Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
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The goal of antihypertensive therapy is to provide effective treatment that can be sustained lifelong, while lowering elevated blood pressure and preventing hypertensive end-organ damage and mortality. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (AIIAs) control blood pressure as well as other available classes of antihypertensive drugs. The ACE inhibitors have been demonstrated to reduce the incidence of stroke, reverse left ventricular hypertrophy, and improve congestive heart failure symptomatology and mortality to a similar degree as diuretics and beta-adrenergic blockers. ACE inhibitors reduce postmyocardial infarction recurrence, improve congestive heart failure symptomatology and mortality, and slow the progression of glomerular renal disease. The AIIAs reverse left ventricular hypertrophy. Several of these agents have been shown to improve congestive heart failure symptomology and mortality, to reduce the occurrence of early atherosclerotic vascular disease, and to slow the progression of renal failure in type 2 diabetes mellitus nephropathy. One AIIA has reduced the incidence of end-stage renal disease in non-insulin-dependence diabetes mellitus nephropathy over 3 years. Ideally, antihypertensive therapy should maintain or improve the patients quality of life without creating side effects or adverse laboratory effects. Among the available nine classes of antihypertensive drugs, ACE inhibitors and the AIIAs come close to meeting the description of an ideal drug. AIIAs and ACE inhibitors, two classes of antihypertensive drugs that reduce the activity of the renin-angiotensin II system, should be among the preferred first-step drugs for the treatment of hypertension.
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PMID:Drugs that interrupt the renin-angiotensin system should be among the preferred initial drugs to treat hypertension. 1267 27

Angiotensin-converting enzyme (ACE) inhibitors are the first-line therapeutic agents for treating hypertension in patients with the cardiometabolic syndrome and those with diabetes. ACE inhibitor therapy reduces both microvascular and macrovascular complications in diabetes and appears to improve insulin sensitivity and glucose metabolism. Several recent studies indicate that ACE inhibitor therapy reduces the development of type 2 diabetes in persons with essential hypertension, a population with a high prevalence of insulin resistance. ACE inhibitor therapy has been shown to improve surrogates of cardiovascular disease (eg, vascular compliance, endothelial-derived nitric oxide production, vascular relaxation and plasma markers of inflammation, oxidative stress, and thrombosis) and reduce cardiovascular disease, renal disease progression, and stroke. This article explores potential mechanism by which ACE inhibition reduces the development of diabetes, improves these surrogate markers, and reduces cardiovascular disease and renal disease.
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PMID:Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. 1281 33

Microalbuminuria is an early marker of diabetic nephropathy and its prevention is considered key for the primary prevention of diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors and nondihydropyridine calcium channel blockers (CCBs) have specific renoprotective properties in diabetes, and preliminary evidence is available that they are more effective in combination than either of the two agents alone in limiting albuminuria either in micro- or macroalbuminuric type 2 diabetic patients. The BErgamo NEphrologic DIabetes Complications Trial (BENEDICT) is a prospective, randomized, double-blind parallel-group study primarily aimed at evaluating the possibility of preventing the progression to microalbuminuria (urinary albumin excretion [UAE] rate 20-200 microg/min, i.e., incipient nephropathy) in 1209 hypertensive, type 2 diabetic patients with a normal UAE rate (<20 microg/min). During phase A of the study, patients are randomized to a 3-year treatment with one of the following: (1) a nondihydropyridine CCB (verapamil SR 240 mg/day); (2) an ACE inhibitor (trandolapril 2 mg/day); (3) the combination of the above study drugs (verapamil SR 180 mg/day plus trandolapril 2 mg/day); or (4) placebo. Phase B of the study evaluates the progression to macroalbuminuria (UAE> or =200 microg/min) in patients who progress to microalbuminuria in phase A or are found with microalbuminuria during the screening phase; these patients are randomized to a 2-year treatment with either trandolapril (2 mg/day) alone or verapamil SR (180 mg/day) plus trandolapril (2 mg/day). BENEDICT final results are expected to be available by the end of 2003 for phase A and 2 years later for phase B. The BENEDICT study, in addition to exploring whether primary prevention of diabetic nephropathy is an achievable goal, will also offer an opportunity to study prospectively risk factors of nephropathy and other chronic complications of type 2 diabetes. Here we provide an overview of the protocol and summarize the main baseline demographic, biochemical, and clinical characteristics of randomized participants.
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PMID:The BErgamo NEphrologic DIabetes Complications Trial (BENEDICT): design and baseline characteristics. 1286 39

Diabetes complications are common and almost triple the annual cost of managing diabetes. Microvascular complications are the major risk in type 1 diabetes, while macrovascular complications are the major cause of morbidity and mortality in type 2 diabetes. Control of hyperglycaemia (target HbA(1c) level < or = 7%) and hypertension (target blood pressure < or = 130/80 mmHg) prevents microvascular complications in both types of diabetes; a multifactorial approach, comprising behaviour modification and pharmacological therapy for all risk factors, reduces the development of micro- and macrovascular complications in type 2 diabetes. The benefit of treating dyslipidaemia is at least as great in the diabetic population as in the non-diabetic population. Angiotensin-converting enzyme inhibitors and low-dose aspirin are indicated in people with diabetes and other cardiovascular risk factors. Regular annual screening for diabetes complications allows treatable disease to be identified. Aggressive management of hyperglycaemia and other risk factors can prevent many complications
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PMID:3: Preventing complications of diabetes. 1458 83

In individuals with diabetes mellitus, higher risk for renal and cardiovascular disease is seen with blood pressure levels >130/80 mm Hg. Findings of several studies, as well as new guidelines, indicate that individuals with diabetes will benefit from more aggressive treatment of hypertension. Angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, diuretics, beta-adrenoceptor blockers, and calcium-channel blockers are effective antihypertensive agents in type 2 diabetes. Moreover, combinations of these agents are frequently required to reach the target blood pressure of <130/80 mm Hg and reduce risk for renal and cardiovascular events. All of these agents have demonstrated benefits in treating patients. Clinical evidence also indicates that the new vasodilating beta-blockers offer advantages beyond blood pressure control, including cardiovascular risk reduction without exacerbating metabolic parameters. With increased awareness of the need for aggressive treatment of hypertension, clinicians can provide significant benefit to their patients with diabetes. The new beta-blockers may play an important role in achieving blood pressure goals.
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PMID:The importance of blood pressure control in the patient with diabetes. 1501 61

The metabolic abnormalities associated with diabetes mellitus result in macrovascular and microvascular complications in multiple organ systems; it is the cardiovascular impact that accounts for the greatest morbidity and mortality associated with this disease. Heart failure, both with reduced and preserved systolic function, is a major complication, arising from the frequent associations with coronary atherosclerosis, hypertension, and a specific heart muscle dysfunction (cardiomyopathy) that occurs independently of coronary artery disease. Hyperglycemia, insulin resistance, and hypertension, together with activation of both the circulating and the tissue renin-angiotensin-aldosterone systems, contribute to structural fibrosis and autonomic neuropathy. Thus, it becomes imperative to identify cardiac abnormalities early in the course of both type 1 and type 2 diabetes to allow early and aggressive intervention to control glucose and blood pressure and to normalize blood lipid profiles. Patients with diabetes should be treated to secondary prevention targets, including blood pressure less than 130/80 mm Hg and low-density lipoprotein cholesterol level less than 100 mg/dL. Angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers,beta blockers, calcium channel-blockers, statins, and aspirin have all been demonstrated to significantly reduce cardiovascular morbidity and mortality in patients with diabetes.
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PMID:Diabetes mellitus and heart failure. 1581 21

The risk of cardiovascular (CV) and renal complications begins at a relatively low blood pressure (BP), and this risk is associated with such disorders as metabolic syndrome. When comparing older antihypertensive agents with newer agents, for the most part no significant differences have been seen in rates of CV events. However, rapidly controlling BP is critical to reduce event rates, particularly rates of stroke. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers consistently decrease the rate of onset of type 2 diabetes.
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PMID:Improving cardiovascular health outcomes through the use of evidence-based medicine. 1582 33

Diabetic nephropathy is characterised by hypertension and persistent proteinuria. If ineffectively controlled, a progressive decline in renal function can result in end-stage renal disease. Patients with diabetic nephropathy are also at greatly increased risk of cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors display additional renoprotective effects beyond systemic blood pressure lowering, perhaps due to reduction in intraglomerular pressure by inhibition of angiotensin II activity. In type 2 diabetics, ACE inhibitors have variable effects, with some studies showing a reduction in microalbuminuria, prevention of the progression to macroalbuminuria and maintenance of renal function. Randomised studies have demonstrated that angiotensin II receptor blockers (ARBs), as well as controlling systemic blood pressure, delay progression of proteinuria in patients with diabetic nephropathy. Telmisartan has a number of features that may make it particularly suitable for the treatment of diabetic nephropathy. In addition to its long duration of action and almost exclusive faecal excretion, its high lipophilicity should assist in tissue penetration. The Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study was designed to compare the long-term renal outcome of treatment with telmisartan 40.80 mg versus enalapril 10.20 mg (with titration to the higher dose after 4 weeks) in patients with type 2 diabetes, mild-to-moderate hypertension and albuminuria. The primary endpoint is the change in glomerular filtration rate after 5 years' randomised treatment. Secondary endpoints are annual changes in glomerular filtration rate, serum creatinine and urinary albumin excretion, as well as incidences of end-stage renal disease, cardiovascular events, all-cause mortality and adverse events. The groundbreaking DETAIL study revealed that telmisartan conferred comparable renoprotection to enalapril and was associated with a low incidence of mortality.
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PMID:Preventing renal complications in diabetic patients: the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study. 1586 19

Long-term type 2 diabetes can lead to numerous biological complications, such as hypertension and cardio-vascular disease. Key enzymes involved in the enzymatic breakdown of complex carbohydrates,pancreatic alpha-amylase and intestinal alpha-glucosidase, have been targeted as potential avenues for modulation of type 2 diabetes-associated post-prandial hyperglycemia through mild inhibition of their enzymatic activities so as to decrease meal-derived glucose absorption. Further, inhibition of hypertension-linked angiotensin I-converting enzyme (ACE) was targeted as a potential approach for modulation of diabetes-linked hypertension. Water-soluble extracts of soybean optimized for phenolic content via sprouting or bioprocessing by dietary fungus (Rhizopus oligosporus, Lentinus edodes) were investigated for inhibitory activity against porcine pancreatic alpha-amylase (PPA), yeast alpha-glucosidase, and rabbit lung ACE in vitro. PPA was allowed to react with each phenolic-optimized extract and the derivatized enzyme-phytochemical mixtures obtained were characterized for residual amylase activity. Alpha-glucosidase and ACE activities were determined in the presence of each phenolic-optimized extract. All of the soybean extracts possessed marked anti-amylase activity, with extracts of R. oligosporus-bioprocessed soybean having the strongest inhibitory activity, but only slight anti-glucosidase activity. The anti-amylase activity of each extract seemed associated with extract antioxidant activity. Anti-enzyme activity was slightly associated with total soluble phenolic content per se, but seemed more associated to the length of sprouting or bioprocessing of the soybean substrate. Short-term sprouting or bioprocessing seemed to improve anti-amylase activity, while long-term sprouting or bioprocessing seemed to aid anti-glucosidase activity. While ACE activity was strongly inhibited by all of the soybean extracts (44-97%), only sprouting was found to increase this inhibition and bioprocessing of soybean with L. edodes decreased inhibitory activity of soybean extract. The results suggest that sprouting and dietary fungal bioprocessing of soybean improve the anti-diabetic potential of soybean extracts, potentially through modulation of the phenolic profile of the extract, and further suggest that enzyme inhibitory activity may be linked to phenolic antioxidant mobilization during spouting and/ or bioprocessing. The significance of food-grade, plant-based enzyme inhibitors for modulation of carbohydrate breakdown and control of glycemic index of foods in the context of preventing hyperglycemia and diabetes mellitus complications such as hypertension in the long-term is hypothesized and discussed.
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PMID:Anti-diabetic and anti-hypertensive potential of sprouted and solid-state bioprocessed soybean. 1592 31

Aggressive treatment of hypertension is effective in reducing both microvascular and macrovascular complications in type 2 diabetes, with target BP < 130/80 mmHg being recommended. Angiotensin-converting enzyme inhibitors were found to be more effective than the other traditional agents in reducing the onset of clinical proteinuria in individuals with both type 1 and type 2 diabetes and incipient nephropathy. However, small trials on patients with type 2 diabetes and overt nephropathy failed to demonstrate a specific renoprotective role for this class of drugs. The aim of the Program for Irbesartan Mortality and Morbidity Evaluation was to ascertain whether angiotensin II receptor blockers are effective in both preventing the development of clinical proteinuria and delaying the progression of nephropathy in type 2 diabetes. The Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) Study showed that, as compared with conventional therapy, irbesartan is better at preventing the development of clinical proteinuria and at restoring normoalbuminuria for comparable BP control in patients with incipient nephropathy. The Irbesartan Diabetic Nephropathy Trial showed that irbesartan is more effective than traditional antihypertensive therapies in reducing the progression toward ESRD in patients with type 2 diabetes and overt nephropathy regardless of changes in BP. Moreover, secondary analysis of the Irbesartan Diabetic Nephropathy Trial showed that the achieved systolic pressure as well as baseline and current proteinuria significantly predict renal outcomes. In conclusion, the results of the Program for Irbesartan Mortality and Morbidity Evaluation demonstrate that irbesartan significantly prevents the development of clinical proteinuria in individuals with microalbuminuria and delays the progression of nephropathy in individuals with proteinuria. Moreover, the renoprotective effects of irbesartan go beyond its effect on BP.
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PMID:Prevention and treatment of diabetic nephropathy: the program for irbesartan mortality and morbidity evaluation. 1593 34


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