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Query: UMLS:C0011860 (type 2 diabetes)
57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, clinical trials evaluating cardiovascular outcomes with antihypertensive drugs that target the renin-angiotensin-aldosterone system have been dramatically increasing in size. The CONSENSUS trial in 1987 enrolled 253 patients, while Val-HeFT in 1999 enrolled 5,010 patients; indeed, the Val-HeFT subgroup of patients not receiving angiotensin-converting enzyme inhibitors was bigger than the whole CONSENSUS trial even though the 366 patients were only 7% of the total trial population. More recent and ongoing cardiovascular trials have even greater patient numbers with 14,703 patients enrolled in VALIANT, 15,314 in VALUE, 23,400 in ONTARGET and 33,357 in ALLHAT. Part of the reason is that in modern trials, patients in the control group are already receiving optimal therapy. Therefore, in order to be adequately powered to detect any benefit of new drugs, trials must recruit thousands of patients. This expanding trend cannot continue forever because of time and economic constraints and as a result, trials are shifting their design to include composite and surrogate endpoints. In addition, more predefined substudies are being carried out to analyze possible benefits in specific patient populations such as those with type 2 diabetes or renal impairment. Modern trials are also placing more emphasis on protection as a long-term strategy to control cardiovascular risks. Examples of these points, particularly regarding the size of modern cardiovascular trials to have the power to show protective effects, are illustrated by Val-HeFT, LIFE, ELITE II, VALIANT, VALUE, CHARM and NAVIGATOR.
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PMID:RAAS inhibitors in the cardiovascular continuum: what is still missing? 1536 29

Frank metabolic acidosis is known to promote renal excretion of hydrogen ion by induction of glutaminase and other enzymes in the renal tubules. This induction, at least in part, reflects an increase in pituitary output of ACTH and a consequent increased production of cortisol and aldosterone; these latter hormones act on the renal tubules to promote generation of ammonia, which expedites renal acid excretion. Recent evidence suggests that the moderate metabolic acidosis associated with a protein-rich diet low in organic potassium salts - quantifiable by net acid output in daily urine - can likewise evoke a modest increase in cortisol production. Since cortisol promotes development of visceral obesity, and has a direct negative impact on insulin function throughout the body, even a modest sustained up-regulation of cortisol production may have the potential to increase risk for insulin resistance syndrome and type 2 diabetes. This thesis appears to be consistent with previous epidemiological reports correlating high potassium consumption, or a high intake of fruits and vegetables, with reduced risk for diabetes and coronary disease. Future prospective epidemiology should assess whether the estimated acid-base balance of habitual diets - calculated from the ratio of dietary protein and potassium - correlates with risk for insulin resistance syndrome and diabetes.
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PMID:Acid-base balance may influence risk for insulin resistance syndrome by modulating cortisol output. 1560 73

Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of diabetic vasculopathy. They are both powerful independent predictors of cardiovascular risk. Advances in non-invasive methodologies have led to widespread clinical investigation of these abnormalities in diabetes mellitus, generating a wealth of new knowledge concerning the mechanisms of vascular dysfunction, risk factor associations and potential treatment targets. Endothelial dysfunction primarily reflects decreased availability of nitric oxide (NO), a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilatation of the brachial artery and plethysmography measurement of forearm blood flow responses to vasoactive agents. Arterial stiffness may be assessed using pulse wave analysis to generate measures of pulse wave velocity, arterial compliance and wave reflection. The pathogenesis of endothelial dysfunction in type 2 diabetes is multifactorial, with principal contributors being oxidative stress, dyslipidaemia and hyperglycaemia. Elevated blood glucose levels drive production of reactive oxidant species (ROS) via multiple pathways, resulting in uncoupling of mitochondrial oxidative phosphorylation and endothelial NO synthase (eNOS) activity, reducing NO availability and generating further ROS. Hyperglycaemia also contributes to accelerated arterial stiffening by increasing formation of advanced glycation end-products (AGEs), which alter vessel wall structure and function. Diabetic dyslipidaemia is characterised by accumulation of triglyceride-rich lipoproteins, small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL)-cholesterol and increased postprandial free fatty acid flux. These lipid abnormalities contribute to increasing oxidative stress and may directly inhibit eNOS activity. Although lipid-regulating agents such as HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates) and fish oils are used to treat diabetic dyslipidaemia, their impact on vascular function is less clear. Studies in type 2 diabetes have yielded inconsistent results, but this may reflect sampling variation and the potential over-riding influence of oxidative stress, dysglycaemia and insulin resistance on endothelial dysfunction. Results of positive intervention trials suggest that improvement in vascular function is mediated by both lipid and non-lipid mechanisms, including anti-inflammatory, anti-oxidative and direct effects on the arterial wall. Other treatments, such as renin-angiotensin-aldosterone system antagonists, insulin sensitisers and lifestyle-based interventions, have shown beneficial effects on vascular function in type 2 diabetes. Novel approaches, targeting eNOS and AGEs, are under development, as are new lipid-regulating therapies that more effectively lower LDL-cholesterol and raise HDL-cholesterol. Combination therapy may potentially increase therapeutic efficacy and permit use of lower doses, thereby reducing the risk of adverse drug effects and interactions. Concomitant treatments that specifically target oxidative stress may also improve endothelial dysfunction in diabetes. Vascular function studies can be used to explore the therapeutic potential and mechanisms of action of new and established interventions, and provide useful surrogate measures for cardiovascular endpoints in clinical trials.
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PMID:Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy. 1561 50

Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects approximately 40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 microg/min and < or =199 microg/min) and macroalbuminuria (UAE > or =200 microg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.
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PMID:Diabetic nephropathy: diagnosis, prevention, and treatment. 1561 52

The inhibition of the renin-angiotensin system (RAS) with either angiotensin converting enzyme inhibitors (ACEIs) or AT1 angiotensin receptor blockers (ARBs) consistently and significantly reduces the incidence of type 2 diabetes in patients with hypertension or congestive heart failure. The mechanisms underlying this protective effect appear to be complex and may involve an improvement of both insulin sensitivity and insulin secretion. These two effects may result, at least in part, from the well known effects of these pharmacological agents on the vascular system on the one hand, on the ionic balance on the other hand. Indeed, the vasodilation induced by ACEIs or ARBs could improve the blood circulation in skeletal muscles, thus favouring peripheral insulin action, but also in the pancreas, thus promoting insulin secretion. Preserving cellular potassium and magnesium pools by blocking the aldosterone effects could also improve both cellular insulin action and insulin secretion. However, besides these classical effects, new mechanisms have been recently suggested. A direct effect of the inhibition of angiotensin and/or of the enhancement of bradykinin on various steps of the insulin cascade signalling has been described as well an increase in GLUT4 glucose transporters after RAS inhibition. Furthermore, it has been demonstrated that angiotensin II inhibits adipogenic differentiation of human adipocytes via A1 receptors and, therefore, it has been hypothesised that RAS blockade may prevent diabetes by promoting the recruitment and differentiation of adipocytes. Finally, some lipophilic ARBs appear to induce PPAR-gamma activity in the adipose tissue. Hence, the protection against type 2 diabetes observed after RAS inhibition may be partially linked to a thiazolidinedione-like effect. In conclusion, numerous physiological and biochemical mechanisms could explain the protective effect of RAS inhibition against the development of type 2 diabetes in individuals with arterial hypertension or congestive heart failure. What might be the main mechanism in the overall protection effect of ACEIs or ARBs remains an open question.
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PMID:Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. 1567 19

Over the next decade, the number of patients with end-stage renal disease (ESRD) treated by dialysis may double, and even developed nations will have difficulty in coping with this alarming increase. This review will outline the proven and unproven strategies that have the potential to retard the progression of chronic kidney disease (CKD). Recently, a number of randomised clinical trials have demonstrated the efficacy of several strategies to slow the progression of CKD. Proven strategies include adequate blood pressure control (with angiotensin blockade), and for diabetic nephropathy good glycaemic control. Other potentially beneficial strategies include smoking cessation, lipid control and aldosterone blockade. The early institution of these strategies has the potential to regress established CKD as well as improve the long-term cardiovascular outcomes of these patients. Proof of the efficacy in humans of promising experimental approaches, such as the administration of growth factors (e.g., recombinant bone morphogenetic protein-7), anti-fibrotic agents (e.g., pirfenidone) and novel anti-proteinuric drugs (e.g., pentosan polysulphate), is awaited. Finally, the primary prevention of CKD, at least in part, by the eradication of type 2 diabetes and obesity (through improvement of lifestyle factors), and adequate treatment of hypertension, have the potential to eliminate up to half of the most common causes of CKD (or ESRD) in developed countries.
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PMID:Retardation of kidney failure -- applying principles to practice. 1572 15

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 circulating and 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 in order 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 LDL less than 100 mg/dL. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, certain 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:Heart failure in diabetes mellitus: causal and treatment considerations. 1572 10

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

A progressive chain of pathophysiological events links cardiovascular risk factors to clinical manifestations of disease and life-threatening cardiovascular events. This chain--the cardiovascular continuum--underlies cardiovascular disease and holds the key to its prevention and treatment. Progressive tissue damage can result in morbidity from congestive heart failure, end-stage heart disease, nephrotic proteinuria and dementia and, eventually, death from cardio- or cerebrovascular causes. The renin-angiotensin-aldosterone system (RAAS) is involved at all stages of the cardiovascular continuum, because the effector molecules of the RAAS, angiotensin II in particular, have direct pathobiological effects on a variety of tissues, including the endothelium, vascular smooth muscle and the renal mesangium. Clinical trials of angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors have demonstrated the essential validity of this hypothesis. Interruption of the RAAS has been shown to reduce cardiovascular morbidity and mortality in patients with left ventricular hypertrophy, heart failure and post-myocardial infarction, as well as renal disease in patients with type 2 diabetes. Key questions remain, however. What are the clinical effects of combination ARB and ACE inhibitor treatment? How will combinations of RAAS blockade with other agents, such as statins, affect the cardiovascular continuum? Answers to these questions will require well-planned, adequately powered clinical trials, such as the Programme of Research tO evaluate Telmisartan End-organ proteCTION (PROTECTION) and the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) programmes. However, it is already clear that RAAS blockade is an essential part of blocking progression along the cardiovascular continuum.
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PMID:The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. 1582 52

Thiazolidinediones (TZDs) are widely used to treat type 2 diabetes mellitus; however, their use is complicated by systemic fluid retention. Along the nephron, the pharmacological target of TZDs, peroxisome proliferator-activated receptor-gamma (PPARgamma, encoded by Pparg), is most abundant in the collecting duct. Here we show that mice treated with TZDs experience early weight gain from increased total body water. Weight gain was blocked by the collecting duct-specific diuretic amiloride and was also prevented by deletion of Pparg from the collecting duct, using Pparg (flox/flox) mice. Deletion of collecting duct Pparg decreased renal Na(+) avidity and increased plasma aldosterone. Treating cultured collecting ducts with TZDs increased amiloride-sensitive Na(+) absorption and Scnn1g mRNA (encoding the epithelial Na(+) channel ENaCgamma) expression through a PPARgamma-dependent pathway. These studies identify Scnn1g as a PPARgamma target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.
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PMID:Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. 1607 71

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