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About 1 in 4 stroke survivors has another. But a second stroke may be preventable. This American Stroke Month, discover what you can do to help prevent another stroke. NOTE: All fields required unless indicated as optional. Home About Stroke Effects of Stroke. Effects of Stroke. Every stroke is unique, but strokes tend to affect people in common ways. Researchers recently evaluated the accuracy of a technology to monitor blood glucose levels without needles or a finger prick. Early results show that the noninvasive technology measures blood glucose levels as effectively as a finger prick test — without drawing blood.

To face the national and worldwide increase in diabetes mellitus cases, the German Federal Ministry of Education and Research initiated the foundation of the German Centre for Diabetes Research DZD , aiming to improve basic research, prevention, diagnostic and therapy of diabetes. Inaugurated in Berlin a few months ago, the centre has five strategic partners. The difference in the prevalence of diabetes in European countries is striking. This discovery, once confirmed in humans, may lead to better treatment of heart problems in diabetics by enabling more targeted drugs to be produced.

Diabetes presents a special challenge for the young. Here we see how a young Swiss girl has successfully come to terms with her metabolic disorder. This week not only one but rather two studies report about a new and independent marker that is associated with type 2 diabetes. The protein that is called fetuin-A is produced in the liver and secreted to the blood stream also indicates a higher risk of developing diabetes disease. The immune system is a complex and precisely regulated system. Various activating and inhibiting signals ensure that the immune cells combat pathogenic agents without eliciting a potentially harmful response to its own structures and cells.

However, if those two forces are imbalanced, the immune cells may attack and damage cells and tissue of the body itself, which will result in the development…. A collaborative study led by Prof. Anke M Schulte at…. Another piece in the puzzle that is non-alcoholic fatty liver disease has been solved by a University of Queensland researcher in a step towards developing treatments for a disease that affects about one in every five Australians.

PhD student Laurence Britton has discovered a pivotal mechanism by which iron is able to make the liver more vulnerable to the injury and metabolic dysfunction that…. Since the number of children in England needing hospital care for complications of diabetes has risen about approximately 25 percent. Optimal treatment of diabetes is very difficult to achieve since many obstacles have to be overcome such as expensive treatments, poor patient compliance or insufficient datac. With these challenges in mind, a new research project titled "Computerassisted Diabetes Risk Management CDRM " was put in place to examine how eHealth solutions can improve diabetes care.

Good news for diabetes patients in the UK: According to a report published recently by the Department of Health, diabetes care in the NHS is improving and focusing more on prevention. The result: More patients have been identified, and in more people at risk development of the condition could be prevented. Despite prevention efforts, researchers have found a significant increase over a year period in the percentage of people with stroke who have high blood pressure, diabetes, smoking and other risk factors for stroke.

Australia's national science agency CSIRO has identified a new gene that plays a critical role in regulating the body's immune response to infection and disease. Type 2 diabetes poses one of the greatest public health threats of the 21st century.

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The majority of the western world is in the grips of a diabetes epidemic driven by type 2 diabetes that goes hand in hand with the escalating incidence of obesity. Alarmingly, in some working class and poor communities, the disease is so prevalent that its victims almost take it as a matter of course. Diabetes fires researchers imagination: Two scientists at the University of Michigan Kellogg Eye Center developed a new screening device that gives early warnings of diabetes and its vision complications within five minutes.

There are about million diabetics worldwide, representing 6. While in the past, Type 2 diabetes was often thought of as a disease of the elderly, there is now a rising trend of Type 2 diabetes in younger age groups. Transition Therapeutics Inc. Gastrin based therapies are an emerging class of potential disease-modifying treatments for patients with diabetes.

Made by EKF Diagnostics, the Lactate Scout 4 hand-held analyser is a fast, accurate sports performance monitoring device designed for use as a training companion for individuals or sports teams. ETH Researchers have used the simplest approach yet to produce artificial beta cells from human kidney cells. Like their natural model, the artificial cells act as both sugar sensors and insulin producers. Ageing populations, a changing disease burden; increasing obesity with associated morbidities — Type 2 diabetes, cancer and cardiovascular disease; climate change pressures and more.

Any new build plan demands a low carbon footprint; respect for the environment is paramount. To capture all those elements, the plan to regenerate a previously 10…. Anja Behringer reports on a neglected risk factor. With an aging population multimorbidity is increasingly a major challenge for hospital care. Diabetes is one of the medical conditions frequently encountered in multimorbid patients since cardiac and vascular diseases are often accompanied by dysfunctions of the blood sugar metabolism. But does ageing affect all organs and tissues in the body in the same way?

And should drugs that are developed to improve health in old age have the same effect on every organ?

Celebrating Health Research: The faces of health research - CIHR

Now scientists from the Max Planck Institute for…. Approximately 31 million people in the European Union are suffering from diabetes, a devastating disease with severe consequences for patients and their families, but also for the society at large and the economic prosperity of Europe.

This week EH Online will focus on innovative strategies in diabetes care and on new management systems to support physicians and patients alike. Moreover, we will…. ESC speaker John Cleland from the University of Hull, UK, sumed up the latest treatment available for patients with diabetes mellitus and expressed his worries about side-effects and efficacy of available anti-diabetic drugs.

A gap in scientific knowledge about a family of drugs that are used to treat Type 2 diabetes has been highlighted in a new study. Swedish researchers from the Karolinska Institutet managed to prevent onset of Type 1 diabetes in mice genetically susceptible to the disease by injecting them with specifically prepared cells. The French have a reputation as early adopters of telemedicine driven by the desire to modernise healthcare by the judicious use of the latest technology. Since , the information stored on the cards has…. When delegates from around countries converge on Munich for ESC Congress they will no doubt reflect on what they themselves eat.

Yes, nutrition is up for debate, questioning, for example, whether weight loss therapies can also prevent heart attacks and strokes. Diabetes, which now affects almost 30 million Americans, can cause serious health complications, including heart disease, blindness, kidney failure and lower-extremity amputations.

A lesser-known but equally grave complication is the effect of diabetes on bone health. People who walk to work are around 40 per cent less likely to have diabetes as those who drive, according to a new study. Omega-3 may protect children at high risk of developing type 1 diabetes, according to a study published in the Journal of the American Medical Association. The first, pan-European guidelines to be published on the treatment of valvular heart disease VHD , diabetes and cardiovascular diseases CVD have made a series of new recommendations that experts hope will contribute to improving the outcome for patients.

Researchers have successfully tested two new potential methods for diagnosing and monitoring diabetes in its standard and gestational forms. Bayer HealthCare supports local projects under the "Excellence across Borders" program in order to improve care of people with diabetes. Among the projects is a Diabetic School Awareness Program in the Kingdom of Saudi Arabia, which is planned to start in autumn this year. Metabolic syndrome, diabetes and vascular disease: What do we need to know? French findings support the notion that gastric bypass can rapidly reverse diabetes symptoms' a side-effect that lap-band surgery does not show.

The benefit results from a new-found element of glucose production by the intestine which also increases insulin sensitivity and lowers blood sugar. Preliminary findings from the largest-ever study of treatments for diabetes provide no evidence that intensive treatment to lower blood glucose sugar increases risk of death. Diabetes mellitus is a lingering disease — for a long time it causes subjectively few complaints or no complaints at all. Despite this, it is life-threatening — especially if undiagnosed, or diagnosed too late. However, although diabetes is the most widespread disease it is often only discovered by accident in a hospital, where many hospital doctors feel that diabetology is the responsibility….

Non-calcified arterial plaque is associated with diabetes, high systolic blood pressure and elevated 'bad' cholesterol levels in asymptomatic individuals, according to a new study published online in the journal Radiology. Pancreatic cancer is currently very difficult to detect while it is still resectable. Born in , Canadian Sir Frederick Banting was destined to become a medical scientist and Nobel Prize winner for work that led to the discovery of insulin. World Diabetes Day, held on his birthday, aims to sensitise the public - including potential patients - to this condition.

Worldwide, around million people suffer Diabetes mellitus. With 5. Although the drug metformin is considered the gold standard in the management of type 2 diabetes, a study by a group of French researchers published in this week's PLoS Medicine suggests that the long-term benefits of this drug compared with the risks are not clearly established - an important finding given that currently, thousands of people around the world are regularly taking metformin to….

A new study, published today in the British Journal of Pharmacology, by scientists from Royal Holloway, University of London, St George's, University of London and University of Surrey have identified that a drug related to commonly used diabetes treatments provides protection against terminal blood loss. Yes, it is, according to a prospective cohort study published in CMAJ. Their result: A V-shaped risk relation between LDL cholesterol and cancer in patients not receiving statin therapy.

A study published by the Journal of the American Medical Association JAMA recently has found that those with type 2 diabetes who had a diet high in low-glycemic foods such as nuts, beans and lentils had greater improvement in glycemic control and risk factors for coronary heart disease than those on a diet with an emphasis on high-cereal fibre. The global prevalence of Type 2 diabetes mellitus is rapidly accelerating towards a disastrous impact in just two decades.

It is also connected with blood, arteries and veins, as blood is the vital component of human body, upon which the heart works and for it we survive. The world cardiology market includes cardiac biomarkers, interventional cardiology and cardiovascular devices. Does diabetes further increase the risk of death in patients diagnosed with cancer?

There's little evidence that newer, more expensive drugs work any better than older, cheaper medications. Diabetes, which came 7th in the list of the USA's top mortality causes in , has hit a new high. Hip and knee joint surgeries are among the most common procedures in orthopaedics and trauma surgery and complications can occur. Rare, but serious, among these is periprosthetic joint infection PJI , which causes high costs in healthcare and stress for patients. PJI is caused by microorganisms that form a biofilm on the surface of the implant and, in this sessile state, they are difficult to….

This is a paradigm shift in healthcare delivery that will make it easier for patients to get accurate diagnoses and treatment, and could especially benefit patients in…. People with diabetes are often interested to be involved in research trials, according to the patient organization UK Diabetes. Therefore, the Diabetes Research Network DRN announced an initiative which shall help diabetics to play a greater role in research.

In Europe, more than ten million people suffer from diabetes mellitus, 90 percent of whom have diabetes type II. A nurse-initiated, nurse-led, and nurse-implemented study shows that nurses taking charge of diabetes care in hospital results in more patients hitting their target glucose levels. They reinforced the believe that improved education measures as a key enabler for patients to better manage the condition.

They predicted that in the number of people with diabetes wil have increased by 20 percent in Europe. Taking cholesterol-lowering drugs, or statins, as a preventive measure can reduce the risk of cardiovascular disease. A study by the University of Zurich now shows that this measure is recommended too often, as current guidelines fail to take into account the risks of side effects.

Even healthy people who don't suffer from a cardiovascular disease are prescribed statins if they meet certain risk…. Here at Medica, the Taiwanese start-up Maisense is demonstrating Freescan, its artificial intelligence AI based solution to screen for stroke through the early detection of atrial fibrillation AFib. Thirteen percent of these are classified as haemorrhagic stroke. Chronic stress is a well-known risk factor for the development of psychiatric illnesses including depression disorders. The brain requires a great deal of glucose, and stress is known to alter glucose metabolism.

However, if stress-associated mental impairments are linked to affected glucose metabolism remains to be seen. Researchers at the Department for Psychiatry and Psychotherapy at the Mainz…. One in two women and one in three men will likely be diagnosed with dementia, Parkinson's disease, or stroke in their lifetime, estimate Dutch researchers in an observational study.

People who consume an egg a day could significantly reduce their risk of cardiovascular diseases compared with eating no eggs, suggests a study carried out in China, published in the journal Heart. Cardiovascular disease CVD is the leading cause of death and disability worldwide, including China, mostly due to ischaemic heart disease and stroke including both haemorrhagic and ischaemic…. Researchers have identified 12 new genes associated with Type 2 diabetes T2D that look set to improve the understanding of the processes underpinning the condition.

The findings could also offer new biological pathways that can be explored as targets for new therapies to tackle T2D. According to the International Diabetes Federation IDF in recent decades the development of diabetes mellitus DM warrants the conclusion that this is among the most important global epidemics. Report: Walter Depner. EH reports on points aired during the supporting press briefing. A team led by the University of California San Diego has developed a chip that can detect a type of genetic mutation known as a single nucleotide polymorphism SNP and send the results in real time to a smartphone, computer, or other electronic device.

The chip is at least 1, times more sensitive at detecting an SNP than current technology. The advance could lead to cheaper, faster and…. A team led by UK-based researchers has found that having diabetes doubles the risk of developing a wide range of blood vessel diseases, including heart attacks and different types of stroke.

The consortium, headed by Dr Nadeem Sarwar and Professor John Danesh of the University of Cambridge, analysed data from the individual records on , people, each of whom was monitored for about a decade…. Researchers have discovered a potential new treatment for diabetes by isolating and killing defective cells which prevent the natural production of insulin. The investigation opens the door to a potential therapy for patients with type 1 diabetes. The panel discussion that closed the evening session revealed unanimous support for the adoption of a German national diabetes plan.

The Danes have shown for some time how e-health can work successfully on a national level. The health portal sundhed. As of January , the Danish national strategy describes sundhed. People who abstain from alcohol or consume more than 14 units a week during middle age midlife are at increased risk of developing dementia, finds a study in The BMJ today. However, the underlying mechanisms are likely to be different in the two groups. As people live longer, the number living with dementia is expected to triple by So understanding the impact of alcohol consumption on…. According to the Swedish Knee Arthroplasty Register, knee arthroplasty — with a revision rate of five percent after ten years — is one of the most successful surgical interventions of the post-World War II decades.

The most frequent reasons for revision are loosening or infections, whereas patient dissatisfaction is often caused by mobility impairment and pain. Since many adverse events are…. Insulin deficiency and hyperglycemia are two well-known culprits behind diabetes, both of which are reflected in blood glucose concentrations. Now, researchers are working to create ultrasensitive lab-on-a-chip devices to quickly measure glucose concentrations with the goal of developing device for early diagnosis and prevent of diabetes.

The daily management of diabetes mellitus is a complex interaction between blood glucose measuring, lifestyle aspects and drug therapy. In type 2 diabetes, which is occurring at alarming rates, the hormone insulin does not work effectively to lower blood sugars and patients also do not make enough insulin. These two processes have been widely considered as separate. However, a surprising discovery was made by Joslin Diabetes Center researchers in animal models of diabetes: insulin is important in regulating its own production.

A study published this week in Lancet suggests that low A1C levels may be just as dangerous as high A1C levels in diabetes patients with respect to mortality and cardiovascular outcomes. Upon review of the study, The Endocrine Society released a statement recommending against any wholesale change in glycemic goals and strongly encourages patients to discuss these issues with their diabetes-care….


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Many methods to treat current or chronic wounds are available. However, the differences in general conditions prevailing in hospital, or for out-patient care, make effective therapy more difficult. Each patient also has other preconditions for healing. Improved communication between everyone involved in the treatment would benefit patients. Diabetic foot syndrome DFS is one of the most serious sequela of diabetes mellitus - Disease management programmes DMP yield first results.

As in many other countries, Belgium faces a significant shortage of health professionals — particularly pathologists to guarantee the diagnostic quality necessary for adequate therapeutic choice. A digital pathology platform can be a true ally; the Brussels Erasmus Hospital opted for that solution. Project manager Dr Ali Ramadhan shared his experience — the good, the bad and the ugly — at….

Diabetics can face a five times increase in the risk of developing cardiovascular disease CVD than non-diabetics. This leads to a seven to ten year reduction in life expectancy and a higher probability of suffering a fatal heart attack. Four different population-based studies, recently published in Diabetelogia, the journal of the European Association for the Study of Diabetes EASD , examine a possible link between insulin glargine brand name, Lantus and cancer. New research, published in the European Heart Journal, has shown deaths from conditions that affect the blood supply to the brain, such as stroke, are declining overall in Europe but that in some countries the decline is levelling off or death rates are even increasing.

Cerebrovascular disease includes strokes, mini-strokes, and narrowing, blockage or rupturing of the blood vessels supplying…. A telemedicine programme, run through Leicester University Hospitals since last November, allows parents and young patients with Type 1 diabetes to use their mobile phone to record blood sugar levels.

With the aid of their results, physicians can enhance survival of islets transplants and improve treatment of type 1 diabetes. In a strategic move intended to enhance the global launch of its 'groundbreaking' diabetes monitoring device, set to help combat the 'worldwide epidemic', the US company Sensys Medical has chosen to relocate its world headquarters to the United Kingdom UK. The new Contour blood glucose meter from Bayer HealthCare Diabetes Care promises enhanced testing features that can be personalised to meet diabetics individual treatments.

The firm has also redesigned the Microlet 2 lancing system. UHB is leading the way in creating key networks with other European centres of excellence to share knowledge between renowned specialists. Morbid obesity is a chronic, lifelong, multifactorial, constitutional disease with negative medical, psychological, physical, social and economic side-effects.

Obesity-related secondary diseases are Type 2 diabetes mellitus T2DM , cardiovascular diseases such as hypertension or sleep apnoea. Report: Holger Zorn. Two small randomised trials published on bmj. France — Re-opening clogged arteries with metal stents has proved a life-saver for a majority of patients with coronary disease. Yet the high rates of complications and mortality for patients with diabetes following a percutaneous coronary intervention PCI continue to baffle cardiologists. Report: John Brosky. UK - A hand-sized, electronic peak flow meter, which measures lung capacity and can be connected to a PDA mobile handset is being tested for use by asthma sufferers.

A survey to launch the 'Active Fat' campaign found that 71 per cent of respondents admitted to carrying excess weight around their middle. Including a small amount of chocolate each day could help prevent diabetes type 2 and insulin resistance. Type 1 diabetes is a life-long autoimmune disease with onset in early childhood. The diagnosis will initially turn the everyday life of children and their families topsy-turvy due to blood glucose testing, insulin injections, thorough calculation of meals, etc.

It takes time before all these new and often frightening procedures become part of the daily routine of small diabetics. The study focused on 24 types of cancer. The effect is most evident for liver cancer and pancreatic cancer. However, by contrast, diabetics have a significantly lower rate of prostate…. Recent advances in percutaneous coronary intervention PCI may offer a new approach to treating this complex group of patients.

With the aid of this imaging technology, they have now described aspects of how the pancreas develops during embryonic development and how the so-called islets of Langerhans are distributed in the adult organ. The findings are important…. People suffering from diabetes-related foot ulcers show different rates of healing according to the way they cope and their psychological state of mind, according to new research by a health psychologist at The University of Nottingham, UK.

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The large study published in the journal Diabetologia has shown that the way patients cope with the condition and their levels of depression, affect how the…. This year the Annual Meeting features almost individual educational events in a variety of formats. Hot topics for include cancer, obesity, diabetes, and healthcare reform. CardioPod will be installed in pharmacies and GP surgeries across England, allowing patients easy access to an NHS Health Check carried out by a trained professional, who will give expert advice on their cardiovascular risk score and what action they can take to reduce the risk of heart disease, stroke, type II diabetes and kidney disease.

A new obesity measurement for the 21st Century, which can help identify individuals at risk of illness such as heart disease, strokes and diabetes, has been officially launched this week. The Body Volume Index BVI , designed by Select Research, uses a 3D white-light scanner to calculate risk factors associated with a person's body shape and type, through analysis of weight and body fat….

Arteriosclerosis is well known as a vascular disease and cardiovascular risk factor. In its generalised form it affects not only the peripheral vessels pelvis, legs but also the coronary vessels and the carotid arteries. Arteriosclerosis is primarily a manifestation of advancing age, hence it is often accompanied by other diseases of the lungs and the heart as well as by metabolic diseases…. Professor Oliver Schnell, of the Diabetes Research Institute, Munich, reports on discussions and findings of a panel of diabetes experts who met this summer in Switzerland.

Expert advises specific strategies should be developed to deal with this relatively new patient group. In patients suffering from Type 1 diabetes, the immune system attacks the pancreas, eventually leaving patients without the ability to naturally control blood sugar. These patients must carefully monitor the amount of sugar in their blood, measuring it several times a day and then injecting themselves with insulin to keep their blood sugar levels within a healthy range.

However, precise control…. Fifteen new research projects aimed at bringing innovative medicines to market faster have been selected to receive million Euros from the European Commission and the European Federation of Pharmaceutical Industries and Associations EFPIA. The projects will foster understanding of health issues such as diabetes, pain, severe asthma and psychiatric disorders while increasing medicine safety.

Obesity is physically debilitating — and costly for healthcare. Losing excess weight has positive effects on the entire metabolism and improves life expectancy. According to a study conducted by researchers at the University of Zurich and the Zurich University Hospital the answer is: Yes. They demonstrated that one injection per month sufficed to improve blood sugar levels significantly. Even more: The insulin production of the patients improved. Small genetic differences between individuals help explain why some people have a higher risk than others for developing illnesses such as diabetes or cancer.

In the journal Nature, the Genomes Project, an international public-private consortium, published the most comprehensive map of these genetic differences, called variations, estimated to contain approximately 95 percent of the genetic…. The Hamburg-based company seca has specialized in the manufacture of weighing and height measuring scales for over years. Today, the firm has locations in Switzerland, the UK, France, Japan, China, Mexico and the USA, and manufactures products in Germany, the Czech Republic and China, and exports its range of products - which include infant, column and flat scales, with height measuring….

HbA1c is the central marker to evaluate the success of diabetes management. But HbA1c measurement has a crucial limitation: current blood glucose fluctuations are not taken into consideration. However, the recognition of steep post-prandial blood…. These results are important to consider because self-monitoring with a blood glucose meter is essential for people with diabetes to obtain accurate blood glucose results that guide….

Innumerable studies e. Ceriello A. Possibilities to co-develop new clinical diagnostic tests for companion diagnostics, metabolic syndrome, oncology and diabetes, are being explored by Siemens Healthcare and Laboratory Corporation of America Holdings LabCorp. Too much unhealthy food, too little exercise — the risk factors for the development of non-alcoholic fatty liver disease and Type 2 diabetes are not only similar but also form a life-threatening alliance.

According to estimates up to million patients will suffer from diabetes in the year currently million. In view of this, glucose monitoring is of utmost importance. Scientific studies and practical experiences with glucose monitoring at the point of care POC were evaluated recently during a meeting of experts in Vienna. New research further illuminates the surprising relationship between blood sugar and brain tumors and could begin to shed light on how certain cancers develop. Little research has been carried out into new therapies for wound healing.

As chronic wounds tend to be classed as side effects of other diseases, e. However, the body's capacity to heal itself often does not set in for weeks. Diabetic eye disease is the leading cause of blindness among people ages 40 to The longer you have diabetes, the greater your likelihood of developing vision problems increases. Keeping blood sugar, blood pressure and cholesterol levels under control can help people with diabetes maintain good eye health. They must also have a dilated eye exam once a year, says Dr. Malav Joshi, an…. German researches have linked the increased production of a certain enzyme in the liver to fatty liver and insulin resistance.

Not long ago, POCT was a specialist diagnostic discipline used by only few laboratory staff. This has changed considerably over recent years. Initially, the main focus had been on determining electrolytes, blood gases, blood clotting and blood count, but further parameters, such as kidney function, cardiac enzymes, urine tests and testing for autoimmune diseases have now been added.

Whilst the…. According to new research, obese women with polycystic ovary syndrome PCOS may be able to improve their health outlook with a particularly enjoyable form of therapy: regular sessions in a hot tub. The research found that soaking in a hot tub several times per week for two months results in improved measures of cardiovascular health, beneficial changes in fat tissue and other improvements….

Electronic eye exams could become popular in the U. After a nationwide telemedicine diabetic screening program in England and Wales, for example, diabetic retinopathy is no longer the leading cause of blindness there. New MRI techniques are set to offer advances in the earlier detection of liver disease in patients. Radiologists are harnessing the potential of highly-targeted MRI, whilst exploring the imaging modality as a means of delivering non-invasive biomarkers, reducing the need for biopsy to measure treatment response.

An experimental treatment in mice allows the reprogramming of blood cells in order to promote the healing process of cutaneous wounds. This approach could prove to be beneficial in healing challenging wounds in diabetics and major-burn victims.

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A vaccine to immunise people against high levels of cholesterol and the narrowing of the arteries caused by build-up of fatty material atherosclerosis may be possible following successful results in mice. Now, a phase I trial in patients has started to see if the findings translate to humans. In February 20th and 22nd and March 15th AEGLE is launching a series of webinars with the objective of demonstrating how the final prototype of the AEGLE platform supports the use of big data analytics in healthcare. The tools and analytics that the AEGLE Platform supports can be used for both clinical research and clinical practice.

The four demos that will take place online through a…. It had already been known that the enzyme known as phosphatidic acid phosphatase plays a crucial role in regulating the amount of fat in the human body. Controlling it is therefore of interest in the fight against obesity.

But scientists at Rutgers University-New Brunswick have now found that getting rid of the enzyme entirely can increase the risk of cancer, inflammation and other ills. A newly developed tissue scanner allows looking under the skin of psoriasis patients. This provides clinically relevant information, such as the structure of skin layers and blood vessels, without the need for contrast agents or radiation exposure.

A clinical trial involving hundreds of participants has shown that one of the most frequently prescribed antidepressants may not benefit millions of patients who also have chronic kidney disease CKD. A system of national quality registers, established in recent decades in Sweden's health and medical services, now numbers 64 registers. The latter has…. In what is believed to be the largest pancreatic cancer genome-wide association study to date, researchers at the Johns Hopkins Kimmel Cancer Center and the National Cancer Institute, and collaborators from over 80 other institutions worldwide discovered changes to five new regions in the human genome that may increase the risk of pancreatic cancer.

The new findings represent one more step toward…. Johns Hopkins researchers have discovered a cell signaling pathway in mice that triggers vision loss in patients with diabetic retinopathy and retinal vein occlusion — diseases characterized by the closure of blood vessels in the retina, leading to blindness. Though these results have not been replicated, Epalrestat is now the standard drug therapy for diabetic neuropathy in Japan.

Myo-inositol is a naturally occurring secondary messenger involved in proper nerve function. Evidence suggests that dietary myo-inositol supplements might slow diabetic neuropathy progression, though further study is needed to assess efficacy. As described above, activation of the hexosamine pathway generates UDPGlcN-Ac, which modulates transcription factors and ultimately induces neurovascular insult.

While ARIs directly target toxic pathways, modulation of the hexosamine pathway can redirect glycolytic flow away from subsequent deleterious pathways. This mode of action offers an intriguing possibility for altering pathways in metabolic disorders. The reduced fructose-6 phosphate input decreases flux through the hexosamine pathway as well as flux through the advanced glycation end product AGE and the diacylglycerol DAG protein kinase C PKC pathways Hammes, The increased flux away from the hexosamine pathway and into the pentose-5 phosphate pathway may offer an additional benefit: increased redox capacity.

One of the products of the pentose phosphate pathway is NADPH, a prime reactant in the formation of the antioxidant glutathione. Since NADPH is depleted in the polyol pathway, benfotiamine holds the speculative possibility of diminishing the effects of this pathway as well. Benfotiamine has successfully inhibited these pathways and prevented diabetic retinopathy in animal models Hammes, In humans, Benfotiamine has been shown to improve pain associated with diabetic neuropathy and to improve NCV in conjunction with vitamins B6 and B12 Haupt, ; Stracke, ; Winkler, Benfotiamine is currently availible as a dietary supplement in the United States.

Addition of benfotiamine, a thiamine analog activates transketolase TK which diverts substrate away from the hexosamine pathway and into the pentose phosphate pathway.

Adapted from Hammes, It has been particularly successful in reducing the progression of diabetic retinopathy, endothelial vasodilation, and to a lesser extent nephropathy Aiello, ; Beckman, ; Ishii, ; Tuttle, Ruboxistaurin was being developed for US marketing by Eli Lilly and was pending FDA approval as a pharmaceutical agent for diabetic retinopathy.

Clearly, glycemic control is the primary means for decreasing AGE formation. Given that this may be difficult to achieve, prevention of RAGE activation is an important alternative therapeutic goal for diabetic neuropathy Figure Numerous compounds have been investigated for anti-glycation activity but their use in humans is still debatable. The following section describes compounds that have been assessed for the ability to decrease activity of the RAGE axis in diabetic neuropathy.

As already mentioned, aspirin acetylsalicylic acid-an NSAID is a commonly used analgesic although long-term use in diabetic patients should be weighted against possible gastrointestinal side effects. In diabetic patients on high doses of aspirin, such as those with rheumatoid arthritis, the incidence of retinopathy is decreased compared with age-matched controls not taking aspirin, which suggested that aspirin may protect against glycation Cotlier, Indeed, aspirin reduces glycation in vitro , and in animal experiments, potentially by acetylation of amino groups Blakytny, Alternatively, it is possible that aspirin does not directly alter glycation, but inhibits glycoxidation and AGE-cross-link formation; therefore its effects may be because of its antioxidant capacity Fu, Besides the analgesic effects of aspirin, studies indicate a reduced risk of cardiovascular events for diabetic patients on low dose aspirin Hennekens, Aminoguanidine also called pimagedine is a nucleophilic hydrazine compound and has received the most attention as a potential anti-glycation drug Thornalley, Initially, it was thought that aminoguanidine prevented AGE formation by blocking carbonyl groups on Amadori products, although it is now known to react with carbonyl groups from reducing sugars or 3-DG Edelstein, ; Lewis, In diabetic animals, aminoguanidine reduces nephropathy Soulis, , retinopathy Chibber, ; Hammes, , and neuropathy in some but not all studies Birrell, ; Miyauchi, Preliminary studies in diabetic patients showed that aminoguanidine therapy for 28 days reduces hemoglobin-derived AGEs Hb-AGE but does not alter levels of Amadori products Makita, Three other phase II and III trials of aminoguanidine have been completed with nephropathy endpoints but produced no benefit.

The last was discontinued because of side effects in patients, which include flu-like symptoms, gastrointestinal disturbances, and anemia Bolton, Despite the earlier promising results with aminoguanidine, it is unlikely to be used for therapeutic purposes. However, studies on anti-glycation compounds like aminoguanidine have provided evidence for the involvement of AGEs in the pathogenesis of diabetic complications. Compounds capable of cleaving AGE cross-links have been described, opening up the exciting possibility of reversing diabetic complications. Whether AGE-cross-link breakers are useful in vivo will also depend on their long-term toxicity.

This compound provides renoprotection in diabetic mice Coughlan, ; Peppa, Patient trials to date have found that ALT is well tolerated and produces significant vascular benefit in the elderly through decreased blood pressure and increased vascular elasticity Little, ; Zieman, Effects on microvascular complications of diabetes including neuropathy are not yet completed. Therefore, blockage of RAGE may be an important mechanism to prevent diabetic complications and the Schmidt group is actively working on translation of sRAGE to a clinical trial. As PARP mediates both neuronal dysfunction and inflammation, inhibition of PARP holds the potential of improving two aberrant causeways in diabetic neuropathy, making it a promising target.

Additionally, Nicotinamide vitamin B 3 has been shown to act as both a PARP inhibitor and antioxidant in rodents, improving the complications of early diabetic peripheral neuropathy Stevens, Nicotinamide is an attractive potential therapeutic due to its limited side effects and toxicity Gale, Given the known mechanisms leading to diabetic neuropathy, a logical therapeutic approach is to prevent oxidative stress by increasing antioxidant defense.

Antioxidant defense arises from Hogan, antioxidant enzymes that catalyze the removal of ROS antioxidant molecules that prevent the oxidation of other molecules Dworkin, a , usually because they are readily oxidized molecules that chelate transition metal ions so they cannot catalyze the generation of ROS in a cell Dworkin, This makes oral antioxidants an attractive strategy for both prevention and treatment of diabetic neuropathy.

Many clinical trials of antioxidant defense therapies have been completed, mostly using a high dose of a single antioxidant compound. The results of these trials have been largely negative, despite the strong rationale for this approach. We will discuss several of the lead candidate compounds and summarize other known trials in Table Vitamin E is a fat-soluble compound that exists in 8 isoforms with varying biological activity Traber, Blood levels of vitamin E can decrease under prolonged oxidative stress and in individuals who cannot absorb dietary fat Triantafillidis, , are on a low fat diet, or are zinc deficient Bunk, This compound has been broadly tested for its ability to prevent chronic diseases involving oxidative stress including cancer and diabetes complications.

While small studies have indicated that high intake of vitamin E may decrease incidence of certain cancers, large studies generally do not support the findings. One study found that regular intake of high does of vitamin E for more than 10 years decreased the risk of death from bladder cancer Jacobs, These studies demonstrate the safety of long-term use of vitamin E.

In addition to potent antioxidant action, vitamin E can promote immune function, DNA repair, and metabolism Traber, ; Wozniak, Alpha-lipoic acid, also termed thioctic acid, is an antioxidant that is available for treatment of DPN in some countries Ziegler, b. It has the potent ability to scavenge ROS, regenerate other antioxidants, and chelate metal ions Packer, Other clinical trials have been completed with varying doses and either parenteral or oral administration of the drug.

In , a review of current evidence assessed trials that met specific requirements of randomization, double masking and placebo-controlled design Foster, This was a 4-year oral treatment in patients in a multicenter evaluation. It improves some neuropathic deficits and symptoms but does not improve nerve conduction in mild and moderate diabetic neuropathy. It has long been recognized that natural dietary products including red grapes, evening primrose, and cruciferous vegetables increase antioxidant status.

In addition to many botanical extracts possessing antioxidant capacity, several compounds are known to increase the expression of antioxidant genes such as glutathione S-transferase and NAD P H:quinone oxidoreductase 1 Halat, These enzymes belong to the class of phase 2 enzymes under the regulation of a specific promoter consensus region known as the antioxidant response element ARE Itoh, Many compounds can activate the transcription factor, known as nuclear factor-E2-related factor-2 Nrf-2 , that binds this promoter.

Oxidative stress can activate the promoter via phosphorylation of the Nrf-2 cytoplasmic chaperone protein Keap-1 Tamasi, Botanical compounds may activate Nrf-2 either by inducing mild intracellular oxidative stress, by directly activating Nrf-2, or by causing recruitment of Nrf-2 co-activators, such as small Maf proteins Dhakshinamoorthy, ; Kang, ; Venugopal, The most widely assessed botanical compound is resveratrol, extracted from red grapes.

Studies in STZ-treated rats demonstrated attenuation of thermal hyperalgesia and cold allodynia as well as decreases in oxidative stress DNA damage, and nerve conduction deficits Kumar, ; Sharma, Similarly, in type 1 diabetic mice resveratrol prevents neuropathic pain Sharma, Resveratrol is likely to provide additional therapeutic benefits in T2DM patients because it also activates the SIRT1 genes that regulate glucose metabolism and insulin sensitivity Chen, ; Sun, ; Zang, Resveratrol was assessed in a trial examining aging and cardiovascular disease and produced positive results Labinskyy, Although trials in diabetes are indicated by these findings, there are none on record to date.

A controlled diabetes patient trial has not been performed for any of these compounds. Several drugs are in common use in T2DM for blood pressure, cardiovascular disease, and nephropathy. The first line of attack for these diabetes-related conditions is inhibition of angiotensin-converting enzyme ACE or of angiotensin receptor. Evaluation of the outcomes of clinical trials suggests that preventing one complication is likely to have a positive impact upon other complications Podar, Specifically, prevention of cardiovascular disease is likely to prevent macro-and microvascular complications.

Large-scale studies of the effects of ACE inhibitors or angiotensin receptor blockers, known as ARBs, have not been done, although some small studies and prospective assessments have been performed. In experimental diabetes, enalapril, an ACE inhibitor, or L, an angiotensin II receptor blocker, decreases neurovascular deficits including blood flow and motor nerve conduction velocity Coppey, Another ACE inhibitor, Perindopril, prevents photoreceptor loss, an indicator of neuropathy Bui, In a small clinical study, the ACE inhibitor trandolapril produced a significant improvement in peripheral neuropathy Malik, Either drug alone improved DAN and cardiac function; in combination the improvement may have been greater.

Peripheral nervous system injury in diabetes may be the result of both hyperglycemia and loss of neurotrophic support normally provided by insulin. This hypothesis is supported by reports of abnormal expression levels of growth factors in diabetes. Thus, there is growing interest in exploring the potential utility of NGFs, insulin, IGFs, and others neurotrophic factors in the treatment of diabetic neuropathy. Insulin receptors are found in the PNS on Schwann cells, pericytes, endothelial cells, and neurons, especially sensory neurons Brussee, ; Sugimoto, ; Sugimoto, Insulin-deficient rat models of diabetes appear to have more severely progressive neuropathy compared to T2DM models, suggesting insulin deficiency itself contributes to the development of neuropathy Kamiya, ; Pierson, Local delivery of insulin to the spinal cords of STZ-treated rats improves nerve condition velocity measurements, and low-dose systemic delivery at a level that does not reduce hyperglycemia is able to decrease signs of mitochondrial distress in sensory neurons Brussee, ; Singhal, ; Toth, C-peptide, long thought to be merely an inert peptide fragment byproduct of insulin synthesis, is now believed to have biological activity of its own, although little is known mechanistically as there is currently no identified receptor Wahren, C-peptide deficiency is concomitant with insulinopenia in T1DM.

When C-peptide is replaced in diabetic rats, a number of measures of peripheral nerve function improve. Proposed mechanisms for these observations include potentiation of insulin signaling, vasodilation via nitric oxide release, and stimulation of the release of other neurotrophic factors Cotter, b ; Kamiya, ; Pierson, ; Sima, ; Sima, ; Zhang, IGFs have been reported to be reduced in some animal models of diabetes, although this varies and may be dependent upon the model, type of diabetes, and tissue examined Craner, ; Ekstrom, ; Kamiya, ; Schmidt, ; Wuarin, ; Zhuang, A number of preclinical studies in diabetic rats suggest systemic or intrathecal IGF therapy can improve neuropathy Brussee, ; Ishii, ; Lupien, ; Schmidt, ; Schmidt, ; Toth, ; Zhuang, Clinical use of IGFs may be complicated by their widespread systemic effects Russo, NGF is not required for sensory neuronal survival in the adult PNS, but it does regulate axonal sprouting and the phenotype of sensory neurons Chudler, ; Lindsay, ; Schwartz, Thus, preclinical studies of NGF in diabetic rats resulted in improvements in both signaling outcomes of the NGF system and PNS function, as well as positive effects on myelination Apfel, ; Christianson, ; Christianson, ; Diemel, ; Elias, ; Fernyhough, b ; Sango, ; Unger, Clinical studies have not progressed past phase 3, however, and there is developing interest in small molecule activators of trkA as a potentially more viable alternative approach Apfel, BDNF is expressed by both peripheral neurons and muscle, and its receptor, trkB, is found on motor neurons and some sensory neurons McMahon, Retrograde transport of endogenous, but not exogenous, BDNF to the neuron cell bodies is impaired in diabetic rats, suggesting there are problems with the local supply of BDNF at the peripheral nerve terminals Mizisin, Exogenous BDNF is protective to large myelinated sensory fibers in STZ rats, but not smaller fibers, which is consistent with the distribution of trkB expression Calcutt, ; Elias, ; Mizisin, Preclinical studies of exogenous NT-3 therapy in diabetic rats have had mixed results.

One study found improvement in large sensory fibers, but not motor fibers Mizisin, Another study found effects on both large sensory and motor fibers Mizisin, Intrathecal NT-3 increased myelinated fibers in the skin of diabetic mice, but without noticeable improvement of function Christianson, Ciliary derived neurotrophic factor CNTF is a cytokine with numerous neurotrophic properties Vergara, It is only expressed in Schwann cells in the peripheral nervous system Kobayashi, , and levels of CNTF are reduced in diabetic rats Calcutt, This deficiency can be improved by ARI therapy Mizisin, Exogenous CNTF itself has therapeutic benefit in diabetic rats, improving function in both sensory and motor fibers, along with increasing regenerative capabilities Calcutt, ; Mizisin, Therapeutic use of CNTF is complicated by its systemic effects, particularly on muscle, and thus more targeted delivery approaches are being considered Bongioanni, While this review has discussed the fusion of over 30 years of research in diabetic neuropathy, glucose control alone still remains the only disease-modifying therapy for diabetic neuropathy Leinninger, b ; Little, ; Vincent, This lack of progress, despite intense research, suggests that a new paradigm is needed.

To date, only one animal study and no human studies has addressed alterations in peripheral nervous system gene expression in response to diabetes. Price and colleagues performed microarray analyses on Wistar rat dorsal root ganglion neurons, 1, 4, and 8 weeks post STZ-induced diabetes Price, Nerve conduction measures confirmed the presence of DPN in these animals at weeks 4 and 8 Price, At week 1, genes involved in glucose metabolism were upregulated, and by week 4 glutathione transferase was upregulated as would be predicted secondary to conditions of oxidative stress Price, What is now required is a comprehensive effort to establish the molecular signatures of neural tissues from genome wide screening of RNA from different animal models without and with DPN and DAN Sullivan, ; Sullivan, A discovery approach for diabetic neuropathy is presented in Figure Genome wide expression profiling of sensory and sympathetic neurons and nerves from different animal models of DPN and DAN will yield differentially regulated transcripts.

These expression profiles will provide the data needed to define categories of genes that are functionally regulated in diabetic neuropathy; possible examples would be genes involved in metabolism or mitochondrial function or nerve regeneration. Further analyses of these data can define shared promoter modules among members of different gene categories, providing one or more specific targets for disease regulation Ashburner, In parallel, an informatics approach can also define relevant pathways related to functional gene categories, providing additional information on novel mechanisms of disease pathogenesis or identifying new disease targets Dennis, Figure The genes that were found to be differentially expressed between healthy and diseased tissue were put into the context of cellular pathways and used to predict regulatory elements controlling the observed changes.

Regulatory elements identified could be used to identify drug targets and also to predict the downstream effects of gene expression, including the presence of biomarkers in chronic renal disease. Activities in blue are hypothesis driven and attempt to identify biomarkers based on the disequilibrium of identified targets in diabetic neuropathy, leading to an abnormal accumulation of products, such as modified proteins or small molecules.

Activities in red are discovery oriented and seek to identify features of the data set that are predictive of diabetic neuropathy without necessarily corresponding to a single target. As emphasized above, we contend a similar comprehensive approach is needed in diabetic neuropathy to further advance our understanding of disease pathogenesis and our development of disease modifying therapies.

Of special interest is how this approach can in parallel lead to biomarker discovery. As outlined in Fig. These data in turn provide the knowledge to predict proteins and macromolecules influenced by gene expression. By using clustering and classification analysis, while maintaining high standards of mathematical validation throughout, one could discover those targets most likely to serve as useful biomarkers, such as modified proteins or small molecule products of targeted pathways.

The data can also be analyzed to see if there is a constellation of genes that cluster in a unique way, suggesting a target not observed by the gene selection or pathway enrichment approach. A flow diagram of this type of analysis plan is presented in Figure 13 and is complimentary to the approach presented in Fig. Genome wide expression profiling of neural tissues from animal models with diabetic neuropathy DN will yield differentially regulated transcripts.

Analyses of these data using Gene Ontology GO will provide the data needed to define categories of genes that are functionally related providing a molecular signature for diabetic neuropathy. Further analyses of these data can define relevant pathways related to functional gene categories and shared promoter modules among members of different gene categories, providing one or more specific targets for disease regulation. These targets can be verified at the mRNA level, confirming the identification of a novel disease target. Neuropathy is one of the most prevalent, devastating and costly complications of diabetes.

Distal symmetrical sensorimotor polyneuropathy DPN is the leading cause of nontraumatic limb amputation. Diabetic autonomic neuropathy DAN can affect virtually any body system and is associated with greatly increased morbidity and mortality and can have a profound influence on quality of life.

Diabetic neuropathies can be diagnosed with relatively simple tests of peripheral and autonomic nerve function. Treatment of diabetic neuropathy should always begin with efforts to optimize glycemic control and with patient education. There are now many useful pharmacologic approaches to treating painful neuropathy and most manifestations of autonomic neuropathy, but disease modifying treatments other than strict glycemic control await a more complete understanding of the underlying mechanisms of diabetic neuropathy and the development of pharmacologic agents based on this emerging knowledge.

Some positive results from preclinical studies with inhibitors implicated in the pathogenesis of diabetic neuropathy have been reported, but only time will tell whether and how these will translate into therapeutics. Discovery of these therapeutic targets will require implementation of bioinformatics, biochemistry, cellular biology, and physiology. NS: not significant, Qid: four times a day.

1. Introduction

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Corresponding Author: Eva L. Feldman, Zina Pitcher Blvd. Copyright notice. The publisher's final edited version of this article is available at Pharmacol Ther. See other articles in PMC that cite the published article. Abstract Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Table 1 Classification of Clinical Diabetic Neuropathy.

Open in a separate window. Figure 1. Stocking Glove Configuration of DPN Diabetic neuropathy is dependent on axon length, initiating in the toes and progressing upward until reaching the calf. Pupillary Decreased dark-adapted pupil diameter Sudomotor Anhidrosis Heat intolerance Gustatory sweating Dry skin - Gastrointestinal Esophageal dysmotility Gastroparesis Constipation Diarrhea, fecal incontinence Cardiovascular Resting tachycardia Exercise intolerance Orthostatic hypotension Silent myocardial ischemia Genitourinary Neurogenic bladder Erectile dysfunction Retrograde ejaculation Female sexual dysfunction.

T2DM Neurological examination and symptoms score Figure 2. Figure 3. Effect of Glycemic Control on Diabetic Neuropathy in DCCT Intensive therapy cohort which showed better glycemic control, results in lower incidences of all forms of diabetic neuropathy compared to conventional therapy. Table 4 Classification and Staging of Diabetic Neuropathy. Figure 4. Figure 5. Pathogenesis of Diabetic Neuropathy There may be multiple etiologies which account for the various neuropathic syndromes seen in patients with diabetes. Figure 6. Figure 7. Oxidative stress and mitochondrial dysfunction Leinninger, b Hyperglycemia increases production of reactive oxygen species ROS in mitochondria.

Growth Factors Growth factors promote the growth and survival of neurons and direct neurite outgrowth Leinninger, Therapeutic Strategies for Diabetic Neuropathy 5a. Glycemic Control Therapies for DPN and DAN may be divided into treatments that target the underlying pathogenetic mechanisms Boulton, a ; Singh, ; Trotta, and those aiming to relieve symptoms Adriaensen, T1DM DCCT As discussed previously, the DCCT compared intensive treatment 3 or more insulin injections or insulin pump aiming to normalize HbA 1c with conventional treatment 1 or 2 insulin injections aiming to prevent hyperglycemic symptoms and hypoglycemia in 1, patients with T1DM.

Continuous Glucose Monitoring Despite the evidence of the DCCT which suggest that HbA 1C levels are strong predictors for diabetic complications, factors other than average blood glucose levels have a profound influence on incidence of diabetic complications. Figure 8. Risk of Diabetic Complications Retinopathy in Control vs. Intensive Therapy as related to Hb A1C Absolute risk of sustained retinopathy progression as a function of updated mean A1C percentage during the DCCT and the time of follow-up during the study years , estimated from absolute Poisson regression models.

Islet Transplantation Pancreas transplantations in T1DM patients are now at a sufficient success rate to assess potential therapeutic effects on diabetic complications. T2DM Evidence that good glycemic control can delay or prevent progression of diabetic neuropathy in patients with T2DM is more limited.

Symptomatic Treatment of Peripheral Neuropathy. Foot Care All patients with diabetes should receive at least an annual foot examination to identify high-risk conditions Association, ; Boulton, Symptomatic Therapies 5b1. Diabetic Polyneuropathy Pain is an early manifestation of diabetic neuropathy and frequently precedes the diagnosis of diabetes Boulton, ; Feldman, Table 10 Therapeutics for the Polyol Pathway. Antidepressants Tricylic and tetracyclic reagents The tricylic and tetracylic antidepressants TCA are considered as the first line treatment for neuropathic pain. Mexelitine Mexelitine is an anti-arrythmia medication and has been used for treating a variety of painful neuropathic conditions including DPN Jarvis, Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs NSAID are a class of medications that inhibits cyclooxygenases, and thus prevent the formation of prostaglandins.

Topical agents Capsaicin is an extract of capsicum peppers. Selection of a Drug Regimen for DPN Recently, the data from most available placebo-controlled trials was used to generate an algorithm and a flow chart Figure 9 for treating neuropathic pain Dworkin, b ; Strokov, Figure 9. Management of Neuropathic Pain Stepwise instructions for treatment of the symptoms for painful diabetic neuropathy based on multiple levels of medications, pain scores and evaluations.

Placebo Effect Recent work by Tesfaye et al. Diabetic Autonomic Neuropathy As discussed previously, the first step in the treatment of all forms of diabetic neuropathy is long-term improvement of glycemic control. Table 7 Approaches to Treatment of Orthostatic Hypotension. Table 8 Approaches to Treatment of Diabetic Gastroparesis. Table 9 Approaches to Treatment of Diabetic Diarrhea. Causal Therapies Topics covered previously in this review discussed proven therapies which either prevent or slow diabetic neuropathy glycemic control or diminish its effects symptomatic therapies.

Polyol Pathway The most common target of diabetic neuropathy therapies is sorbitol the first metabolic product of the polyol pathway, through the enzyme AR. Aldose Reductase Inhibitors Aldose Reductase Inhibitors ARIs have historically been the primary target of diabetic neuropathy treatment, due largely to their success in reducing cataract-forming osmotic stress associated with polyol accumulation in the diabetic lens Chylack, ; Kinoshita, Sorbinil In , Sorbinil was the prototype ARI to be developed solely for diabetic neuropathy treatment.

Ponalrestat Ponalrestat is a carboxylic acid that effectively lowers nerve sorbitol levels in vitro and in rats, but fails to do so in human diabetic nerves Greene, ; Stribling, Zopolrestat Zopolrestat is a carboxylic acid analog of Ponalrestat that dose-dependently decreased diabetic rat nerve sorbitol and fructose levels. Zenarestat Zenarestat is a carboxylic acid ARI also showing a dose-dependant increase of NCV; notably, higher doses of Zenarestat continue to improve NCV, increase nerve fiber density and nerve health even after nerve sorbitol levels have stabilized Greene, AS AS, or Ranirestat, is a well-tolerated spirosuccinimide discovered in Epalrestat In , Epalrestat entered the Japanese market as a carboxylic acid ARI with minimum side-effects, but without conclusive evidence of efficacy backed by a randomized, double-blind placebo-controlled study.

Myo-inositol Myo-inositol is a naturally occurring secondary messenger involved in proper nerve function. Hexosamine Pathway As described above, activation of the hexosamine pathway generates UDPGlcN-Ac, which modulates transcription factors and ultimately induces neurovascular insult. Figure Aspirin As already mentioned, aspirin acetylsalicylic acid-an NSAID is a commonly used analgesic although long-term use in diabetic patients should be weighted against possible gastrointestinal side effects.

Aminoguanidine Aminoguanidine also called pimagedine is a nucleophilic hydrazine compound and has received the most attention as a potential anti-glycation drug Thornalley, Phenacylthiazolium bromide Compounds capable of cleaving AGE cross-links have been described, opening up the exciting possibility of reversing diabetic complications. Table 11 Antioxidant therapy in diabetic neuropathy. Effective in experimental diabetes and currently in a type 1 diabetes patient trial.

Bonnefont-Rousselot, ; Eriksson, ; Stevens, Eugenol From clove oil; both anit-inflammatory and antioxidant. Improves vascular and neural deficits in STZ-treated rats. Nangle, Taurine Plasma taurine is depleted in diabetic rats and replacement decreases hyperalgesia and other neural and vascular deficits. Sayyed, Oleuropein From olive leaf, decreases blood glucose as well as oxidative stress in alloxan-treated rabbit.

Al-Azzawie, Minerals Metal ions including vanadium, chromium, magnesium, zinc, selenium, copper contribute to antioxidant defense. They may become depleted in diabetic patients and should be included in the diet. Bonnefont-Rousselot, Vitamin C While vitamin C does not improve diabetes complications when given alone, it is used in combination with vitamin E or other antioxidants, since it facilitates effective antioxidant recycling.

Dorchy, ; Jacobs, ; Will, Quercetin A flavonoid that attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats Anjaneyulu, Melatonin Plasma levels decrease in diabetic patients with complications, supplementation reverses antioxidant status deficits and prevents complications. May both activate antioxidant response and scavenge ROS. Prevents oxidative stress in diabetic rats. Je, Dimethylthiourea A hydroxyl radical scavenger, prevents diabetes-induced mechanical and thermal nociceptive sensitivity and never blood flow deficits.

Cameron, Evening primrose oil Initially used for therapeutic benefit of polyunsaturated fatty acids, also decreases oxidative stress. Efficacy further enhanced by conjugation with an antioxidant. Cameron, ; Ford, Nitecapone Catechol-O-methyltransferase inhibitor with potent antioxidant properties. Had some ability to prevent diabetic mechanical hyperalgesia, but essentially ineffective in preventing the development of diabetic neuropathy Pertovaara, Troglitazone Used as an insulin sensitizer in diabetic patients, but also operates as an antioxidant.

May improve peripheral neuropathy in STZ-induced diabetic rats irrespective of blood glucose concentrations. Vitamin E Vitamin E is a fat-soluble compound that exists in 8 isoforms with varying biological activity Traber, Botanicals It has long been recognized that natural dietary products including red grapes, evening primrose, and cruciferous vegetables increase antioxidant status. Resveratrol The most widely assessed botanical compound is resveratrol, extracted from red grapes. The Search for Novel Therapeutic Targets While this review has discussed the fusion of over 30 years of research in diabetic neuropathy, glucose control alone still remains the only disease-modifying therapy for diabetic neuropathy Leinninger, b ; Little, ; Vincent, Summary Neuropathy is one of the most prevalent, devastating and costly complications of diabetes.