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)

The factors that initiate chronic renal failure in patients with hypertension, diabetes mellitus, and chronic glomerular disease are largely unknown. The likely genetic contribution to ESRD, particularly in African Americans, suggests that linkage analysis may be useful to evaluate the role of candidate genes in the pathogenesis of chronic renal failure. The renin-angiotensin-aldosterone (RAA) axis has been intensively evaluated for its contribution to cardiovascular disease and nephropathy. This study tested for linkage between candidate genes in the RAA axis and chronic renal failure, using 85 African-American sibling pairs (from 65 families) concordant for ESRD. Angiotensinogen was selected because of the putative link between it and mild to moderate essential hypertension and nephrosclerosis; angiotensin-converting enzyme because of its possible contribution to diabetic nephropathy; and renin, the angiotensin II receptor, and kallikrein because of their roles in hypertension and renal perfusion. These candidate loci did not demonstrate linkage to either diabetic or nondiabetic renal disease in this study's collection of sibling pairs. These results suggest that polymorphisms at these RAA axis loci do not make major contributions to the pathogenesis of renal disease in African Americans.
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PMID:Linkage analysis between loci in the renin-angiotensin axis and end-stage renal disease in African Americans. 898 34

A review of recent studies suggests that the use of angiotensin-converting enzyme (ACE) inhibitors may be preferred (usually along with a diuretic drug) as initial therapy in several subsets of hypertensive patients (i.e., those with diabetes and nephropathy or with diminished left ventricular function with or without symptoms of heart failure). Limited long-term data are available for the angiotensin II receptor antagonists. The use of nondihydropyridine calcium channel blocking agents (CCBs) appears to reduce reinfarction in patients with ischemic heart disease (however, mortality is not reduced). Long-acting formulas of CCBs appear to decrease congestive heart failure in patients with dilated, but not ischemic, cardiomyopathy and to decrease strokes and arrhythmias in hypertensive subjects. Short-acting agents (primarily those that increase heart rate) may increase coronary heart disease events in hypertensive patients. There is little evidence at present that CCBs offer a major advantage over other antihypertensive agents or that they should be recommended as initial therapy, except in special situations.
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PMID:Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and calcium channel blocking agents: a review of potential benefits and possible adverse reactions. 918 98

We explored the relative roles of the suppression of angiotensin II and the prevention of bradykinin degradation in mediating the renoprotective effects of ACE inhibitors in experimental diabetic nephropathy. Over a 24-week period, we studied male Sprague-Dawley diabetic and control rats and Sprague-Dawley diabetic rats treated with the ACE inhibitor ramipril, the angiotensin II-AT1 receptor antagonist valsartan, the bradykinin-B2 receptor antagonist HOE 140 (icatibant), and a combination of ramipril and icatibant. Serial measurements of urinary albumin excretion, blood pressure, and glycated hemoglobin were performed monthly. After 6 months, the animals were killed for the measurement of kidney weight and the assessment of glomerular ultrastructure. Over 24 weeks, urinary albumin excretion showed a continuous rise in the untreated diabetic rats. Both ramipril and valsartan, which were equihypotensive, prevented the increase in urinary albumin excretion over the whole study period. Icatibant therapy did not attenuate the antialbuminuric effect of the ACE inhibitor, nor did it have any effect as the sole therapy. Diabetes was associated with increased glomerular basement membrane thickness, glomerular volume, and total mesangial volume. Both ACE inhibition and angiotensin II receptor antagonism attenuated the glomerular ultrastructural changes to a similar degree. Icatibant did not attenuate the effects of ramipril on glomerular morphology. ACE inhibitors and angiotensin II-AT1 receptor blockers appear to confer similar benefits in experimental diabetic nephropathy, and bradykinin-B2 receptor blockers do not influence this effect. These findings suggest that the blockade of angiotensin II is the major pathway responsible for renoprotection afforded by ACE inhibition in experimental diabetic nephropathy.
Diabetes 1997 Oct
PMID:Role of angiotensin II and bradykinin in experimental diabetic nephropathy. Functional and structural studies. 931 58

ACEIs, angiotensin II receptor antagonists, and calcium antagonists are effective and well-tolerated antihypertensive agents but, except in special situations, should be considered alternative drugs for first line therapy until randomized trials show that they are at least as effective as diuretics and beta-blockers in preventing cardiovascular morbidity and mortality for a broad spectrum of hypertensive patients. ACEIs are particularly indicated for managing patients with congestive heart failure due to systolic dysfunction and patients with diabetic nephropathy, especially in Type I diabetes. Theoretically, the AII receptor antagonists will be equally effective for these indications, and randomized trials are now underway to demonstrate this. Special indications for calcium antagonists in the management of hypertension include angina pectoris, and for the non-dihydropyridine calcium antagonists, paroxysmal supraventricular tachycardia, and atrial fibrillation with rapid ventricular rate. Isolated systolic hypertension in the elderly is a special indication for long-acting dihydropyridine calcium antagonists, although diuretics are preferred. Calcium antagonists have been particularly effective in managing hypertension induced by cyclosporine. They are contraindicated in CHF due to systolic dysfunction and in the management of acute myocardial infarction. The long-term cardioprotective effect of calcium antagonists after a myocardial infarction has been demonstrated only for verapamil and diltiazem in patients with no evidence of LV dysfunction during their infarction. Calcium antagonists should be prescribed for this purpose only when beta-blockers are poorly-tolerated or contraindicated.
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PMID:Antihypertensive therapy. Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium antagonists. 935 1

A cardiomyopathy that is characterized by an impairment in diastolic relaxation and a loss of calcium sensitivity of the isolated myofibril has been described in chronic diabetic animals and humans. To explore a possible role for protein kinase C (PKC)-mediated phosphorylation of myofibrillar proteins in this process, we characterized the subcellular distribution of the major PKC isoforms seen in the adult heart in cardiocytes isolated from diabetic rats and determined patterns of phosphorylation of the major regulatory proteins, including troponin I (TnI). Rats were made diabetic with a single injection of streptozotocin, and myocardiocytes were isolated and studied 3 to 4 weeks later. In nondiabetic animals, 76% of the PKC epsilon isoform was located in the cytosol and 24% was particulate, whereas in diabetic animals, 55% was cytosolic and 45% was particulate (P < .05). PKC delta, the other major PKC isoform seen in adult cardiocytes, did not show a change in subcellular localization. In parallel, TnI phosphorylation was increased 5-fold in cardiocytes isolated from the hearts of diabetic animals relative to control animals (P < .01). The change in PKC epsilon distribution and in TnI phosphorylation in diabetic animals was completely prevented by rendering the animals euglycemic with insulin or by concomitant treatment with a specific angiotensin II type-1 receptor (AT1) antagonist. Since PKC phosphorylation of TnI has been associated with a loss of calcium sensitivity of intact myofibrils, these data suggest that angiotensin II receptor-mediated activation of PKC may play a role in the contractile dysfunction seen in chronic diabetes.
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PMID:Experimental diabetes is associated with functional activation of protein kinase C epsilon and phosphorylation of troponin I in the heart, which are prevented by angiotensin II receptor blockade. 940 Mar 84

Classically, the renin-angiotensin system (RAS) in diabetes was thought to be suppressed, and relatively unimportant in the regulation of hemodynamics and the development of complications. However, studies of pharmacologic interruption of the RAS with angiotensin converting enzyme (ACE) inhibition have implicated the RAS in the progression of diabetic nephropathy. Preliminary evidence also suggests a beneficial effect of angiotensin II receptor antagonists. The relative roles of the systemic versus intrarenal RAS in this process are under active investigation. Though plasma renin is generally low, there may be subtle changes in angiotensin (Ang) II metabolism that sustain relatively higher plasma Ang II levels. Furthermore, the intrarenal RAS may not be suppressed. Renal renin levels tend to be disproportionately elevated, as compared to plasma values. Renal Ang II levels are normal, and renal mRNAs for RAS components have been variable. In general, lack of intrarenal RAS suppression (despite plasma volume and increased exchangeable sodium) may indicate inappropriate activity of the local tissue RAS, and act as a proximate cause of the systemic RAS suppression. Ang II-mediated injury may occur via stimulation of sclerosing mediators, and there is evidence that hyperglycemia acts synergistically with Ang II to promote cellular injury. Together, these recent investigations lend further support to the notion that the RAS plays an important role in diabetic nephropathy, and are helping to shed light on the mechanisms of progressive renal injury.
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PMID:Role of local and systemic angiotensin in diabetic renal disease. 940 35

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, and accounts for 35% of all the patients with ESRD entering a dialysis program; 63% of patients with diabetic nephropathy have type II diabetes mellitus. Hypertension is a major risk factor for renal disease and is common in people with diabetes mellitus. Strategies for preventing the progression of renal failure in patients with diabetes mellitus include glycemic control, and control of blood pressure. Blocking the renin-angiotensin system (RAS) slows the progression of established diabetic nephropathy in type I diabetes mellitus, and inhibiting angiotensin II formation retards or impedes the progression from microalbuminuria to established diabetic nephropathy (macroproteinuria) in people with type I diabetes mellitus. The situation could be the same for people with type II diabetes mellitus. The ability of RAS blockade using irbesartan, an AT1 angiotensin II receptor antagonist, to slow the progression in renal failure has been compared with that of the calcium channel blocker amlodipine and placebo in a pilot study. The results suggest that blockade of the RAS, in this case with irbesartan, is at least equivalent to calcium channel blockers with respect to antihypertensive efficacy, but provides better renoprotective benefits.
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PMID:Renoprotection and renin-angiotensin system blockade in diabetes mellitus. 943 77

Renal protective effects in diabetic patients. Blocking the renin-angiotensin system slows the progression of nephropathy and end-stage renal disease in diabetes mellitus. While substantial evidence exists for the renal protective effects of angiotensin converting enzyme (ACE) inhibitors in patients with insulin-dependent diabetes mellitus (IDDM), the role of renin-angiotensin system blockade in non-insulin-dependent diabetes mellitus (NIDDM) is less clear. The evidence regarding ACE inhibitors has been attained through the traditional channels of evidence-based medicine: observational studies, trials in animal models, preliminary human analyses, and large, randomized trials. While a sound approach, these pathways to elucidating therapeutic effects require the expenditure of substantial time and resources. Accelerated trials with angiotensin II receptor antagonists have relied on the proven effects of ACE inhibitors in the diabetic patient, as well as on pharmacologic principles dictating that renin-angiotensin blockade is more complete when the system is interrupted at the rate-limiting or receptor level. Irbesartan and creatinine clearance in NIDDM patients. The Collaborative Study pilot trial has already shown that the angiotensin II receptor antagonist irbesartan is significantly more effective than the calcium antagonist amlodipine on creatinine clearance in hypertensive NIDDM patients. Subsequent to this trial, a large, randomized study of over 1600 hypertensive patients with NIDDM has been initiated. Other trials have indicated that the response to blocking angiotensin II receptors with irbesartan in patients with NIDDM is substantially larger than it is in healthy humans.
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PMID:Non-insulin-dependent diabetes mellitus, nephropathy, and the renin system. 953 15

Increasing worldwide rates of diabetes mellitus, combined with the significant micro- and macrovascular complications that accompany the disease, point to a heightened need to develop simple, rational strategies to protect against end-organ damage, particularly diabetic nephropathy. Although simple strategies do exist, i.e., early diagnosis of microalbuminuria (MAU) followed by nephroprotective therapy with angiotensin-converting enzyme (ACE) inhibitors, the use of these techniques should be increased. This is especially true for primary care physicians, who will continue to handle the majority of diabetic patients. To combat the underuse of this dual approach, this article reviews a stepwise approach to identifying early MAU so that therapeutic measures can be undertaken before the disorder progresses to diabetic nephropathy and, consequently, to end-stage renal disease in the majority of patients. Once a diagnosis of MAU is made, a variety of trials have demonstrated that ACE inhibitor therapy should be considered the standard therapy to retard worsening albuminuria and subsequent renal disease. ACE inhibitors can retard the progression of microalbuminuria and can lower the percentage of patients who progress to end-stage renal disease and death. Significant data indicate that ACE inhibitors should be used in MAU diabetics regardless of the level of blood pressure. In particular, the ACE inhibitor fosinopril may offer advantages because of its dual route of elimination, thus simplifying dosing in renally impaired patients. The newly developed angiotensin II receptor antagonists should be considered in patients intolerant to ACE inhibitors because of the similar effect on the interruption of the renin-angiotensin system.
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PMID:Relationships among diabetes, microalbuminuria, and ACE inhibition. 973 36

Several trials have shown that antihypertensive drug treatment decreases cardiovascular morbidity and mortality rates. They have also shown, however, that the risk is not decreased to the level of nonhypertensive patients. Trials are therefore underway to determine whether the benefits achieved by older drugs, such as diuretics and beta blockers, can be enhanced by using newer classes of antihypertensive agents, such as calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. Among these trials, the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT) is of special interest because it is the first study to address, in a prospective fashion, the prognostic influence of antihypertensive treatment (nifedipine GITS vs a combined thiazide and potassium-sparing diuretic) in hypertensive patients with concomitant risk factors such as hypercholesterolemia, cigarette smoking, diabetes, and left ventricular hypertrophy. This article briefly describes the rationale and design of the INSIGHT trial and cites the substudies and the preliminary data available.
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PMID:The International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT) trial. 982 40


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