Kidney diabetic complications

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Epidemiologic studies have correlated the results of the OGTT with the current and subsequent development of the microvascular complications of DM in the eye (diabetic retinopathy) and in the kidney (diabetic nephropathy). Their development is usually limited to those patients whose fasting blood glucose level exceeds 140 mg/dL (7.8 mM) or whose 2-hour postprandial blood glucose level exceeds 200 mg/dL (11.1 mM). 

Tissue Location and Role of Aldose Reductase in Animal Models of Diabetic Complications. Aldose reductase (AR) has been located immunohistochemically in many tissues of the dog and rat, most notably, in corneal epithelium, retina, optic nerve, kidney papillae, aortic endothelium and smooth muscle cells as well as peripheral nerve and lens. AR has also been measured in human and monkey retinal mural cells. These cells are thought to provide the structural support for retinal capillaries and their loss is the first abnormality seen in clinical diabetic retinopathy. In addition, AR-like activity has been reported in a human retinoblastoma cell line and sorbinil inhibits this activity in these cells. Finally, a recent report has demonstrated that AR is present in isolated capillaries from bovine retina and cerebral cortex. Therefore, AR appears to be present in all tissues which are uniquely susceptible to deterioration during prolonged exposure to the hyperglycemia of diabetes. Accumulation of the products of the polyol pathway, sorbitol and fructose, has been demonstrated in these tissues and, where tested, sorbinil and other AR inhibitors have been shown to inhibit this accumulation. 

Uncontrolled or poorly controlled plasma glucose levels will result in the development and progression of microvascular and macrovascular diabetic complications that involve the eyes (retinopathy), kidneys (nephropathy), nerves (neuropathy), heart, and blood vessels (9). 

The use of psyllium helps the human body in improving glymeric and lipids control, and reducing the risk factors involving in diabetic complications(26) like poor wound healing, higher risk of infections, and many other problems involving the eyes, kidneys, nerves, and the heart. 

Since advanced glycation end-products (AGEs) inhibitors such as pyridoxamine and aminoguanidine significantly inhibit the development of diabetic complications such as retinopathy and kidney failure in the streptozotocin-induced diabetic rat, treatment with AGEs inhibitors is believed to be a potential strategy for the prevention of life style-related diseases. We previously developed monoclonal antibodies for AGEs such as CML, carboxymethyl-cysteine (CMC), N -(carboxyethyl)lysine (CEL)", ... 

Diabetes mellitus is a complicated, chronic disorder characterized by either insufficient insulin production by the beta cells of die pancreas or by cellular resistance to insulin. Insulin insufficiency results in elevated blood glucose levels, or hyperglycemia As a result of the disease, individuals with diabetes are at greater risk for a number of disorders, including myocardial infarction, cerebrovascular accident (stroke), blindness, kidney disease, and lower limb amputations. 

World-wide, about 130 million people are believed to suffer from diabetes, a disease which occurs when the body does not adequately produce the insulin needed to maintain a normal circulating blood glucose (80-120 mg/dl). It is estimated that the disease is in rapid expansion (300 million in 2025). Frequent monitoring of blood glucose is crucial for effective treatment and to reduce the morbidity and mortality of diabetes. Blindness, kidney and heart failure, peripheral neuropathy, pure circulation, gangrene are the severe complications which, over time, are related to diabetes. 

Diabetes is a global epidemic affecting more than 240 million people worldwide. The incidence of this disease is growing at an alarming rate, with 380 million cases predicted by 2025. Each year over 3.8 million people die from complications of diabetes, including heart disease, stroke and kidney failure. The vast majority... 

Chronic renal failure is a common consequence of diabetes but this case is complicated by the loss of fluid and electrolytes (sodium and potassium) due to diarrhoea and vomiting. Normally, the kidneys would respond to such a challenge and maintain homeostasis but Mrs Amin s kidneys were unable to do so. Mrs Amin was put on haemodialysis and treated to control the diabetes. 

A number of chronic conditions such as high blood pressure or diabetes bear certain similarities to snbstance use disorders. These illnesses prodnce a variety of physical symptoms that, if left untreated, can resnlt in significant medical complications and even death. Complications of uncontrolled diabetes inclnde blindness, kidney failure, neuropathies, and limb amputation. Similarly, inadeqnately controlled hypertension is a risk factor for stroke, heart attack, and other serions complications. Recognizing that these are diseases does not relieve the patient of responsibility indeed, the knowledge that one has snch an illness imposes significant responsibility. For example, knowing the likely ontcome of nncontrolled diabetes is hopefully an impetus for the diabetic to exercise, take medication, and... 

Another important consideration associated with specific diseases is co-morbidity, which often complicates chronic diseases such as diabetes or congestive cardiac disease. For example, medicines which could be perfectly safe in the early phase of type II diabetes could cause serious side effects if nephropathy develops. This could be the consequence of the impaired route of elimination or by direct effect on the damaged kidney. 

Such islet grafts permanently returned blood glucose levels in the diabetic animals to normal values. Even more encouraging, this treatment prevented development of diabetic-associated complications of kidney and eye function (which, in human diabetics, can lead to kidney failure and partial blindness). 

Influenza is responsible for several thousand deaths each year. Individuals over the age of 65, residents of long-term care facilities, and patients with long-term health problems (i.e., diabetes, HIV or AIDS, heart disease, kidney disease, lung disease, cancer) are at highest risk for severe influenza and complications. Yearly vac-... 

Another complication of diabetes is blindness, which is due to blood vessel damage at the back of the eye (proliferative retinopathy), this accounts for about 12% of all blindness. In hyperglycemia, fructose is only slowly metabolized, and sorbitol accumulates in tissues. Because aldose reductase is found in kidneys, optic nerve, and peripheral neurons, retinopathy and painful neuropathies develop in poorly controlled or long-standing diabetes as a result of sugar alcohol (sorbitol) accumulation. Aldose reductase inhibitors, such as tokestat (5.129) or sorbinil (5.130), have been evaluated as agents to ameliorate these additional symptoms of diabetes. 

Renal insufficiency is a late complication of hypertension (354). This is why the choice of the antihypertensive drug selected as the firs (dine treatment of a condition that will persist for many years is so important. From this viewpoint, the fall in blood pressure induced by ACE inhibitors might have beneficial renal effects, in addition to those induced by any decrease in perfusion pressure of the kidneys, especially in diabetic patients (222, 355-358). It is unknown if, independendy of the hemodynamic effect, at an early stage of hypertension and before the initiation of a progressive decrease in renal function, a local decrease in angiotensin II (or increase in bradykinin) explains or direcdy participates in a so-called renoprotective effect (359). 

Good blood glucose control can prevent the development and slow the progression of diabetic nephropathy, as well as preventing the other complications of diabetes, even if kidney failure has developed. This cannot be achieved by insulin alone, but requires a good diet too. Ideally HbAlc levels (a measure of average blood sugar control over three months) should be less than 7%. 

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