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)

This study examined whether telmisartan, a unique angiotensin II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, improved insulin resistance in advanced glycation end-product (AGE)-exposed human hepatoma (Hep3B) cells. AGE increased phosphorylation of insulin receptor substrate-1 (IRS-1) at serine-307 residues in Hep3B cells. It also decreased tyrosine phosphorylation of IRS-1 and, subsequently, reduced the association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by telmisartan. The insulin-sensitizing properties of telmisartan in AGE-exposed Hep3B cells were significantly blocked by GW9662, an inhibitor of PPAR-gamma. Candesartan, another ARB, did not affect AGEs-induced serine phosphorylation of IRS-1 at serine-307 residues in Hep3B cells. Our study suggests that telmisartan could improve AGE-elicited insulin resistance in Hep3B cells by inhibiting serine phosphorylation of IRS-1, at least in part, via activation of PPAR-gamma. Telmisartan may play a protective role against hepatic insulin resistance in diabetes.
 ...
PMID:Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-elicited hepatic insulin resistance via peroxisome proliferator-activated receptor-gamma activation. 1838 Sep 32

Volume depletion due to persistent glucosuria-induced osmotic diuresis is a significant problem in uncontrolled diabetes mellitus (DM). Angiotensin II receptor blockers (ARBs), such as candesartan, slow the progression of chronic kidney disease in patients with DM. However, mice with genetic knockout of components of the renin-angiotensin system have urine concentrating defects, suggesting that ARBs may exacerbate the volume depletion. Therefore, the effect of candesartan on UT-A1, UT-A3, NKCC2, and aquaporin-2 (AQP2) protein abundances was determined in control and 3-wk DM rats. Aldosterone levels in control rats (0.36 +/- 0.06 nM) and candesartan-treated rats (0.34 +/- 0.14 nM) were the same. DM rats had higher aldosterone levels (1.48 +/- 0.37 nM) that were decreased by candesartan (0.97 +/- 0.26 nM). Western analysis showed that UT-A1 expression was increased in DM rats compared with controls in inner medullary (IM) tip (158 +/- 13%) and base (120 +/- 25%). UT-A3 abundance was increased in IM tip (123 +/- 11%) and base (146 +/- 17%) of DM rats vs. controls. UT-A3 was unchanged in candesartan-treated control rats. In candesartan-treated DM rats, UT-A3 increased in IM tip (160 +/- 14%) and base (210 +/- 19%). Candesartan-treated DM rats had slightly higher AQP2 in IM (46%, P < 0.05) vs. control rats. NKCC2/BSC1 was increased 145 +/- 10% in outer medulla of DM vs. control rats. We conclude that candesartan augments compensatory changes in medullary transport proteins, reducing the losses of solute and water during uncontrolled DM. These changes may represent a previously unrecognized beneficial effect of type 1 ARBs in DM.
 ...
PMID:Candesartan augments compensatory changes in medullary transport proteins in the diabetic rat kidney. 1841 38

Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of the angiotensin II receptor blocker (ARB) candesartan and the calcium channel blocker (CCB) amlodipine on the incidence of cardiovascular (CV) events in Japanese high-risk hypertensive patients. After 3.2years follow-up, CV events rate was 17.6-17.7 per 1000 person-years in each group, which was much lower than we expected. Since it has not been known whether the same efficacy of two drugs is sustained beyond the current trial, a longer follow-up period will be needed. The Steering Committee of CASE-J trial decided to extend the trial for 3years as an observational study (CASE-J Ex). In CASE-J Ex, the primary end point is a composite of CV events and the secondary endpoints are all-cause death and new-onset diabetes. After Committee's decision, 245 doctors agreed to participate in CASE-J Ex and 2236 patients (1141 with candesartan-based regimens and 1095 with amlodipine-based regimens) were re-enrolled. The baseline characteristics of CASE-J Ex participants were similar to CASE-J participants and still balanced well between candesartan and amlodipine. Recently, the interest of antihypertensive treatment has focused to differentiation of the effects of antihypertensive agents on the incidence of CV events as well as blood pressure lowering effect. CASE-J Ex will clarify the long-term effects of ARB and CCB on CV mortality and morbidity. Additionally, because the number of diabetic patients is increased, the evidences from CASE-J Ex will be valuable.
 ...
PMID:Long-term effects of candesartan and amlodipine on cardiovascular mortality and morbidity in Japanese high-risk hypertensive patients: rationale, design, and characteristics of candesartan antihypertensive survival evaluation in Japan extension (CASE-J Ex). 1882 34

The aim of the research was to evaluate some clinical and hemodynamic characteristics in patients with diabetes mellitus type 1 and type 2 (DM type 1 and DM type 2), to diagnose diabetic retinopathy (DR) on early stage of its development for the correction of the disease by treating with angiotensin II type 1 receptor blocker (AT I)--Candesartan. Totally 250 patients (pts) with DM type 1 and DM type 2 were studied; they were divided into 3 groups (Gr.): Gr.1 (n=115)--pts with DM and without DR; Gr. 2 (n=43)--pts with DM type 1 and DR; Gr.3 (n=92)--pts with DM type 2 and DR. A comprehensive physical examination was conducted to obtain baseline information about the patient: clinical status, lipid profile, microalbuminuria and urine creatinine, as well as glycemia levels. Patients were treated with Candesartan (16 or 32 mg) or placebo. When necessary, other antihypertensive agents (except ACE-inhibitors) were initiated. Eye fundus monitoring was performed with evaluation of 7,300 standard zone stereoscopic pictures of the retina according to ETDRS (Early Treatment of Diabetic Retinopathy Study). The results of three year observation revealed no pathologic changes on the retina in normotensive and normoglycemic pts; pts with mild diabetic retinopathy at baseline demonstrated normal levels of ABP and blood glucose which resulted in the regression of the changes. The changes of various severity demonstrated no positive shifts in 96% of cases; DR deterioration (proliferative DR, neovascularisation stage) was observed in 4% of cases. Results of the study showed that Candesartan treatment of pts with DM resulted in positive shifts in the pathologic changes, registered on the retina and decrease in urine albumin excretion rate. Thus, we recommend to include Candesartan in the standard treatment, as the have positive effect on the course microvascular complications of diabetes mellitus both in males and females.
 ...
PMID:[Positive effects of angiotensin [corrected] receptor blockers on the course of microvascular complications of diabetes mellitus]. 1883 32

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was a comparative study of the angiotensin II receptor blocker (ARB), candesartan, and a calcium channel blocker (CCB), amlodipine, regarding the incidence of cardiovascular events in high-risk Japanese hypertensive patients. The study design was a prospective, multicenter, randomized, open-label, active-controlled, two-arm, parallel-group comparison study with a response-dependent dose titration and blinded assessment of the end point. The CASE-J trial enrolled 4728 patients, with a mean age of 63.8 years and a mean BMI of 24.6 kg/m(2), who were randomly assigned to either candesartan- or amlodipine-based treatment regimens. Blood pressure was well controlled to the level of less than 140/80 mmHg in both of the treatment regimens. During 3.2 years of follow-up, primary cardiovascular events occurred in 134 patients in each of the two treatment-based regimens, resulting in no significant difference in the incidence of cardiovascular events between them (hazard ratio: 1.01; 95% confidence interval: 0.79-1.28; p = 0.969). In 404 patients with left ventricular hypertrophy, a significantly larger decrease in left ventricular mass index 3 years after enrollment was observed in candesartan-based (n = 205) than amlodipine-based (n = 199) regimens (-22.9 vs -13.4 g/m(2), respectively; p = 0.023). Furthermore, new-onset diabetes occurred in fewer patients taking candesartan than in those taking amlodipine, resulting in a 36% relative risk reduction (p = 0.030). The CASE-J trial demonstrated that both an ARB, candesartan, and a CCB, amlodipine, equally suppressed the incidence of cardiovascular events. The ARB may confer more beneficial effects to hypertensive patients with left ventricular hypertrophy or for those at-risk of diabetes than CCB.
 ...
PMID:ARB candesartan and CCB amlodipine in hypertensive patients: the CASE-J trial. 1893 7

Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P<or=0.01). Liver fat content was higher (P<0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (P<0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (P<0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides.
 ...
PMID:Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study. 1925 58

The nonlinearity of cardiovascular regulation is higher in normal physiology, whereas several diseases are characterized by a reduction in this nonlinearity. Reduced nonlinearity of heart rate regulation is a robust risk factor for high mortality in patients with myocardial infarction. We investigated the changes in linear and nonlinear correlations of cardiovascular regulation after administering drugs in hypertensive diabetic rats. Type 1 diabetes was induced in rats by intraperitoneally injecting spontaneously hypertensive rats with streptozotocin. The animals were then divided into 4 groups and each group was given vehicle, candesartan, amlodipine, or insulin for 2 weeks. Blood pressure, heart rate, renal sympathetic nerve activity, and renal blood flow were simultaneously recorded in the conscious state, and the linear and nonlinear correlations were compared by using coherence and the mutual information method. Candesartan and amlodipine decreased blood pressure to a similar extent, but renal sympathetic nerve activity was significantly lower in the candesartan group than in the vehicle group. The renal sympathetic nerve activity in the insulin group was also lower than in the vehicle group. There were no significant differences in linear correlation among the 4 groups. In contrast, the nonlinear correlations between renal sympathetic nerve activity and blood pressure in the candesartan group and the insulin group were significantly higher than in the vehicle group. Candesartan and insulin decreased renal sympathetic nerve activity and increased the nonlinearity. These results suggest that reducing the activity of renin-angiotensin system and insulin that lowers blood glucose level may improve autonomic nervous system dysfunction and neurohumoral regulation of the cardiovascular system in diabetic hypertensive rats.
 ...
PMID:Candesartan and insulin reduce renal sympathetic nerve activity in hypertensive type 1 diabetic rats. 1901 2

We examined the effects of candesartan and amlodipine on cardiovascular events in hypertensive patients with chronic kidney disease (CKD) using the data from the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial. CKD was defined as proteinuria and/or decreased GFR (<60 ml per min per 1.73 m(2)) at enrollment. Among 2720 subjects with CKD, there were 1376 and 1344 patients in the candesartan and the amlodipine group, respectively. During a 3.2-year follow-up, cardiovascular event rate did not differ in the two groups (7.2% for candesartan and 7.6% for amlodipine). In the subgroup analysis based on the CKD stage, there were no significant differences in the incidence rates of cardiovascular events between the two groups in stages 1+2 and 3 CKD. In stage 4 CKD, however, candesartan reduced the incidence of cardiovascular events (55% risk reduction), particularly of renal events (81% risk reduction), compared with amlodipine. Furthermore, composite cardiovascular events were increased as the CKD stage progressed, and this effect was exaggerated in the presence of proteinuria. Finally, the new onset of diabetes was less in the candesartan-based regimen in stage 3 CKD. In conclusion, candesartan protected hypertensive patients with CKD more potently against renal events, particularly in moderately-to-severely impaired CKD. Furthermore, candesartan prevented a new onset of diabetes in CKD, which would be favorable for the long-term management of CKD.
 ...
PMID:Effects of candesartan and amlodipine on cardiovascular events in hypertensive patients with chronic kidney disease: subanalysis of the CASE-J Study. 1939 May 35

The prevalence of heart failure is ever increasing around the world, particularly due to aging populations. Despite improvements in treatment over the last 20 years, the prognosis for heart failure remains poor. Among the treatments recommended for chronic heart failure, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers are crucial, provided of course that they are not contraindicated. However, angiotensin II receptor blockers (ARBs) can also be a beneficial treatment option. Candesartan is a particular ARB, characterized by a strong binding affinity to the angiotensin II type 1 receptor and slow dissociation. The benefits of candesartan have been demonstrated by the CHARM programme, which showed that candesartan significantly reduces the incidence of cardiovascular death, hospital admissions for decompensated heart failure, and all-cause mortality in chronic heart failure patients with altered left ventricular systolic function, when added to standard therapies or as an alternative to ACE inhibitors when these are poorly tolerated. Furthermore, candesartan can protect against myocardial infarction, atrial fibrillation and diabetes. Tolerance to candesartan is good, but blood pressure and serum potassium and creatinine levels must be monitored.
 ...
PMID:Candesartan cilexetil in the treatment of chronic heart failure. 1943 50

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial assessed cardiovascular outcomes in high-risk hypertensive patients receiving either candesartan or amlodipine. The aim of this study was to examine the role of pre-existing diabetes or obesity on these outcomes as a sub-analysis of the trial. We examined the influence of pre-existing diabetes on cardiovascular morbidity and mortality using a multivariate Cox regression model. The cardiovascular morbidity and mortality of candesartan and amlodipine were compared between subgroups with or without pre-existing diabetes or by body mass index (BMI) category, and new-onset diabetes was compared by BMI category. Pre-existing diabetes greatly increased the cardiovascular mortality and morbidity, regardless of the allocated drugs. Furthermore, all-cause mortality was significantly higher with amlodipine than with candesartan among patients with BMI >or=27.5 kg m(-2) (adjusted hazard ratio (HR)=0.32; range=0.13-0.75; P=0.009). New-onset diabetes occurred significantly less frequently with candesartan than with amlodipine, with an adjusted HR of 0.66 (P=0.043). Furthermore, the increase in new-onset diabetes was dependent on BMI among patients receiving amlodipine, whereas no such dependency was observed for candesartan (interaction P=0.016). In conclusion, preexisting diabetes increased the risk of experiencing a cardiovascular event among high-risk Japanese hypertensive patients. Candesartan treatment may suppress all-cause death and reduce the incidence of new-onset diabetes in patients with obesity.
 ...
PMID:Role of diabetes and obesity in outcomes of the candesartan antihypertensive survival evaluation in Japan (CASE-J) trial. 2066 48


<< Previous 1 2 3 4 5 Next >>