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)

Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.
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PMID:RAAS escape: a real clinical entity that may be important in the progression of cardiovascular and renal disease. 1294 34

Rosiglitazone and pioglitazone are two new additions to the therapeutic options for the treatment of type 2 diabetes mellitus. These agents differ from our current therapies in their mode of action. They have potential non-glucose lowering effects that may reduce cardiovascular risk and are effective both as monotherapy and in combination with sulfonylureas, metformin, and insulin. They are generally well tolerated, with the main side effects being weight gain and fluid retention. However, special precaution is warranted in patients with congestive heart failure or hepatic disease, and monitoring of liver enzymes is recommended for the first year of therapy. Despite their effectiveness, rosiglitazone and pioglitazone remain second-line agents to metformin and glyburide, agents that have demonstrated efficacy in decreasing the microvascular and macrovascular complications associated with type 2 diabetes mellitus.
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PMID:The "glitazones": rosiglitazone and pioglitazone. 1453 48

The May 2003 COM. A 57-year-old woman presented with slurring of her speech and right arm weakness. Her past medical history included idiopathic hypertrophic subendocardial stenosis (IHSS), arthritis, asthma, congestive heart failure, hypertension and NIDDM. Neurological examination showed persistent word finding difficulty but her motor and sensory function had essentially returned to normal. Extensive laboratory studies were unrevealing. Imaging studies showed a meningeal lesion over the left posterior parietal lobe and the findings suggested an infectious or inflammatory process. A biopsy of the involved dura and meninges was performed and revealed leptomeningeal Rosai-Dorfman disease. Emperipolesis was noted. The finding of emperipolesis is characteristic of Rosai-Dorfman disease of the leptomeninges, but in 30% of cases, this feature will not be identified. Large pale histiocytes of Rosai-Dorfman disease are immunoreactive for S-100 protein and KP1, but negative for CD1a. The differential diagnosis of a chronic inflammatory infiltrate containing numerous, large histiocytes includes granulomatous diseases such as Wegener graulomatosis and sarcoid, Hodgkin disease, and Langerhans histiocytosis. CNS Rosai-Dorfman most commonly involves patients between 20- and 40-years-old, with a slight male predominance. Approximately 75% of cases are intracranial, whereas 20% involve the spine. Over 90% of CNS Rosai-Dorfman cases involve the leptomeninges and are seen by neuroimaging as a dural-based, contrast-enhancing masses that often elicit vasogenic edema in the underlying brain. Thus, clinically and radiologically, the disease is thought to represent meningioma. Leptomeningeal Rosai-Dorfman disease is considered a benign condition and in most cases surgical resection is the treatment of choice. Although the number of cases in the literature is small, disease progression following surgical resection is uncommon. Little is known regarding the pathogenesis of Rosai-Dorfman disease. Most have suggested that it represents either an autoimmune disease or a reaction to an infectious agent that has yet to be discovered. Currently it is best considered a benign, idiopathic histiocytosis.
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PMID:May 2003: 57-year-old-woman with acute loss of strength in her right upper extremity and slurred speech. 1465 68

The risk for cardiovascular disease, particularly congestive heart failure, is significantly higher in patients with type 2 diabetes mellitus than in individuals without diabetes. The presence of hyperglycemia has been associated with changes in the myocardium that are characteristic of diabetic cardiomyopathy and heart failure. Furthermore, insulin resistance may be associated with cardiomyopathy, even in the absence of hyperglycemia, and has been linked with cardiovascular remodeling. The association between heart failure and insulin resistance suggests that agents that improve insulin sensitivity, such as the thiazolidinediones (TZDs), are likely to be of cardiovascular benefit in patients with diabetes and heart failure. Although TZDs have beneficial cardiovascular effects in patients with type 2 diabetes, such as reducing blood pressure, improving endothelial function, and exerting potential antiatherosclerotic effects, one must be aware of the potential of these agents to cause edema or weight gain as a result of fluid retention and fat accumulation. These issues are of particular concern in patients with diabetes who have heart failure. However, the glycemic and cardiovascular benefits of TZDs may outweigh the potential problems of weight gain and fluid retention noted in some patients. Thus the risk-benefit ratio of using TZDs in patients who have diabetes and heart failure must be carefully considered in this patient population with comorbid disorders.
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PMID:The patient with diabetes mellitus and heart failure: at-risk issues. 1467 75

Thiazolidinediones (TZDs) can cause weight gain and fluid retention in some patients. In most cases, fluid retention is expressed as mild hemodilution. The incidence of clinically evident edema is relatively uncommon. In large clinical trials with rosiglitazone and pioglitazone, the frequency of edema in TZD-treated patients was about 3 to 4 times higher than in placebo-treated patients. The precise mechanisms responsible for weight gain, fluid retention, and edema associated with TZD therapy are unclear but appear to be both dose- and host-related. Weight gain is most likely multifactorial, reflecting increased body fat and fluid retention. Available data are conflicting and do not completely support the concept that increased body weight and decreased hemoglobin/hematocrit are linked with evidence of fluid retention and hemodilution. As uncommon as edema is, new-onset heart failure is even less common in patients treated with a TZD. In controlled clinical trials, the frequency of congestive heart failure (CHF) was identical in rosiglitazone- and placebo-treated patients. The incidence of CHF is higher in patients receiving combination therapy with insulin and a TZD. Patients in the insulin-treated population who develop CHF tend to be older, have a longer history of type 2 diabetes mellitus, and have risk factors for heart failure in addition to diabetes. TZDs do not necessarily require discontinuation in patients who develop fluid retention or weight gain. Mild fluid retention can be treated by decreasing the TZD dose and/or adding a diuretic. Patients who are taking a TZD should be monitored for signs and symptoms of CHF, including excessive weight gain, edema, and dyspnea. Patients with New York Heart Association (NYHA) class I or II CHF can be treated with TZDs. Therapy should be initiated at low doses and slowly titrated to the lowest effective dose. If CHF worsens or becomes refractory to treatment, it may be necessary to discontinue the TZD. Diagnoses of NYHA class III and IV CHF were not studied in clinical trials of TZDs, and thus TZDs are not recommended for patients with CHF of this severity.
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PMID:Considerations for management of fluid dynamic issues associated with thiazolidinediones. 1467 76

Greater myocardial injury in response to ischemia/ reperfusion (I/R) and increased incidence of congestive heart failure and death in noninsulin-dependent diabetes mellitus, or type 2 diabetes, patients has been clearly identified. Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, act as insulin sensitizers and are a novel class of oral antidiabetic drugs. An emerging body of evidence, mainly from preclinical studies, suggest that TZDs protect the heart from acute I/R injury and also might attenuate cardiac remodeling and heart failure. The mechanisms involved in this cardioprotection by TZDs are multi-factorial and not completely understood. These novel activities of TZDs could benefit type 2 diabetes patients and offer benefits beyond glycemic control. This new knowledge about the cardioprotective effects of TZDs is still limited, and more investigations, especially clinical studies, are required.
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PMID:Cardioprotective effects of thiazolidinediones, peroxisome proliferator-activated receptor-gamma agonists. 1474 40

The activity of the renin-angiotensin-aldosterone system (RAAS) is elevated both in the circulation and in the renal tissue of diabetic and nondiabetic nephropathies. The increased RAAS activity plays an important role in the hemodynamic and nonhemodynamic pathogenetic mechanisms involved in kidney disease. Previous studies have demonstrated that albuminuria is not only a marker of glomerular lesions, but also a progression promoter, and finally a powerful predictor of the long-term beneficial effect of blood pressure-lowering therapy. Randomized crossover and parallel blind studies in patients with diabetic nephropathy have demonstrated that angiotensin II receptor blockers (ARB) induce favorable changes in systemic blood pressure, renal hemodynamics, and proteinuria similar to those induced by angiotensin-converting enzyme (ACE) inhibition. Studies have revealed the optimal renoprotective dose for some ARBs; however, additional dose titration studies are urgently needed to obtain the maximum benefit of this valuable new class of compounds. The combination of ARB and ACE inhibition is well tolerated and even more effective than monotherapy in reducing systemic blood pressure and albuminuria in diabetic nephropathy. In addition, dual RAAS blockade is safe and well tolerated. Impaired autoregulation of glomerular filtration rate (GFR); demonstrated with some blood pressure-lowering agents implies disturbances in the downstream transmission of the systemic blood pressure into the glomerulus, leading to capillary hypertension or hypotension depending of the level of blood pressure. ARB does not interfere with GFR autoregulation in hypertensive diabetic patients. In contrast to previous observational studies with ACE inhibition, long-term treatment with ARB has similar beneficial renoprotective effect on progression of diabetic kidney disease in hypertensive diabetic patients with ACE II and DD genotypes. ARB can prevent/delay development of diabetic nephropathy independently of its beneficial blood pressure-lowering effect in patients with type 2 diabetes and microalbuminuria. Recently, two landmark studies led to the following conclusion: "Losartan and Irbesartan conferred significant renal benefit in patients with type 2 diabetes and nephropathy. This protection is independent of the reduction in blood pressure it causes. The ARB is generally safe and well tolerated." A recent metaanalysis indicates that ARBs reduce cardiovascular events mainly because of reduction in first hospitalization for congestive heart failure in hypertensive type 2 diabetic patients with albuminuria. The studies mentioned here suggest that ARB represents a beneficial treatment of hypertension and proteinuria in incipient and overt diabetic nephropathy.
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PMID:Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular end points. 1501 27

Hypertension is one of the most important modifiable risk factors for cardiovascular pathology, such as atherosclerosis and cardiac left ventricular hypertrophy, including acute events such as stroke and myocardial infarction (MI). In particular, the risk of ischaemic and haemorrhagic stroke is directly and continuously related to high blood pressure levels. The renin-angiotensin system (RAS) plays an important role in volume homeostasis and blood pressure regulation. It also helps to prevent cell and organ damage from ischaemia during acute volume loss. However, angiotensin-II (A-II)--the main effector peptide of the RAS--also exerts a number of pathological effects, which are mediated by the AT 1 receptor. The Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) programme consists of two parallel trials where ONTARGET as a large, long-term study compares the efficacy of the angiotensin-receptor antagonist, telmisartan, the renin-angiotensin-converting enzyme (ACE) inhibitor, ramipril and combination therapy with telmisartan plus ramipril for reducing cardiovascular and cerebral risk. Telmisartan, due to its long duration of action, compares favourably with other angiotensin-receptor antagonists. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril was shown to reduce the risk for MI and other cardiovascular events in patients at high risk for pathological cardiac events, but without heart failure or a low ejection fraction. The cardiovascular outcomes of high-risk patients using the same criteria as those of the HOPE study will be assessed in both trials. TRANSCEND differs from ONTARGET in that this trial will enrol patients who do not tolerate ACE inhibitors. This parallel study will therefore be able to compare telmisartan and placebo treatment. Both ONTARGET and TRANSCEND trials feature the same primary composite end point: death caused by cardiovascular disease, acute MI, stroke and hospitalisation because of congestive heart failure. The secondary end points will focus on reductions in the development of Type 2 diabetes mellitus, nephropathy, cognitive decrease and dementia as well as atrial fibrillation.
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PMID:Challenges in improving prognosis and therapy: the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial programme. 1515 18

We assessed the effects of angiotensin-converting enzyme (ACE) inhibition on survival and cardiorenal outcomes in a consecutive cohort of Chinese type 2 diabetic patients with varying degree of albuminuria, ranging from normoalbuminuria to macroalbuminuria. A total of 3773 consecutive Chinese type 2 diabetic patients were followed prospectively for a mean period of 35.8 months. Clinical end points included all-cause mortality, with cardiovascular end point defined as first hospitalization because of ischemic heart disease, congestive heart failure, revascularization procedures, or cerebrovascular accident as well as renal end point defined as dialysis, doubling of baseline plasma creatinine, or plasma creatinine > or =500 micromol/L. The use of ACE inhibitor was 26.3% in normoalbuminuric (NA), 70.1% in microalbuminuric (MI), and 82.6% in macroalbuminuric (MA) groups. Albuminuria was a major predictor for all-cause mortality with 4-fold difference between NA and MA patients. The 7-year cumulative mortality rate was 7.1%, 10.8%, and 21.7% in the NA, MI, and MA groups, respectively. The use of ACE inhibition was associated with significant reduction of mortality (hazard ratio 0.41 and 95% confidence interval, 0.29, 0.58) in the entire group and was most evident in high-risk patients who had cardiorenal complications or retinopathy at baseline for all albuminuric groups (NA 0.76 [0.31,1.87]; MI 0.32 [0.16, 0.65]; and MA 0.20 [0.13, 0.33]). The prognostic value of albuminuria for death in type 2 diabetes and the beneficial effects of ACE inhibitors in Chinese type 2 diabetic patients with micro- or macroalbuminuria has been confirmed. The effects of ACE inhibitors in type 2 diabetic patients with normoalbuminuria require further evaluation.
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PMID:Effect of angiotensin-converting enzyme inhibition on survival in 3773 Chinese type 2 diabetic patients. 1524 44

Thiazolidinediones, also called glitazones, are insulin sensitisers that act as agonists of the peroxisome proliferator-activated receptors-gamma (PPARgamma). After the withdrawal of troglitazone due to hepatotoxicity, only pioglitazone and rosiglitazone can be used for treating patients with type 2 diabetes mellitus, either as monotherapy or in combination with metformin or with sulphonylureas (or glinides). The combination of glitazones with insulin is also appealing, as it allows improvement of glycaemic control while decreasing the daily insulin requirement. Insulin dosage has to be adjusted regularly to avoid hypoglycaemic episodes. However, some concerns have been raised about such combined glitazone-insulin therapy because it may favour weight gain due to both enhanced adipogenesis and fluid retention. Such adverse effects are commonly observed in all diabetic individuals receiving glitazones, whatever the mode of use, but they appear to be exacerbated in insulin-treated patients. Body fat gain is a major drawback of treatment with adipogenic compounds such as glitazones. However, some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots, although no long-term follow-up is yet available. An estimated 2-5% of patients receiving glitazone monotherapy and 5-15% receiving concomitant insulin therapy experience peripheral oedema. Some anecdotal cases of pulmonary oedema have also been reported, especially in insulin-treated patients, although the actual incidence of this complication is unknown. All glitazones increase the intravascular volume by approximately 6-7% in a dose-dependent manner. Rather than a direct effect on cardiac or renal function, fluid retention and tissue oedema seem to be part of a vascular 'leak' syndrome. Such a phenomenon may have greater consequences in patients with type 2 diabetes treated with insulin because such patients are usually older, have had the disease long-term and have worse cardiac or renal function. Additionally, glitazones may potentiate the renal effects of insulin on sodium and water retention. Regardless of the mechanism, it is conceivable that additional fluid retention caused by glitazones may alter the already precarious volume status in patients with underlying cardiac or renal dysfunction, thus leading to oedema and congestive heart failure. Thus, it is prudent to either avoid glitazones or use them cautiously in individuals with impaired cardiac function. Further studies are clearly needed to define the mechanisms of fluid retention associated with glitazone use and to determine the safety of cautious use of these new insulin sensitisers in insulin-treated patients with type 2 diabetes.
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PMID:Combined thiazolidinedione-insulin therapy: should we be concerned about safety? 1536 73


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