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Excretion of albumin with urine (UAE) in small amounts, i.e. microalbuminuria (MAU), also referred to as "incipient nephropathy", has long been considered a marker of early nephropathy and increased cardiovascular risk in the specific setting of diabetes mellitus. However, numerous clinical studies found an association between MAU and other cardiovascular risk factors, target organ damage and risk of cardiovascular disease in clinical contexts different from diabetes and including arterial hypertension. The present article reviews the available evidence on the clinical value of MAU in subjects with primary hypertension. In these subjects, prevalence of MAU varied from about 4% to 46% across different studies and these differences may be explained by the huge intra-individual variability in UAE, discrepancies in the technique of measurement and different definitions of MAU. A direct and continuous association between UAE and blood pressure (BP) has been found in many studies. A continuous association between UAE and left ventricular mass has also been found in most studies. In contrast, it is not yet clear whether the association between UAE and other factors including age, gender, smoking, ethnicity, insulin resistance, lipids and obesity is independent or mediated by confounders, particularly BP. From a prognostic standpoint, several longitudinal studies showed an association between MAU and the risk of future cardiovascular disease. Of particular note, in some of these studies the incidence of major cardiovascular events progressively increased with UAE starting below the conventional MAU thresholds. Thus, besides being a direct risk factor for progressive renal damage, MAU can be considered a marker, which integrates and reflects the long-term level of activity of several other detrimental factors on cardiovascular system. Antihypertensive treatment reduces UAE and such effect may be detected after just a few days of treatment. Among available antihypertensive drugs, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonists seem to be superior to other antihypertensive drugs in reducing UAE. The dual blockade of the renin-angiotensin system with an ACE inhibitor and an angiotensin II receptor antagonist is a new and promising approach to control UAE in hypertensive patients. Determination of MAU is recommended in the initial work-up of subjects with primary hypertension.
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PMID:Hypertension and microalbuminuria: the new detrimental duo. 1558 33

Recent trials have suggested that inhibitors of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may reduce the incidence of new-onset diabetes in patients with or without hypertension and at high risk of developing diabetes. In this review, we critically evaluate the evidence from recent clinical trials for such a potential preventive effect of ACE inhibitors and ARBs, including a meta-analysis of these recent trials. The reduced incidence of diabetes in patients at high risk of developing diabetes by ACE inhibitors or ARBs has been explained by haemodynamic effects, such as improved delivery of insulin and glucose to the peripheral skeletal muscle, and non-haemodynamic effects, including direct effects on glucose transport and insulin signalling pathways, all of which decrease insulin resistance. There is now evidence that the pancreas may contain an in situ active RAS, which appears to be upregulated in an animal model of type 2 diabetes. Thus, ACE inhibitors and ARBs may act by attenuating the deleterious effect of angiotensin II on vasoconstriction, fibrosis, inflammation, apoptosis and beta-cell death in the pancreas, thereby protecting a critical beta-cell mass essential for insulin production. New evidence is presented that ACE inhibitors and ARBs may delay or prevent the development of insulin resistance and diabetes, for which novel mechanisms are suggested. The actions of agents that interrupt the RAS on insulin resistance, obesity and diabetes warrant further investigation in other animal models. Prospective clinical studies with the primary endpoint of the prevention of diabetes are now indicated to (i) further explore whether the inhibitors of the RAS are superior compared to other antihypertensive agents such as calcium channel blockers (CCBs) and (ii) to evaluate the potential beneficial effects of combination antihypertensive regimens on the development of diabetes.
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PMID:Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. 1571 83

Proteins are particularly attractive targets for product analysis, which is used to understand pathology. Protein modifications, such as advanced glycation end products (AGEs), serve as footprints of biochemical processes and also help in the search for novel agents that efficiently inhibit protein damage. Interestingly, several medical agents that are used clinically interfere with oxidative protein damage through different mechanisms characteristic of their chemical structures. We recently found that angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) lower the in vitro formation of the AGEs pentosidine and carboxymethyllysine. Their inhibition for AGE formation is more striking than aminoguanidine. Unlike aminoguanidine, ARBs and ACEIs do not trap reactive carbonyl precursors of AGEs. Rather, they inhibit AGE formation, possibly as a result of their potent ability to scavenge hydroxyl radicals and to chelate the transition metals necessary for the Fenton reaction. We tested their AGE-lowering ability in vivo in a unique type-2 diabetic model with nephropathic SHR/NDmcr-cp rats, which exhibits the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, hyperinsulinemia) in addition to hypertension. Obesity and associated metabolic derangements, in addition to hypertension, markedly accelerate renal injury. Expectedly, correction of hyperglycemia and hyperinsulinemia partially but significantly improves renal injury. A low-calorie diet greatly improves renal injury despite persistent hypertension. Among antihypertensive agents, ARBs, unlike nifedipine and atenolol, are renoprotective despite persistent metabolic syndrome, but their action is independent of blood pressure lowering and is observed in a dose-dependent manner despite the complete blockade of angiotensin II receptor. Interestingly, the improvement of renal injury by ARBs as well as a low-calorie diet is associated with a significant reduction in local oxidative stress and AGE formation in the kidney. During the characterization of the AGE-lowering profile of our chemical compound libraries ( approximately 2000), we identified several inhibitors of oxidative stress and advanced glycation. They are indeed renoprotective, independently of correction of hypertension and metabolic syndrome, in experimental diabetic nephropathy and other nephritis models. Altogether, our data are in good agreement with the recent therapeutic concept for diabetic nephropathy that multiple risk factor interventions are critical in the treatment of diabetic renal injury, and further implicate a therapeutic potential of inhibition of oxidative stress and advanced glycation.
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PMID:From molecular footprints of disease to new therapeutic interventions in diabetic nephropathy. 1603 1

An elevated urinary albumin excretion (UAE) below the proteinuric level, i.e. microalbuminuria (MAU), has long been recognized as a marker of kidney disease and increased cardiovascular risk in both types of diabetes mellitus. Subsequent clinical evidence documented an association between MAU and other cardiovascular risk factors, target organ damage and risk of cardiovascular disease in the general population and in specific clinical contexts including essential hypertension. This article reviews the available evidence on the clinical value of MAU in subjects with essential hypertension. In these subjects, the reported prevalence of MAU ranges from about 4% to 46% across different studies and these differences may be explained by the huge intraindividual variability in UAE, age and ethnicity, discrepancies in the technique of measurement and different definitions of MAU. A direct and continuous association between UAE and blood pressure (BP) and left ventricular mass has been found in most studies. In contrast, it is not yet clear whether the association between UAE and other factors including age, gender, smoking, ethnicity, insulin resistance, lipids and obesity is independent or due to confounders, particularly BP. Several prospective studies disclosed an association between MAU and the risk of future cardiovascular disease. Of particular note, in some of these studies the incidence of major cardiovascular events progressively increased with UAE starting below the conventional MAU thresholds. Thus, besides being a direct risk factor for progressive renal damage, MAU can be considered a marker which integrates and reflects the long-term level of activity of several other detrimental factors on cardiovascular system. Antihypertensive treatment reduces UAE and such effect may be detected after just a few days of treatment. Among available antihypertensive drugs, angiotensin converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonists seem to be superior to other antihypertensive drugs in reducing UAE. The dual blockade of the renin angiotensin system with an ACE inhibitor and an angiotensin II receptor antagonist is a new and promising approach to control UAE in hypertensive patients. Determination of MAU is recommended in the initial work-up of subjects with essential hypertension as suggested in the most recent European hypertension guidelines, even though, as upcoming evidence suggest, the periodic evaluation of this simple, inexpensive and predictive marker might be valuable and cost-effective.
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PMID:Microalbuminuria and hypertension. 1617 93

While diabetes mellitus is most often associated with hypertension, dyslipidemia, and obesity, these factors do not fully account for the increased burden of cardiovascular disease in patients with the disease. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease and, more specifically, diabetes-associated atherosclerosis. In addition to the recognized metabolic abnormalities associated with diabetes mellitus, upregulation of putative pathological pathways such as advanced glycation end products, the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines have been shown to play a causal role in atherosclerotic plaque formation and may explain the increased risk of macrovascular complications. This review discusses the methods used to assess the development of atherosclerosis in the clinic as well as addressing novel biomarkers of atherosclerosis, such as low-density lipoprotein receptor-1. Experimental models of diabetes-associated atherosclerosis are discussed, such as the streptozocin-induced diabetic apolipoprotein E knockout mouse. Results of major clinical trials with inhibitors of putative atherosclerotic pathways are presented. Other topics covered include the role of HMG-CoA reductase inhibitors and fibric acid derivatives with respect to their lipid-altering ability, as well as their emerging pleiotropic anti-atherogenic actions; the effect of inhibiting the renin-angiotensin system by either ACE inhibition or angiotensin II receptor antagonism; the effect of glycemic control and, in particular, the promising role of thiazolidinediones with respect to their direct anti-atherogenic actions; and newly emerging mediators of diabetes-associated atherosclerosis, such as advanced glycation end products, vascular endothelial growth factor and platelet-derived growth factor. Overall, this review aims to highlight the observation that various pathways, both independently and in concert, appear to contribute toward the pathology of diabetes-associated atherosclerosis. Furthermore, it reflects the need for combination therapy to combat this disease.
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PMID:Diabetes mellitus-associated atherosclerosis: mechanisms involved and potential for pharmacological invention. 1648 46

The incidence of diabetes is increasing at an alarming rate to the point where it is becoming an epidemic. An ageing population, sedentary lifestyle and an unhealthy diet are considered to have contributed toward this. What we must now consider is not only the burden of the disease but the complications that arise from diabetes, in particular kidney and heart disease. Foremost, more than half of the diabetic population will die from cardiovascular-related causes. Whilst diabetes is most often associated with hypertension, dyslipidaemia and obesity, these factors do not fully account for the increased burden of cardiovascular disease in people with diabetes. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease, and more specifically, diabetes-associated atherosclerosis. In addition to the recognised metabolic abnormalities associated with diabetes, upregulation of putative pathological pathways such as advanced glycation endproducts, renin-angiotensin system, oxidative stress and increased expression of growth factors and cytokines have been observed in the setting of diabetes. All of these have been shown to play a causal role in atherosclerotic plaque formation and thus may explain the increased risk of macrovascular complications in those patients with diabetes. In this review the effect of inhibiting the renin-angiotensin system with angiotensin converting enzyme inhibition and a comparison to angiotensin II receptor antagonism is discussed, with the results of clinical trails reflecting the more recently discovered, non-haemodynamic, proatherogenic actions of angiotensin II. The need for experimental models of diabetes-associated atherosclerosis will be covered, with particular emphasis given to the streptozotocin-diabetic apolipoprotein E knockout mouse. Finally, growth factors, including vascular endothelial growth factor and platelet-derived growth factor are discussed in detail.
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PMID:Preventing atherosclerosis with angiotensin-converting enzyme inhibitors: emphasis on diabetic atherosclerosis. 1650 70

Epidemiological reports show that about half of all adults suffer from hypertension, and the incidence of diabetes mellitus, dyslipidemia and obesity is markedly increasing in Japan. Recent progress in gene determination has shown that lifestyle-related diseases, including hypertension, are multigenetic diseases. In particular, renin-angiotensin genes play an important role in the pathogenesis of hypertension. Upregulation of the transcription of angiotensinogen and angiotensin-converting enzyme genes increases blood pressure and cardiovascular organ damage through increased levels of angiotensin II. In this review, I first introduce the history of the recognition, understanding and the development of treatment for hypertension. Secondly, the basic relationship of the pathogenesis between hypertension and the new concept of metabolic syndrome will be shown, and the usefulness of angiotensin II receptor antagonist for hypertensive patients with obesity and/or metabolic syndrome. Finally, I will reveal the utility of gene diagnosis for acute myocardial infarction and cerebral infarction by detecting the polymorphism of renin-angiotensin genes. On the other hand, the positive correlation between blood pressure and body mass index is affected by the Gln27Glu genotype of the beta2-adrenoceptor gene. These studies investigating the gene-environmental relationship will contribute to the development of tailor-made medicine in the future.
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PMID:[Increasing menace of cardiovascular diseases in the era of obesity]. 1654 38

The potential effects of angiotensin II receptor blockers (ARBs) on adipose tissue biology and body weight are of considerable interest, because these agents are frequently used to treat hypertension in patients who are prone to visceral obesity, the metabolic syndrome, and diabetes. In rats fed a high-fat, high-carbohydrate diet, we compared the effects of 2 ARBs, telmisartan and valsartan, on body weight, food intake, energy expenditure, fat accumulation, fat cell size, and hepatic triglyceride levels. Telmisartan, but not valsartan, promoted increases in caloric expenditure and protected against dietary-induced weight gain. In the telmisartan-treated rats, absolute food intake, but not food intake adjusted for body weight, was lower than in valsartan-treated rats or controls. Telmisartan reduced the accumulation of visceral fat and decreased adipocyte size to a much greater extent than valsartan and was also associated with a significant reduction in hepatic triglyceride levels. Moreover, telmisartan, but not valsartan, increased the expression of both nuclear-encoded and mitochondrial-encoded genes in skeletal muscle known to play important roles in mitochondrial energy metabolism. Thus, in addition to a class effect of ARBs in modulating adipocyte size, these findings raise the possibility that certain molecules, like telmisartan, may have a particularly strong impact on fat cell volume and fat accumulation, as well as distinctive effects on energy metabolism, that may help protect against dietary-induced visceral obesity and weight gain.
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PMID:Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. 1656 92

The aim of the present study was to clarify the effect of telmisartan, an angiotensin II receptor blocker, on the development of obesity and related metabolic disorders in diet-induced obese mice. Treatment with telmisartan dissolved in drinking water at a dosage of 5 mg/kg per day for 14 days attenuated the diet-induced weight gain without affecting food intake in diet-induced obese mice compared with controls using nontreated water. Telmisartan treatment decreased the weight of visceral adipose tissue and the triglyceride content in the liver and skeletal muscle. In addition, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in diet-induced obese mice all improved with telmisartan treatment. Furthermore, telmisartan treatment increased adiponectin mRNA in visceral white adipose tissue and was associated with a concomitant change in the serum adiponectin level. In contrast, the treatment reduced the serum level of resistin. Finally, telmisartan treatment increased the mRNA expression of uncoupling protein 1 in brown adipose tissue and was accompanied by an increase in oxygen consumption. In conclusion, telmisartan treatment might prevent the development of obesity and related metabolic disorders by altering the levels of adiponectin, resistin, and uncoupling protein 1 in diet-induced obese mice. Our results indicate that telmisartan can be used as a therapeutic tool for metabolic syndrome, including visceral obesity.
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PMID:Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice. 1671 45

Epidemiological studies have proven that obesity is a significant risk factor for type 2 diabetes. Long-term progression of diabetes leads to various microvascular complications, of which diabetic nephropathy has become of increasing importance, and is the main cause of end-stage renal failure in occidental countries. Microalbuminuria is the first marker of incipient diabetic nephropathy, an early stage glomerulopathy which can progress to renal failure and which historically has been treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists. We report a severely obese diabetic patient on treatment for diabetic nephropathy with ACE-inhibitors and poor results, which resolved after Roux-en-Y gastric bypass.
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PMID:Resolution of early stage diabetic nephropathy in an obese diabetic patient after gastric bypass. 1705 53


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