diabetes. In mesenteric arteries isolated from OLETF rats [vs. those from age-matched control Long-Evans Tokushima Otsuka (LETO) rats]: (1) the acetylcholine (ACh)-induced relaxation was impaired, (2) the NO- and EDHF-mediated relaxations were reduced, (3) the ACh-induced EDCF-mediated contraction and the production of prostanoids were increased, and (4) superoxide generation was increased. After such OLETF rats had received losartan (25 mg/kg/day p.o. for 4 weeks), their isolated mesenteric arteries exhibited: (1) improvements in ACh-induced NO- and EDHF-mediated relaxations, (2) reduced EDCF- and arachidonic acid-induced contractions, (3) suppressed production of prostanoids, (4) reduced PGE(2)-mediated contraction, and (5) reduced superoxide generation. Within the timescale studied here, losartan did not change the protein expressions of endothelial NO synthase, COX1, or COX2 in mesenteric arteries from either OLETF or LETO rats. Losartan thus normalizes vascular dysfunction in this type 2 diabetic model, and the above effects may contribute to the reduction of adverse cardiovascular events seen in diabetic patients treated with angiotensin II receptor blockers.
 ...
PMID:Mechanisms underlying the losartan treatment-induced improvement in the endothelial dysfunction seen in mesenteric arteries from type 2 diabetic rats. 2030 70

Diabetic nephropathy is a leading cause of renal failure requiring replacement therapy. Diabetic nephropathy is typically characterized by persistent microalbuminuria progressing to nephrotic syndrome, a progressive decline in glomerular filtration rate, and hypertension. Diabetic nephropathy prevention strategies may involve early angiotensin-converting enzyme (ACE) inhibitor treatment and the control of diabetes to reduce glomerular hypertension and hyperfiltration. Treatment strategies include the use of ACE inhibitors or angiotensin receptor blockers (ARBs), and cholesterol-lowering agents. Early intervention is key to the prevention of more severe renal outcomes. Although intensive and early control of blood pressure (BP) is key to renoprotection, the class of antihypertensive has an important bearing on outcome. There is evidence for the efficacy of ARBs in preventing the progression from microalbuminuria to overt nephropathy (urine protein excretion >500 mg/day) from the IRbesartan in patients with diabetes and MicroAlbuminuria (IRMA 2) Study using irbesartan and the INcideNt to OVert: Angiotensin II receptor blocker, Telmisartan, Investigation On type 2 diabetic Nephropathy (INNOVATION) Study using telmisartan. For the management of overt nephropathy, the findings of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) demonstrate that losartan and irbesartan, respectively, reduce the time to doubling of serum creatinine levels and development of end-stage renal disease.
 ...
PMID:Slowing the progression of kidney disease in patients with diabetes. 2040 36

There are many methods to screen for abnormal amounts of proteinuria to identify patients at risk for progression of renal disease, but which method best predicts renal risk is unknown. Here, we analyzed a subset of 701 patients with type 2 diabetes and nephropathy participating in the Reduction of Endpoints in Non Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial to compare the ability of urinary protein excretion (UPE) and urinary albumin excretion (UAE) from a 24-hour urine collection and urinary albumin concentration (UAC) and the albumin:creatinine ratio (ACR) from a first-morning void in predicting renal events. The primary outcome measure was the time to a doubling of serum creatinine or end-stage renal disease. During follow-up, 202 events occurred. The hazard ratios for the risk of a renal outcome (95% CIs) associated with 1-SD increment in the log-transformed measures were 3.16 (2.60 to 3.86) for UAE, 3.02 (2.53 to 3.62) for UPE, 3.23 (2.67 to 3.91) for UAC, and 4.36 (3.50 to 5.45) for ACR. The area under the ROC curve was significantly higher for ACR compared with the other measures. In conclusion, measurement of the albumin:creatinine ratio in a first-morning void is the superior method to predict renal events in patients with type 2 diabetes and nephropathy.
 ...
PMID:Comparison of different measures of urinary protein excretion for prediction of renal events. 2063 99

Exogenous insulin therapy improves endothelial function in insulin resistant patients, indirectly indicating that nitric oxide synthase activity and NO production may be impaired. Insulin stimulates production of NO by activating a signaling pathway including insulin receptor substrate-1, phosphatidylinositol-3-kinase and protein kinase B (PKB/Akt). Angiotensin II type I (AT1) receptor-evoked oxidative stress is implicated in the inactivation of NO, impairing endothelium-dependent vasodilatation. Blocking the actions of Angiotensin II with an AT1 receptor antagonist (Losartan), has beneficial effects in patients with insulin resistance or type 2 diabetes mellitus. This study investigated whether elevated Angiotensin II influences myocardial insulin resistance, insulin signaling and NO production in a rat model of diet-induced obesity (DIO) by antagonizing the actions of the AT1 receptor with Losartan. Isolated, perfused hearts, Western blotting and flow-cytometric methods were utilized to determine myocardial function, expression and phosphorylation of key proteins and NO production, respectively. Results showed that hearts from DIO rats are insulin resistant (higher serine phosphorylation of IRS-1, lower insulin-stimulated phosphorylation of PKB/Akt and eNOS, lower NO production) and had poorer functional recovery and larger infarct development after ischaemia/reperfusion. Losartan improved the impaired functional recovery, and NO production and enhanced eNOS expression and phosphorylation and reduced infarct size in hearts from the DIO animals. Data obtained from Losartan treatment also revealed that Angiotensin II signaling modulates myocardial PKB/Akt expression. We conclude that Angiotensin II signaling exacerbates inhibition of NO production in insulin resistance and that this can be improved by AT1 antagonism.
 ...
PMID:ANG II type I receptor antagonism improved nitric oxide production and enhanced eNOS and PKB/Akt expression in hearts from a rat model of insulin resistance. 2115 3


<< Previous 1 2 3 4 5 6 Next >>