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

Diabetes mellitus type 2 (DM type 2) is associated with depressive symptomatology and intermittent hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis. DM type 2 is also accompanied by increased tissue levels of angiotensin II (Ang II), which stimulates the HPA axis through the Ang II type 1 receptors (AT1). We investigated the effect of candesartan, an angiotensin receptor blocker (ARB) that crosses the blood brain barrier, on the activity of the HPA axis and on the affect of 17 patients with DM type 2, aged 40-65 years, who were treated with 4 mg/day candesartan per os for at least 3 months. Before and after candesartan administration, a corticotropin-releasing hormone (CRH) stimulation test and psychological tests were performed. In response to hCRH, time-integrated secretion of ACTH was not altered by candesartan administration, however, the cortisol response was decreased significantly compared to baseline (mean +/- SEM, 2327 +/- 148.3 vs. 1943 +/- 131.9 microg/dl, P = 0.005) suggesting reduced sensitivity of the adrenals to ACTH. In parallel, there was a significant improvement in interpersonal sensitivity (0.91 +/- 0.16 vs. 0.70 +/- 0.15, P = 0.027) and depression scores (0.96 +/- 0.15 vs. 0.71 +/- 0.10, P = 0.026). We suggest that candesartan resets the HPA axis of patients with DM type 2 and improves their affect.
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PMID:Chronic administration of an angiotensin II receptor antagonist resets the hypothalamic-pituitary-adrenal (HPA) axis and improves the affect of patients with diabetes mellitus type 2: preliminary results. 1785 61

Recent studies questioned the existence of a specific renoprotective effects of ACE-inhibitors (ACE-i) and angiotensin receptor blockers (ARBs) besides their blood pressure lowering effect. In the ALLHAT study patients were randomly assigned to receive chlorthalidone, amlodipine and lisinopril. Results showed that, even in patients with reduced GFR, neither lisinopril nor amlodipine was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR. Because of inclusion criteria the ALLHAT population was selected as at low risk for renal outcomes. Moreover, over 50% of the patients who were randomized to lisinopril either never received the medication or received the lower possible dose. Casas et al selected RCT comparing ACE-i and ARBs with other regimens. They concluded that ACE-i and ARBs are not more renoprotective that can be explained by lowering of blood pressure (BP) in diabetic nephropathy, while in non diabetic kidney disease a blood pressure independent renoprotective effect is uncertain. They made a very heterogeneous selection of trials that was dominated by the ALLHAT study; the analysis was not based on individual patient data. The Benedict Study showed that in hypertensive, normoalbuminuric patients with type 2 diabetes, BP reduction and ACE-i therapy both independently may prevent microalbuminuria. ACE-i therapy is particularly effective when BP is poorly controlled. We conclude that the recommendation of the Guidelines to use ACE-i and/or ARBs as first-line antihypertensive drugs for renoprotection in patients with diabetic and non diabetic kidney disease is still valid.
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PMID:[Antihypertensive therapy and renoprotection: do we really need to block the renin-angiotension system?]. 1788 9

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.
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PMID:Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects. 1798 25

The blood pressure (BP) goals set by hypertension management guidelines (<140/90 mm Hg in uncomplicated hypertension; <130/80 mm Hg in type 2 diabetes or kidney disease) are not being achieved in a high proportion of patients, partly because monotherapy is insufficient in many patients. In particular, patients with uncontrolled moderate or severe hypertension and/or associated cardiovascular risk factors remain at high risk for cardiovascular events and hypertensive emergency. In recognition of the urgency of treating moderate and severe hypertension, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) advocates the initial use of 2-drug therapies in patients with systolic BP levels >20 mm Hg above goal or diastolic BP level >10 mm Hg above goal. Regimens should usually include a thiazide diuretic and, for patients with diabetes or kidney disease, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Recently, clinical trial data have shown that first-step antihypertensive treatment of moderate and severe hypertension with carefully chosen fixed-dose combinations provides a high rate of BP goal achievement, a simplified dosing regimen, and superior tolerability compared with monotherapy.
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PMID:Emerging insights in the first-step use of antihypertensive combination therapy. 1804 7

Diabetic nephropathy is an important cause of morbidity and mortality in patients with either type 1 or type 2 diabetes mellitus. The pathogenesis and natural history of diabetic nephropathy, characterised by a progressive decline in glomerular function, were initially described in patients with type 1 diabetes. Reports that describe the glomerulopathy and progression of renal disease in patients with type 2 diabetes suggest that the disease process is similar to that observed in patients with type 1 diabetes with diabetic nephropathy. An emerging body of evidence supports the notion that glomerular capillary wall and mesangial alterations in diabetic nephropathy involve pathobiochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic, reveal that the administration of heparin and other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria. Clinical reports of the use of sulodexide, a preparation of low molecular weight glycosaminoglycan polysaccharides, have shown that proteinuria is significantly diminished in patients with diabetic nephropathy, even when these patients are receiving either an ACE inhibitor or angiotensin receptor antagonist.
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PMID:The role of sulodexide in the treatment of diabetic nephropathy. 1806 18

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can decrease hemoglobin, causing anemia and this may be an independent risk factor for chronic kidney disease progression. We studied the relationship between a decline in hemoglobin and outcome in 1513 patients with type 2 diabetes and kidney disease by a post hoc analysis of the RENAAL Study (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) with an average follow-up of 3.4 years. The relationship between baseline and year-1 hemoglobin and treatment on end-stage renal disease (ESRD) and ESRD or death was evaluated using multivariate Cox models (covariates: baseline hemoglobin, proteinuria, serum albumin, serum creatinine, and year-1 hemoglobin). Compared with placebo, losartan treatment was associated with a significant decrease of hemoglobin, with the largest between-group difference at 1 year. After adjustment, there were significant relative risk reductions for losartan compared with placebo for ESRD and for ESRD or death regardless of the baseline hemoglobin even in those patients with a baseline hemoglobin below 120 g l(-1). Hence, the renoprotective properties of losartan were maintained despite a significant lowering of the hemoglobin concentration.
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PMID:The effect of losartan on hemoglobin concentration and renal outcome in diabetic nephropathy of type 2 diabetes. 1809 75

The secondary analysis of the Irbesartan/Hydrochlorothiazide Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) clinical trial investigated whether baseline demographic and clinical variables are predictive of different degrees of blood pressure reduction following an angiotensin II receptor blocker/diuretic treatment regimen. Irbesartan/hydrochlorothiazide and other angiotensin receptor blocker combinations with a diuretic have been shown to be effective in reducing systolic blood pressure in a diverse patient population previously uncontrolled on monotherapy. Ordinary least squares regression analysis was performed on the intent-to-treat population of the INCLUSIVE study to identify variables predictive of variations in blood pressure changes in response to irbesartan/hydrochlorothiazide combination therapy. Higher baseline systolic blood pressure, female sex, type 2 diabetes, and statin therapy were found to be predictive of additional blood pressure lowering with this combination. The impact of higher baseline systolic blood pressure and diabetic state on changes in systolic blood pressure were diminished in female patients compared with male patients. In conclusion, a significant correlation may exist between certain clinical/demographic characteristics and the extent of the therapeutic response with irbesartan/hydrochlorothiazide treatment.
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PMID:Predictors of blood pressure response to angiotensin receptor blocker/diuretic combination therapy: a secondary analysis of the irbesartan/hydrochlorothiazide blood pressure reductions in diverse patient populations (INCLUSIVE) study. 1817 68

Advanced glycation endproducts (AGEs) are unavoidable byproducts of various metabolic pathways. They are formed by reactive metabolic intermediates such as methylglyoxal (MG), glyoxal, and 3-deoxyglucosone. These reactive intermediates bind to proteins, DNA, and other molecules and disrupt their structures and functions, which leads to different diseases such as vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, and aging. In recent years, more compounds that prevent the formation of AGEs or degrade the existing AGEs have been produced and patented. They include: 1) aminoguanidine, 2) drugs used in the treatment of type 2 diabetes such as metformin and pioglitazone (patented), 3) angiotensin receptor blockers and angiotensin converting enzyme inhibitors, 4) pentoxyfylline (patented), 5) metal ion chelators desferoxamine and penicillamine, 6) antioxidants such as vitamin C or E, 7) amino group capping agents such as aspirin, 8) enzymes that cause deglycation of Amadori products, the Amadoriases, 9) compounds that mostly break alpha-dicarbonyl cross-links such as phenacylthiazolium bromide and its stable derivative ALT-711 (Alagebrium), and 10) derivatives of aryl ureido and aryl carboxaminido phenoxy isobutyric acids (patented). While some of these anti-AGE compounds are being used in clinical practice (such as metformin, pioglitazone, pentoxyfylline and aspirin) or tested in clinical trials (such as aminoguanidine and ALT-711), most of them are commonly used as experimental tools to investigate the role of AGEs in different disease conditions.
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PMID:Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? 1822 Nov 7

Treatment with different antihypertensive drug classes has varied effects on glucose metabolism. Thiazide diuretic use in hypertensives has been associated with the development of glucose intolerance and diabetes. Some findings suggest that the probability of worsening glucose metabolism and the development of new diabetes after thiazide initiation is associated with increasing body mass index. Nonselective or beta(1) selective beta-blockers may also lead to decreased insulin sensitivity in hypertensive patients. Newer beta-blockers that cause vasodilatation and beta-blockers that have intrinsic sympathomimetic activity may not have these deleterious effects on insulin sensitivity and glucose metabolism. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers may exert beneficial effects on glycemic control through a variety of mechanisms related to the inhibition of angiotensin II. These agents may be particularly useful in patients with microalbuminuria to slow the progression of renal disease. While there may be some small differences among different classes of calcium channel blockers, there is little net effect of these agents on glucose metabolism. The prevalence of obesity, hypertension, and type 2 diabetes mellitus is increasing in the US. In this setting, it is important to individualize antihypertensive therapy and to monitor its metabolic consequences so that potential adverse effects that would negate some of the benefits of blood-pressure lowering are minimized.
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PMID:Effects of antihypertensives on glucose metabolism. 1837 Jul 75

Increased arterial stiffness, as estimated from aortic pulse wave velocity (Ao-PWV), and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus (T2DM). Whether angiotensin receptor blockers (ARBs), drugs with cardio-renal protective effects, improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear. After a 4-week washout phase, we compared the effects of valsartan (n=66), an ARB, with that of amlodipine (n=65), a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure (PP) >or=60 mm Hg and raised albumin excretion rate (AER) in a 24-week randomized, double-blind, parallel group study. Hydrochlorothiazide (HCTZ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control. After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean (SD) brachial and central PP of 61.6 (13.6) and 47.3 (14.1) mm Hg in the valsartan/HCTZ group and 61.5 (12.2) and 47.3 (9.9) mm Hg in the amlodipine group, respectively. Ao-PWV showed a significantly greater reduction, mean (95% CI), -0.9 m/s (-1.4 to -0.3) for valsartan/HCTZ compared to amlodipine (P=0.002). AER fell significantly only with Val/HCTZ from 30.8(20.4, 46.5) to 18.2(12.5, 26.3) mcg/min, (P=0.01) with between treatment difference in favor of Val/HCTZ of -15.3mcg/min (P<0.001). Changes in AER and Ao-PWV were not correlated. Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control. These 2 effects, which appear independent of each other, may explain the specific cardio-renal protective properties of ARBs.
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PMID:Valsartan improves arterial stiffness in type 2 diabetes independently of blood pressure lowering. 1842 91


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