August 2007 - Researchers at Warwick Medical School, University of Warwick, have discovered that deficiency of thiamine (Vitamin B1) may be key to a range of vascular problems for people with diabetes. They have also solved the mystery as to why thiamine deficiency in diabetes had remained hidden until now.

Diabetes is increasing in incidence in the UK and elsewhere and one of the most significant health problems associated with the condition are vascular complications: microvascular complications, such as damage to the kidney, retina and nerves in arms and legs; and macrovascular complications, such as heart disease and stroke.

The University of Warwick researchers, led by Professor Paul Thornalley, have shown conclusively that diabetic patients are thiamine deficient in blood plasma. They were also able to solve the mystery of what was happening to thiamine in diabetic patients and connect it more closely to vascular complications in diabetic patients.

In a paper entitled "High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease", published in Diabetologia on 4th August, the team found that thiamine concentration in blood plasma was decreased 76% in type 1 diabetic patients and 75% in type 2 diabetic patients. This significant decrease had been previously masked as the conventional way of assessing levels of thiamine status was to measure the activity of an enzyme called transketolase in red blood cells. Past studies had seen normal activity of this enzyme and assumed normal levels of thiamine when in fact the normal enzyme activity was due to increased amounts of two proteins THTR-1 and RFC-1 that help transport thiamine into red blood cells. The increased levels of these proteins were a direct response to there being a deficiency of thiamine in the body.

The researchers found that the decreased availability of thiamine in vascular cells in diabetes was linked to a marker of microvascular and macrovascular complications. It likely reflects problems in endothelial cells (endothelial cells line the body's entire circulatory system) and increased risk of atherosclerosis (chronic inflammatuion in the artery walls).

The researchers found that the decreased plasma thiamine concentration in clinical diabetes was not due to a deficiency of dietary input of thiamine. Rather it was due to a profound increased rate of removal of thiamine from the blood into the urine.

The researchers feel that important areas for future study are: confirmation of low plasma thiamine concentrations in diabetic populations of other countries independent of local diet; the evaluation of thiamine and thiamine derivatives to correct low plasma thiamine concentration in diabetes, reverse vascular dysfunction and prevent vascular complications; and investigation of the mechanism of increased removal of thiamine from the blood into the urine in diabetes.

This study was funded by a project grant from Diabetes UK. View complete paper here

Source: Diabetes UK

DATE: September 07, 2007

Diabetes patients could benefit from new research at the University of Liverpool that has identified a molecule in the intestine that can ‘taste’ the sugar content of the diet. Researchers found that the sweet taste receptor that senses sugar and artificial sweeteners is not only present in the tongue, but also in the intestine. The discovery will open new avenues for the treatment of diabetes and obesity, as well as suggest reasons for why artificially sweetened foods and beverages sometimes fail to result in weight loss, according to Eurekalert, the news service of the American Association for the Advancement of Science. Scientists have previously shown that the absorption of dietary sugars in the intestine is mediated by a protein – a sugar transporter – that varies in response to the sugar content of foods. The intestine uses a glucose sensing system to monitor these variations, but until now the nature of this system was unknown. Professor Soraya Shirazi-Beechey, from the Faculty of Veterinary Science, said: “We found that the sweet taste receptor and the taste protein, gustducin, are present in the taste cells of the gut. These sweet sensing proteins allow humans and animals to detect glucose within the intestine. We discovered that mice missing the gene for either of these proteins were unable to process the production of the intestinal sugar and were therefore unable to regulate the intestinal capacity to absorb dietary sugars. “Surprisingly we also found that the receptor was able to detect artificial sweeteners in foods and drinks resulting in increased capacity of the intestine to absorb dietary sugars, which would explain why these sweeteners are unsuccessful at helping people lose weight. “We are now researching mechanisms in which these receptors can be adjusted to benefit those with diet-related disorders. Diabetes for example, is where the body’s blood sugar level is higher than normal; if we could use the taste receptor like a dimmer switch we could set it so that the appropriate amount of sugar is absorbed in the body. “From a veterinary perspective, the discovery could also have implications for race horses. Horses need high levels of glucose to sustain them in long races; activating the receptor through dietary supplements, before and during the race, will increase intestinal absorption of glucose.”

Two studies published this summer have found that the injected diabetes drug pramlintide (brand name Symlin) may help obese people lose weight.

Pramlintide is a synthetic analog of the hormone amylin, which is usually secreted by the pancreas along with insulin in response to meals. In the body, amylin works with insulin to control the rise in blood glucose levels after eating. People with diabetes whose pancreases don't produce enough insulin (or any insulin) also don't produce enough amylin at mealtimes.

Pramlintide was approved by the U.S. Food and Drug Administration (FDA) in March 2005 for use in people with Type 1 diabetes and people with Type 2 diabetes who use insulin. Pramlintide helps control blood glucose levels by several mechanisms, including slowing stomach emptying. This action can also help people feel more full and eat less food.

Previously published studies have shown that using pramlintide can help people with Type 2 diabetes, who are often overweight, lower both their HbA1c levels and their weight. Now, two new studies have looked specifically at pramlintide's role in helping obese people lose weight.

In one study, published in the August issue of The Journal of Clinical Endocrinology and Metabolism, researchers recruited 204 people with an average body-mass index (BMI) of 37.8 (a BMI over 30 is classified as obese). These people were randomly assigned to take injections of either pramlintide or a placebo three times a day before meals for four months. Both groups also received lifestyle interventions aimed at weight loss.

Compared with the placebo group, the participants who received pramlintide lost about eight pounds and almost 1 1/2 inches from their waistlines. Also, a greater percentage of the pramlintide group (31%) lost 5% or more of their body weight compared to 2% of the placebo group, and a substantially higher percentage of people in the pramlintide group reported better appetite control and improved well-being. Nausea was the most common side effect associated with pramlintide, and both groups had a similar percentage of withdrawal from the study: 29% of the pramlintide group and 25% of the placebo group.

Another study, published in the American Journal of Physiology - Endocrinology and Metabolism in August looked at 88 obese people randomly assigned to inject either pramlintide or a placebo before each meal for six weeks. Over this period, the people who received pramlintide ate between 500 and 750 fewer calories per day than the people who received the placebo. They also ate smaller portions and were less likely to binge eat when presented with food such as pizza, soda, and ice cream during "fast food challenges." At the end of the study period, members of the pramlintide group had lost an average 2% of their body weight while members of the placebo group had gained a small amount of weight.

Both studies received funding from Amylin Pharmaceuticals, Inc., which manufactures pramlintide.

FDA approval for pramlintide purely as a weight-loss drug is probably still years in the future; meanwhile, other studies are under way to test the weight-loss effects of combining pramlintide with other drugs and synthetic hormones. For people with diabetes who are overweight and use insulin, however, pramlintide may be able to help them lose weight in addition to helping control postmeal blood glucose levels.

7-Aug-2007

Insulin Grown in Plants Relieves Diabetes in Mice, Holds Promise for Humans

August 2007 - Capsules of insulin produced in genetically modified lettuce could hold the key to restoring the body's ability to produce insulin and help millions of Americans who suffer from insulin-dependent diabetes, according to University of Central Florida biomedical researchers.

Professor Henry Daniell's research team genetically engineered tobacco plants with the insulin gene and then administered freeze-dried plant cells to five-week-old diabetic mice as a powder for eight weeks. By the end of the study, the diabetic mice had normal blood and urine sugar levels, and their cells were producing normal levels of insulin.

Those results and prior research indicate that insulin capsules could someday be used to prevent diabetes before symptoms appear and treat the disease in its later stages, Daniell said. He has since proposed using lettuce instead of tobacco to produce the insulin because that crop can be produced cheaply and avoids the negative stigma associated with tobacco.

The National Institutes of Health provided $2 million to fund the UCF study. The findings are reported in the July issue of Plant Biotechnology Journal.

Insulin-dependent, or Type 1, diabetes is an autoimmune disease in which the body's immune system attacks and destroys insulin and insulin-producing beta cells in the pancreas. Insulin is a hormone that is needed to convert sugar, starches and other food into energy.

Insulin typically is given through shots and not pills so the hormone can go straight into the bloodstream. In Daniell's method, plant cell walls made of cellulose initially prevent insulin from degrading. When the plant cells containing insulin reach the intestine, bacteria living there begin to slowly break down the cell walls and gradually release insulin into the bloodstream.

"Currently, the only relief for diabetes is a momentary relief," Daniell said. "Diabetics still have to monitor their blood and urine sugar levels. They have to inject themselves with insulin several times a day. Having a permanent solution for this, I'm sure, would be pretty exciting."

Though produced in lettuce, the insulin would be delivered to human patients as a powder in capsules because the dosage must be controlled carefully.

If human trials are successful, the impact of Daniell's research could affect millions of diabetics worldwide and dramatically reduce the costs of fighting a disease that can lead to heart and kidney diseases and blindness.

About 20.8 million children and adults in the United States, or about 7 percent of the population, have Type 1 or 2 diabetes, according to the American Diabetes Association.

The number of Americans with diabetes is projected to double by 2025, according to a study released last month by the National Changing Diabetes Program during a congressional briefing. That study by Mathematica Policy Research Inc. also reported that one of every eight federal health care dollars, $79.7 billion out of $645 billion, is spent on treating people with diabetes.

"Diabetes is a big health and financial burden in the United States and in the rest of the world," Daniell said. "This study would facilitate a dramatic change because so far there is no medicine that will cure insulin-dependent diabetes."

Daniell's method of growing insulin in plants is similar to what he used for an earlier study to produce anthrax vaccine in tobacco. In the earlier study, which also involved mice, Daniell showed and the National Institutes of Health confirmed that enough safe anthrax vaccine to inoculate everyone in the United States could be grown inexpensively in only one acre of tobacco plants.

Daniell, who is the first UCF Trustee Chair in Life Sciences, began teaching at UCF in 1998. His research led to the formation of UCF's first biotechnology company, called Chlorogen, for the commercial development of patented chloroplast genetic engineering technology. In 2004, he won UCF's Pegasus Professor Award, the top honor given to a faculty member who excels in teaching, research and service. Daniell also became only the 14th American in the last 222 years to be elected to the Italian National Academy of Sciences.

7-Aug-2007

Researchers Present New Diabetes Findings

August 2007 - A new drug is showing great promise in returning patients with type 1 diabetes to insulin independence. Diabetes researchers at the University of Miami Miller School of Medicine were able to re-establish long term insulin independence in diabetes patients who underwent a supplemental islet cell infusion while being treated with exenatide at the same time. The late-breaking findings were presented during the 67th scientific sessions of the American Diabetes Association.

Patients at UM's Diabetes Research Institute received exenatide, which is a drug used to treat type 2 diabetes, for at least three months and continued to receive it after the supplemental islet infusion. Exenatide is the first in a new class of medicines known as incretin mimetics which reduce blood sugar levels and improve islet function.

"Our research suggests that supplemental islet infusions during treatment with exenatide are more successful in achieving and maintaining insulin independence," said Raquel Faradji, M.D., lead author of the study and assistant director of the clinical islet transplant program at the Diabetes Research Institute. "This may be due to improved islet function and perhaps an increase in the amount of islets. Given the shortage of donor pancreases, exenatide may help achieve and maintain insulin independence in more islet transplant recipients using only one donor pancreas."

Transplants using islet cells are currently considered the most promising method for curing diabetes. During the procedure islets are separated from a donor pancreas and infused into the liver of a patient with diabetes. In the liver, within a short time, they begin to produce insulin.

The four patients who underwent the supplemental islet infusion in 2006 while taking exenatide were compared to a control group of five patients who underwent a supplemental infusion without the drug treatment. Only one patient without the drug treatment remained insulin independent after one year, while all the patients in the drug-treated group were insulin independent at one year.

"All of the patients had achieved insulin independence after their initial islet cell transplants, but eventually developed graft dysfunction and had to go back on insulin," said Faradji. "To be able to re-establish insulin independence with a supplemental infusion is a big step forward, and we now need a larger trial to see if using exenatide is making the difference."

Metabolic Syndrome - Don't Blame the Belly Fat

July 2007 - Abdominal fat, the spare tire that many of us carry, has long been implicated as a primary suspect in causing the metabolic syndrome, a cluster of conditions that includes the most dangerous heart attack risk factors: prediabetes, diabetes, high blood pressure, and changes in cholesterol.

But with the help of powerful new imaging technologies, a team of Howard Hughes Medical Institute (HHMI) researchers at Yale University School of Medicine has found that insulin resistance in skeletal muscle leads to alterations in energy storage that set the stage for the metabolic syndrome.

Insulin resistance is a condition in which the body's cells become resistant to insulin, a hormone secreted by the pancreas that plays an essential role in regulating the carbohydrates, lipids, and proteins obtained from food.

The new study, published July 16, 2007, in the Proceedings of the National Academy of Sciences demonstrates that insulin resistance in skeletal muscle -- caused by decreased ability of muscle to make glycogen, the stored form of carbohydrate from food energy -- can promote an elevated pattern of lipids or fats in the bloodstream that underpins the metabolic syndrome.

The study was led by HHMI investigator Gerald I. Shulman and Kitt Falk Petersen, both of the Yale University School of Medicine. Coauthors of the paper were from Yale and Harvard Medical School.

The metabolic syndrome is a very common metabolic abnormality and the prevalence is growing. However, the underlying factors that cause it are poorly understood." The syndrome afflicts more than 50 million Americans and roughly half of all Americans are predisposed to it, making it one of the nation's most serious human health issues.

To begin to shed light on the earliest molecular events that lead to the metabolic syndrome, Shulman and his colleagues used powerful new magnetic resonance imaging techniques to observe how nutrients are channeled in the body in both insulin resistant and insulin sensitive human subjects.

The subjects for the study were all young, lean, non-smoking, healthy individuals who were sedentary and matched for physical activity. Aside from insulin resistance in one cohort, these volunteers had none of the other confounding factors typically associated with obesity and type 2 diabetes, which have been thought to play a key role in the pathogenesis of the metabolic syndrome.

"Our hypothesis was that the metabolic syndrome is really a problem with how we store energy from food," Shulman explained. "The idea is that insulin resistance in muscle changes the pattern of energy storage."

After providing the study's subjects with two meals high in carbohydrates, Shulman and his colleagues turned to magnetic resonance spectroscopy to measure the production of liver and muscle triglyceride, the storage form of fat, and of glycogen, the storage form of carbohydrate. "What we found is that (insulin) sensitive individuals took the energy from carbohydrate in the meals and stored it away as glycogen in both liver and muscle," said Shulman.

In the insulin resistant subjects, the energy obtained from their carbohydrate rich meals was rerouted to liver triglyceride production, elevating triglycerides in the blood by as much as 60 percent and lowering HDL cholesterol (the "good cholesterol") by 20 percent. "In contrast to the young, lean, insulin-sensitive subjects, who stored most of their ingested energy as liver and muscle glycogen, the young, lean, insulin-resistant subjects had a marked defect in muscle glycogen synthesis and diverted much more of their ingested carbohydrate into liver fat production," Shulman and his colleagues reported.

"What we see," he noted, "is alterations in patterns of energy storage. An additional key point is that the insulin resistance, in these young, lean, insulin resistant individuals, was independent of abdominal obesity and circulating plasma adipocytokines, suggesting that these abnormalities develop later in the development of the metabolic syndrome."

The new findings promise to help untangle the early molecular events of a syndrome at the root of one of the world's most significant health issues. "Knowing how insulin resistance alters energy storage before it leads to more serious problems can help those susceptible prevent the onset of the metabolic syndrome," Shulman said.

Another key observation was that skeletal muscle insulin resistance precedes the development of insulin resistance in liver cells, and that fat production in the liver is increased. "These findings also have important implications for understanding the pathogenesis of nonalcoholic fatty liver disease, one of the most prevalent liver diseases in both adults and children" Shulman said.

The good news, according to Shulman, is that insulin resistance in skeletal muscle can be countered through a simple intervention: exercise.

Most Diabetes Drugs Provide Similar Glucose Control

July 2007 - Most oral medications prescribed for type 2 diabetes are similarly effective for reducing blood glucose, but the drug metformin is less likely to cause weight gain and may be more likely than other treatments to decrease so-called bad cholesterol, according to a report funded by HHS' Agency for Healthcare Research and Quality. A version of the analysis was posted in the on-line version of Annals of Internal Medicine.

The federally funded analysis is based on scientific evidence found in 216 published studies. The report summarizes the effectiveness, risks, and estimated costs for 10 drugs: acarbose (sold as Precose), glimepiride (Amaryl), glipizide (Glucotrol), glyburide (Micronase, DiaBeta, Glynase PresTab), metformin (Glucophage, Riomet, Fortamet), miglitol (Glyset), nateglinide (Starlix), pioglitazone (Actos), repaglinide (Prandin), and rosiglitazone (Avandia).

Type 2 diabetes is an increasingly common chronic disease that occurs in people who have difficulty converting glucose (a sugar) into energy. Blood glucose levels are high either because their cells are resistant to insulin (a hormone that helps convert glucose into energy) or because their pancreas does not produce enough insulin. Diabetes can cause severe problems with the heart, eyes, kidneys, and nerves. Obesity increases the risks of developing type 2 diabetes. From 1980 through 2005, the number of Americans diagnosed with diabetes soared from 5.6 million to 15.8 million.

"As more people are diagnosed with type 2 diabetes and with the growing array of treatment choices, this is a landmark review," said AHRQ Director Carolyn M. Clancy, M.D. "This summary of scientific evidence is not only an important tool for clinicians and patients seeking the most appropriate therapy, but it also points out in what areas we need more research to confront this disease."

As new classes of oral diabetes medications have become available, patients and clinicians have faced a growing list of treatment options. Earlier scientific reviews have highlighted some differences between medications, but AHRQ's new analysis is the first to summarize evidence on the effectiveness and adverse events for all approved oral medications commonly used in the United States for type 2 diabetes.

Diabetes patients typically are monitored with tests that check the percentage of hemoglobin A1c (HbA1c) in their blood. Checking for HbA1c is a more reliable indicator of chronic high blood sugar than checking blood glucose itself. According to the AHRQ review, most diabetes drugs offer about a one point absolute reduction in HbA1c. In those cases, for example, a diabetes patient's HbA1c might drop from 8 to 7 (with 5 being normal in patients who don't have diabetes). Nateglinide, acarbose, and miglitol lower HbA1c by about half that much. Combining diabetes medications, evidence shows, often works better at reducing HbA1c.

AHRQ's analysis of published studies, completed by the Agency's Johns Hopkins University Evidence-based Practice Center in Baltimore, also concluded:

• Metformin and acarbose do not increase weight among diabetes patients. Other diabetes drugs (glimepiride, glipizide, glyburide, pioglitazone, repaglinide, and rosiglitazone) have been shown to increase weight by an average of 2 pounds to 11 pounds.

• Blood levels of low-density lipoprotein, which is known as "bad cholesterol" because it may amplify risks of heart attack and stroke, consistently decrease (by about 10 milligrams per deciliter) in patients taking metformin and increase (by similar amounts) in patients taking rosiglitazone and pioglitazone.

• Pioglitazone and rosiglitazone cause a small but significant increase in high-density lipoprotein, often called "good cholesterol" because it promotes the breakdown and removal of cholesterol from the body.

• Glimepiride, glipizide, glyburide, and repaglinide are associated with hypoglycemia (when blood glucose levels go too low) more than other diabetes drugs.

• Metformin and acarbose are generally more likely than other diabetes medications to cause gastrointestinal problems such as diarrhea. Patients who used metformin alone were more likely to experience problems than those using the drug at a lower dose in combination with glimepiride, glipizide, glyburide, pioglitazone, or rosiglitazone.

• Patients who take pioglitazone and rosiglitazone have a greater risk of congestive heart failure compared with those who take metformin, glimepiride, glipizide, or glyburide. While one recent analysis raised the possibility that rosiglitazone may also increase heart attack risks, authors of the AHRQ analysis concluded that current evidence is not sufficient to make a meaningful assessment.

• More, longer studies are needed to understand the impact of oral diabetes drugs on patients' quality of life and whether long-term use causes adverse side effects or reduces important complications of diabetes such as heart disease and kidney disease. Additional research is needed to study interactions between the drugs and to compare therapeutic combinations of the drugs, according to the report.

The report, titled "Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes," is the newest analysis from AHRQ's Effective Health Care program, authorized by the Medicare Prescription Drug, Improvement and Modernization Act. That program represents an important federal effort to compare alternative treatments  [report anonymous abuse]

Study Targets Australian Pharmacists to Help Diabetes Sufferers

July 2007 - A new Wesley Research Institute project aims to make it much easier for people to manager their Type 2 Diabetes by using community pharmacists.

There are more than one million Australians with Type 2 Diabetes who are at an increased risk of developing serious health problems including heart disease, stroke, kidney disease and blindness.

Chief investigator of the project, Mr David Brand of The Wesley Pharmacy, said this study had the potential to benefit sufferers by enabling them to better understand and manage their own blood glucose levels, thus helping to prevent long-term health problems.

"With around 600 new cases of diabetes diagnosed every week in Australia, it is imperative that we continue to look for better, more user friendly ways of managing this condition," he said.

"A major problem in Type 2 Diabetes management is the lack of understanding of how lifestyle influences day to day variations in blood glucose levels. If the particular cause of the unhealthy level is better understood, it may be corrected through lifestyle changes."

Funded by the MBF Foundation, the project is providing participants with education and advice about the control of their blood glucose levels based on individual glucose meter uploads during the day. The study will then determine whether lifestyle advice from pharmacists has a positive impact on participants' glycaemic control.

"Educating pharmacists to help people manage their diabetes may be one way to reduce the burden of Type 2 Diabetes on our health care system," Mr Brand said.

Type 2 Diabetes sufferer Ms Deborah Lennon said that being able to access advice from pharmacists would be extremely beneficial in the management of her diabetes.

"It is quite difficult and expensive to get an appointment to see my GP so to be able to access a pharmacist for advice and information would be absolutely brilliant," she said.

"I have had Type 2 Diabetes for five years now and as I get older I know the risks of harmful outcomes from the disease increase. I believe that having my local pharmacist help monitor my blood glucose levels would enable me to take greater control of my condition and improve my overall health."

It is hoped that the year long study will lead to new Australia-wide treatment standards for Type 2 Diabetes where patients and pharmacists work together to manage the disease.

The Wesley Research Institute is a leading medical research facility with a commitment to patient care, ethical conduct and quality research that aims to improve quality of life through better diagnosis and treatment.

Blood Sugar: A Piece in the Cancer Risk Puzzle

A major new study has added to evidence suggesting that high blood sugar and problems in sugar metabolism may increase cancer risk. The link between high blood sugar and cancer is not new. We don’t know whether risk comes from high blood sugar itself or from the elevated insulin levels that generally develop with it, which can lead to type 2 diabetes.

The latest research suggests that high blood sugar may increase cancer risk even before diabetes develops. Either way, since studies show that lifestyle dramatically lowers the risk of high blood sugar developing into diabetes, healthy eating and exercise offer the double benefit of reducing risk of diabetes and some types of cancer.

In the recent study, published in March, researchers found that women with the highest blood sugar showed a 26 percent increase in overall cancer risk compared to those with the lowest blood sugar. Overall cancer risk in men was not affected. In both men and women, however, the study confirmed an association between high blood sugar and increased pancreatic, kidney and urinary tract cancers, along with a doubled risk of melanoma.

The study spanned 13 years and followed more than 64,000 Swedish people. Blood sugar was measured after eight hours of fasting. Other studies have shown an increased cancer risk linked to type 2 diabetes. But this study found an increased cancer risk with pre-diabetics – people with smaller blood sugar elevations – as well as diabetics. High blood sugar is often related to overweight, but the link to cancer here was independent of weight. This is one of many studies investigating cancer risk as it relates to blood sugar and diabetes.

• Pancreatic cancer: In the March Swedish study, men and women with the highest levels of fasting blood sugar were almost 2.5 times as likely to develop pancreatic cancer as those with the lowest blood sugar. High-sugar diets, which can temporarily (but frequently) raise blood sugar, may also play a role in cancer risk. A 2006 study of almost 78,000 Swedish adults found that after 7 years, high consumption of sugar (including regular soft drinks) was associated with 70 to 90 percent increased risk of pancreatic cancer.

• Endometrial cancer: The March Swedish study found a link between high blood sugar and endometrial (uterine) cancer. In another recent Swedish study of more than 36,000 women, diabetics were almost twice as likely to develop endometrial cancer compared to nondiabetic women. Sedentary or obese women with diabetes faced three to six times greater risk, and women having all three conditions (diabetes, inactivity and obesity) were almost ten times more likely to develop endometrial cancer as those with none of the conditions.

• Breast Cancer: Studies have shown conflicting findings on a link between high blood sugar and breast cancer. In the March Swedish study, higher blood sugar was linked to about double the breast cancer risk for women under age 49 (there was no link for overall breast cancer). Yet a large study of American women showed no tie between a marker of blood sugar levels and breast cancer risk.

• Colon Cancer: Colon cancer was not one of the cancers tied to blood sugar elevations in the March Swedish study. However, diabetes has been linked with colon cancer risk in other studies. In a 19-year study of more than 22,000 U.S. men, overweight and diabetes each increased risk of colon cancer 40 to 50 percent, respectively.

  Blood sugar itself may not be the risk; in one study, blood sugars were only modestly related to colon cancer risk in a group of men. Elevated insulin levels and insulin resistance (which often accompany type 2 diabetes) increased risk of colorectal cancer about 85 percent.

Researchers say that we could probably reduce the risk of cancer linked to high blood sugar by following the same recommendations for preventing diabetes: maintain a healthy weight, get regular activity and eat a healthy diet, filled with fruits, vegetables and fiber, and scarce on saturated fat.

Study Tests Oral Insulin to Prevent Type 1 Diabetes

June 2007 - University of Florida researchers have begun a clinical study of oral insulin to prevent or delay type 1 diabetes in people at risk for the disease.

The UF Health Science Center and Shands at UF are among 14 centers in the United States working with affiliate sites and participating physicians in Type 1 Diabetes TrialNet, a research group dedicated to the understanding, prevention and early treatment of type 1 diabetes.

"This is a unique opportunity to attempt to prevent the disease in relatives at risk for type 1 diabetes," said Desmond Schatz, M.D., medical director of UF's Diabetes Center of Excellence and principal investigator with the UF TrialNet Clinical Center. "The intervention may also offer hope for delaying the onset of the disease."

An estimated 1 to 2 million people with the disease have type 1 diabetes, which occurs when white blood cells vital to the body's defenses against infectious diseases attack insulin-producing beta cells in the pancreas. The insulin these cells produce regulates how the body uses and stores sugar and other food nutrients for energy.

Research has shown the pancreas is resilient and more than half its insulin-producing beta cells must be irreversibly destroyed before an individual develops symptoms of the disease, which can take months or even years to occur.

That long period prior to the onset of symptoms provides an opportunity for interventions aimed at preventing the disease's development, Schatz said.

In the study, University of Florida researchers are testing whether an insulin capsule taken by mouth once a day can prevent or delay type 1 diabetes in a specific group of people at risk for the disease.

An earlier trial suggested that oral insulin might delay type 1 diabetes for about four years in some people with islet cell autoantibodies in their blood. The presence of these autoantibodies alerts physicians to the destruction of insulin-producing cells up to 10 years before symptoms set in and indicates an individual is at greater risk of developing the disease.

For a person with high-risk genes and all three autoantibodies, the risk of developing diabetes in the next five years is greater than 50 percent, Schatz said.

"We hope that learning about the underlying immune events that set the stage for diabetes will help us identify ways to rein in the autoimmune attack on beta cells," he said.

Animal studies have also suggested that insulin taken orally might even prevent type 1 diabetes. Some scientists think that introducing insulin via the digestive tract induces tolerance, a quieting of the immune system.

First- and second-degree relatives of people with type 1 diabetes who may be at risk are initially being screened through TrialNet's natural history study, which is examining the immune and metabolic events that precede diabetes symptoms. Screening involves a simple blood test. Individuals enrolled in the natural history study are closely monitored for diabetes development and may be eligible to participate in the oral insulin trial or future studies that try to arrest the autoimmune process.

To lower blood sugar levels once diabetes occurs, patients need three or more insulin injections a day or treatment with an insulin pump. To prevent complications, they must regularly monitor their blood glucose, striving for a range that is as close to normal as possible.

Other diabetes studies under way at UF include a trial aimed at preserving insulin production in people recently diagnosed with type 1 diabetes, who often still have a supply of functioning beta cells. If these remaining beta cells can be protected with the help of insulin injections, more patients would be able to tightly control their blood glucose, preventing or delaying damage to the eyes, nerves, kidneys, heart and blood vessels.

Another TrialNet study seeks to turn off the body's attack on beta cells with rituximab, a monoclonal antibody that binds to and temporarily destroys a class of immune cells. The rituximab trial is recruiting patients with type 1 diabetes diagnosed within the previous three months. Also under way is a study testing whether a combination of two drugs approved by the FDA to prevent rejection after an organ transplant can slow or arrest the autoimmunity of type 1 diabetes.

Lastly, the Environmental Determinants of Diabetes in the Young, or TEDDY, study aims to discover the genes and environmental exposures that may cause type 1 diabetes through a newborn screening program. Babies found to be at a high risk of developing the disease may enroll in TEDDY II and will be tracked over time to examine environmental risk factors.

The Type 1 Diabetes TrialNet studies are funded by the National Institutes of Health. The Juvenile Diabetes Research Foundation International and the American Diabetes Association also support the initiative.

Source: University of Florida Health Science Center, Newswise

DATE: May 11, 2007

The study, conducted by Medical College of Georgia researchers, studied an animal model for type I diabetes and primary Sjogren's syndrome, which damages the glands that generate tears and saliva. They found that there was considerably less salivary gland damage in a group treated with green tea extract, signifying a lessening of the Sjogren's symptom generally referred to as dry mouth. Dry mouth can also be caused by certain drugs, radiation and other diseases.

Around 30 percent of aged Americans are ill with degrees of dry mouth, says Dr. Stephen Hsu, a researcher in the MCG School of Dentistry and lead investigator on the study. On the other hand only 5 percent of the elderly in China, where green tea is extensively consumed, suffer from the problem. "Since it is an autoimmune disease, Sjogren's Syndrome causes the body to attack itself and produce extra antibodies that mistakenly target the salivary and lacrimal glands," he says. To search for inflammation and the number of lymphocytes, a type of white blood cells that congregate at sites of inflammation to repel foreign cells, the researchers studied the salivary glands of the water-consuming group and a green tea extract-consuming group. Results showed that the group treated with green tea had notably fewer lymphocytes, Dr. Hsu says. Their blood also showed lower levels of autoantibodies, protein weapons produced when the immune system attacks itself, he says. Researchers are already aware that one component of green tea , EGCG, helps suppress inflammation, according to Dr. Hsu. "So, we suspected that green tea would suppress the inflammatory response of this disease. Those treated with the green tea extract beginning at three weeks, showed significantly less damage to those glands over time," he says.

Researchers also suppose that the EGCG in green tea can activate the body's defense system against TNF-alpha, a set of proteins and molecules involved in systemic inflammation. Produced by white blood cells, TNF-alpha can stretch out to target and kill cells. "The salivary gland cells treated with EGCG had much fewer signs of cell death caused by TNF-alpha," Dr. Hsu says. "We don't yet know exactly how EGCG makes that happen. That will require further study. In some ways, this study gives us more questions than answers." According to Dr. Hsu additional studies could help find out green tea's defensive role in other autoimmune diseases, including lupus, psoriasis, scleroderma and rheumatoid arthritis. (ANI)

DATE: March 09, 2007

Pigs may hold the key to curing juvenile diabetes, and the Emory Transplant Center just received $2.5 million to unlock the puzzle. The Juvenile Diabetes Research Foundation is funding the center's efforts to study whether implanting parts of a pig's pancreas into a human diabetes patient can help the cure the disease. Juvenile diabetes, also called Diabetes Type I, develops when a patient's pancreas stops producing insulin, a chemical necessary to process sugar. Without an artificial source of insulin, the patient could die. One possible source is implanting another healthy human pancreas into the child. But sources are very limited, and that's where the pigs may come in handy.

Chris Larsen, director of the Emory Transplant Center, and members of his staff are studying whether components of pigs' pancreases called islets can be successfully implanted into humans and produce insulin. "Our goals are to serve patients with organ failure - to make them healthy," Larsen wrote in an e-mail to the Wheel. "We just don't have enough donors to meet the need. Our experiments using islets from porcine [pig] donors offer hope to address this problem." Larsen and the other scientists will use a nonhuman primate from Emory's Yerkes National Primate Research Center as they try to develop a transplantation method. Transplant patients must typically adhere to a complicated regimen of highly toxic medications to suppress their own immune systems and prevent them from attacking the foreign organs. With a xenotransplant, or transplant from another species, the problem of immunosuppression could be compounded. "That would seem logical," Larsen wrote. "However, our current protocols aren't very different from what could be applied in patients."

The Emory grant is a part of the Juvenile Diabetes Research Foundation's billion-dollar campaign to find a cure to Diabetes Type I. The foundation supports diabetes research all over the world in an effort to develop a cure. "The sense of urgency that's driving us forward is the knowledge of what type I diabetes really does to people," wrote Foundation Chair James Tyree in a general case statement for the campaign. Islet transplantation is one of several major initiatives the Foundation is pursuing in search of a cure. Besides immunosuppression issues, the researchers must overcome several other challenges before the estimated 1 million patients who suffer from the disease can look to pig islet transplant for a cure. The entire pig pancreas is not used for the transplant process, so scientists must first figure out how to optimally harvest the necessary components. Then they have to ensure the pig islets can survive once transplanted to another species. Finally, Larsen wrote, health care institutions will have to develop the facilities to extract the islets and actually perform the transplants on a mass scale. So far, Emory is the only center in the state to have performed human-to-human islet transplantation. Even if the new research does work, a reliable cure for Diabetes Type I patients is still many years away, Larsen stressed. "We've made considerable progress but there is still much work to be done before we can test this in patients," he wrote.

DATE: January 12, 2007

Increasing the intake of the soluble fiber beta-glucan decreased the glucose and insulin response in overweight men, and could help reduce the risk of diabetes, says a new study.

Beta-glucan, a non-starch polysaccharide found in oats and barley, has been the subject of increasing attention with some reports showing the soluble fiber can decrease LDL-C levels.The new study, published in the journal Nutrition Research, investigated the effect of barley beta-glucan and preformed resistant starch separately or together on glucose and insulin responses in 10 normal and 10 overweight men (average BMI 23.8 and 29.0 kg per sq.m, respectively; average age 41.9). Acute consumption of barley beta-glucan, but not resistant starch, in muffins was effective in reducing glucose and insulin responses in men who were mildly insulin-resistant, wrote lead author Kay Behall from the USDA ARS in Beltsville, Maryland.

Elevated glucose and insulin concentrations are the primary indicators for insulin resistance and type-2 diabetes, explained Behall. Delaying the delivery of glucose through dietary means may assist in the management of insulin resistance. The participants consumed a control diet for two days before the study (30 per cent fat, 55 per cent carbohydrate, 15 per cent protein) and then fasted for 10 hours before consuming glucose or one of nine experimental muffins containing three resistant starch levels (0.1, 6.1, or 11.6 g/tolerance) and 3 levels of beta-glucan (0.1, 3.1, or 5.8 g/tolerance). The researchers report that one hour after consuming the high beta-glucan-containing muffins resulted in the lowest blood glucose concentrations (7.55 for the glucose group compared to 6.98 for low beta-glucan and 6.83 millimoles per liter for the high beta-glucan meal).

Similar results were observed for insulin responses (506 for the glucose group compared to 477 for low beta-glucan and 360 picomoles per litre for the high beta-glucan meal). Resistant starch content was less effective than beta-glucan in reducing glucose or insulin response, said the researchers.

They said that improvements in insulin sensitivity might require at least seven grams of resistant starch, or chronic consumption, which are far from the current typical intakes in the US and Europe. Beneficial reductions in glucose and insulin can result when sufficient soluble fibre from isolates or grain sources such as oats or barley is consumed, concluded the researchers. Consumption of food sources containing adequate levels of beta-glucan and RS should reduce the rise of type 2 diabetes.

Source: Nutrition Research

Research Yields New Insights Into The Cause Of Diabetes

December 2006: The cause of insulin-dependent, permanent, diabetes in newborn babies may be a deficiency in the enzyme Pancreatic Endoplasmic Reticulum Kinase (PERK) during a critical period of development before birth, according to a new hypothesis put forward by a team of researchers from Penn State University. In this most severe type of diabetes, individuals are unable to regulate glucose normally because they have few insulin-producing beta cells in their pancreas and the remaining cells do not produce enough insulin.

Using special strains of mice bred to be PERK-deficient, the researchers demonstrated that the lack of this enzyme blocked the proliferation of beta cells, hampered the normal functioning of beta cells, and also kept beta cells from clustering into islets. "What happens during fetal development predisposes people either to be able to maintain glucose levels normally or to have diabetes," says team leader Douglas Cavener, professor and head of the Department of Biology. The research results will be published in the journal Cell Metabolism on 6 December 2006.

The team, consisting of graduate students Wei Zhang, Yulin Li and Kaori Iida, Postdoctoral Fellow Daorong Feng, and Research Assistant Professor Barbara McGrath, made use of the lab's earlier discovery that mice deficient in PERK show many parallels to human sufferers of Walcott-Rallison Syndrome (WR, in which diabetes is combined with skeletal and growth abnormalities. The research provided an experimental model for investigating the cause of permanent neonatal diabetes that was more revealing than cell culture studies.

"Being able to develop special strains of mice that are PERK-deficient in specific organs or tissues was vital to our research," says Cavener. "These mice allowed us to discover exactly how PERK participates in the development and growth of the beta cells in the pancreas that secrete insulin. Using genetics in this way lets the organism tell you what is important to normal function."

Normally, the beta cells of the pancreas respond to high levels of glucose in the blood by producing the precursor of insulin -- proinsulin -- in the endoplasmic reticulum. Inside this and other organelles, the proinsulin is assembled and modified into insulin. Then the hormone is exported from the cell to stimulate other tissues to take up glucose and generate energy.

PERK-deficient mice differ significantly from normal mice. At birth, PERK-deficient mice have only about one-half the mass of beta cells that normal mice have. During the first few weeks after birth, PERK-deficient mice have fewer and fewer beta cells compared to normal mice and the remaining cells do not function normally in producing insulin. By three weeks after birth, the PERK-deficient mice are fully diabetic and have only one-tenth the mass of beta cells as normal mice.

Until now, the dominant hypothesis of the cause of diabetes in mice and humans deficient in PERK was developed by Heather Harding and David Ron, of New York University Medical Center, in 2001. They suggested that too much proinsulin in the endoplasmic reticulum triggers a stress response and causes many beta cells to die. The shortage of beta cells in PERK-deficient mice was thought to be caused by a high death rate of those cells.

Data collected by the Cavener team casts doubt on this hypothesis. First, they found that mice deficient in PERK made new beta cells at a much lower rate than normal mice. The mass of beta cells in deficient mice only doubled during the first few weeks of life, while that in normal mice increased twenty-fold. Second, the Penn State group found the rate of beta-cell death in PERK-deficient mice was not significantly different from that in normal mice. Finally, the team did not detect molecular markers of endoplasmic reticulum stress in the beta cells of their PERK-deficient mice.

The alternative hypothesis of the Penn State Team is that PERK deficiency blocks both the proliferation of beta cells after birth and the differentiation of those cells into fully functioning units. They found that thirty to forty percent of the beta cells of PERK-deficient mice are physically unusual. The most obvious abnormality is that proinsulin is found the endoplasmic reticulum, instead of being found in or around the nucleus. Apparently, proinsulin is produced as usual, but the normal modification process is blocked, leaving large quantities of proinsulin trapped inside the enlarged and distended organelle.

Another important finding was that beta cells in these mice do not develop into organized clusters or islets within the pancreas. Normally, the protein GLUT2 transports glucose across plasma membranes among the islets, triggering the secretion of insulin in the beta cells. But without the islet architecture, communication among the beta cells breaks down and the cells fail to respond to glucose by secreting insulin. Thus, PERK-deficiency both hampers cell-to-cell signaling of glucose levels and greatly diminishes insulin production at the cellular level.

The Penn State team's understanding of the role of PERK was advanced by additional experiments to pinpoint the time during development when PERK is required. Cavener's team found that PERK must be expressed during a critical period between 13.5 fetal days and 4 days after birth if the beta cells of the pancreas are to regulate glucose normally for the rest of the animal's life. PERK may play an essential role in sensing fetal environment and modulating the development of beta cells in response to it.

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27-Oct-2006

Study Confirms: Caffeinated Coffee Helps Prevent Diabetes

October 2006: People who drink coffee, including those who used to drink it but quit, are less likely to get type 2 diabetes than those who never drank it, according to a study by researchers at the University of California in San Diego.

This should come as welcome news to Americans, more than half of whom drink a cup of joe or more on a daily basis. Previous studies have presented contradictory evidence regarding a protective benefit for coffee, but this new research confirms a "striking" reduction in risk, including, for the first time, for people who already exhibit impaired glucose tolerance.

Numerous studies have been done examining the role that caffeine may play in reducing the risk for type 2 diabetes. One study actually found that drinking caffeinated coffee raised glucose concentrations, but subsequent studies found those levels fell 30 minutes after coffee consumption.

Studies in laboratory animals revealed that caffeine stimulates the body's metabolism and may induce a mechanism that helps to reduce obesity, which is also strongly linked to type 2 diabetes. Other research suggests that a reduction in risk for diabetes may be due to compounds in coffee other than caffeine.

Unlike previous studies, this study included people who were already at risk for diabetes due to impaired glucose tolerance. It found that even among those individuals, the ones who were past or present coffee drinkers were less likely to develop type 2 diabetes than those who never drank coffee. Drinking caffeinated coffee reduced the risk of developing type 2 diabetes by as much as 60 percent

Metformin and Lifestyle Intervention Prevents Metabolic Syndrome
posted 04/27/2006

Lifestyle intervention is better then any drug and along with metformin works to prevent the metabolic syndrome (MS).

"The metabolic syndrome is a high-risk state for diabetes and cardiovascular disease," write Trevor J. Orchard, MD, from George Washington University in Rockville, Maryland, and colleagues from the Diabetes Prevention Program Coordinating Center. "Little is known about its prevalence and prevention in those with impaired glucose tolerance."

In the Diabetes Prevention Program taking place at research and community-based centers, participants had IGT defined by World Health Organization criteria plus fasting plasma glucose (FPG) levels at least 5.3 mmol/L (95 mg/dL). After randomization to intensive lifestyle intervention, metformin therapy (850 mg twice daily), or placebo, participants were followed up for a mean of 3.2 years. The lifestyle intervention included a diet designed to achieve and maintain a 7% weight loss, and 150 minutes of exercise per week.

In the group that did not have MS at baseline, both metformin and the lifestyle intervention reduced development of the syndrome. In the group that already had MS at baseline, both lifestyle change and metformin compared with placebo increased the probability that the syndrome would resolve. In both of these groups, the benefit of the lifestyle intervention was larger than the benefit of the drug.

At baseline, 53% of participants (n= 1,711) had the MS, which was defined by three or more characteristics (waist circumference [WC], blood pressure [BP], and high-density lipoprotein cholesterol [HDL-C], triglyceride, and FPG levels) meeting criteria from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III).
The incidence of MS did not vary significantly by age. However, older participants aged 60 to 82 years were more likely to have low levels of HDL-C.

Compared with placebo, the lifestyle group had 41% lower incidence of the MS (P < .001), and the metformin group had 17% lower incidence (P = .03) based on life-table analyses (log-rank test). Three-year cumulative incidence was 51% in the placebo group, 45% in the metformin group, and 34% in the lifestyle group. Ethnic group did not significantly affect incidence.
"The metabolic syndrome affected approximately half of the participants in the Diabetes Prevention Program at baseline," the authors write. "Both lifestyle intervention and metformin therapy reduced the development of the syndrome in the remaining participants."

Diabetes Management Getting Better

The report is based on information from more than 14 million blood tests of hemoglobin A1c (HbA1c) performed from 2001 to 2005 on people with diagnosed diabetes.

The HbA1c test is considered a key indicator of how well a person is managing and controlling his diabetes. The test measures the amount of sugar attached to hemoglobin (the primary protein in red blood cells) and indicates the average blood sugar level over the previous two to three months.

Researchers found that the number of blood test results that showed poor diabetes control decreased by 26% from early 2001 to late 2005.

The ADA recommends that people with diabetes maintain their hemoglobin A1c levels below 7%.

The report showed that the average hemoglobin A1c test decreased from 7.8% of total hemoglobin in January 2001 to 7.2% in December 2005.

Hospitals fail to record concurrent diabetes diagnoses during hospitalization, signifying a lack of attention to the diabetic needs of patients.

According to recent research from the United States, "Patients with diabetes frequently are hospitalized, and quality of inpatient care for diabetes is of great concern. Rehospitalization after hospital discharge is a frequent adverse outcome experienced by patients with diabetes. We assessed the frequency of and risk factors for rehospitalization among all Philadelphia residents with diabetes."

"Individual histories of hospitalization were ascertained from hospital discharge summaries for Philadelphia residents ages 25-84 who had at least 1 diabetes hospitalization from 1994 through 2001. Logistic regression was used to assess predictors of nonelective rehospitalization within 30 days of discharge, including recording of diabetes diagnosis," described J.M. Robbins and D.A. Webb at the Philadelphia Department of Public Health.

"Nonelective rehospitalizations within 30 days of hospital discharge were ascertained for 58,308 (20.0%) of 291,752 discharges. The proportion rehospitalized was 9.4% after a patient's first diabetes diagnosis hospitalization; after later discharges for which a diabetes diagnosis was not recorded, rehospitalizations occurred in 30.6% of all cases.

The absence of a diabetes diagnosis was a highly significant predictor of rehospitalization after adjustment for age, year, gender, race/ethnicity, insurance status, admission type, severity code, length of stay, discharge status, and number of previous hospitalizations."

The researchers concluded, "Failure to record a diabetes diagnoses in administrative hospital discharge data may reflect lack of attention to the critical needs of patients with diabetes who are being treated for other conditions, whereas the attention to patient education and follow-up planning for patients with incident diabetes diagnoses may reduce the risk of rehospitalization."

Gene Variant Protects Against Type 2 Diabetes, Heart Disease, and Hypertriglyceridemia

April 2006 - A rare gene variant in humans helps to protect against two of the country's top killers -- type 2 diabetes and heart disease -- as well as against hypertriglyceridemia, a condition that increases the risk of heart disease, obesity, and pancreatitis. A team of researchers from Harvard School of Public Health (HSPH) and the Channing Laboratory published their findings in this week's issue of the Proceedings of the National Academy of Sciences.

Individuals who had the gene variant had 12 percent lower levels of triglycerides in their blood serum than subjects who did not have the variant. Risk of heart disease was 34 percent lower for those with the variant. Risk for type 2 diabetes was 48 percent lower among obese individuals when compared to other obese individuals who did not have the variant.

"This is a perfect example of the interdisciplinary studies between population sciences, nutrition, and basic scientists at HSPH," said G?n Hotamisligil, a senior author and James Stevens Simmons Professor of Genetics and Metabolism. The lead author was HSPH Research Associate Gurol Tuncman.

The gene was first identified in mouse studies as a mediator of metabolic disease. Mice that lack this gene, which encodes for a lipid-binding protein called aP2, were partially resistant to type 2 diabetes and exhibited strong protection against atherosclerosis. The HSPH and Channing team -- representing scientific contributions from five separate research groups -- investigated whether the same held true in humans. They reviewed the medical and genetic records and studied the genetic material of 7,899 participants in the Nurses' Health Study and the Health Professionals Follow-Up Study. Of the group, 4.3 percent had the variant.

The team utilized molecular and cellular techniques in fat cells as well as in human fat tissue samples. They found that the variant T-87C, which sits on the promoter region of the gene that produces the aP2 protein, interferes with the gene and results in less production of aP2 in individuals that carry this variant.

"In other words, this genetic variant in humans looked like a milder version of the mouse knockout model," said Eric Rimm, HSPH Associate Professor of Epidemiology and Nutrition. In the U.S., more than 65 percent of adults and 16 percent of children are overweight. Nearly 24 percent of adults have metabolic syndrome, a constellation of conditions that includes obesity, insulin resistance, and hypertension.

The identification of the T-87C variant indicates that aP2 might play a similar role in humans as it does in mice. The significance of this finding may include a potential target for drugs designed to reduce aP2 levels, offering a possible means to protect against some of the world's most prevalent chronic diseases, say the authors.

This work was supported in part by grants from the Iacocca Foundation, NIH, and American Diabetes Association. Samples used from the Nurses' Health Study and Health Professionals Follow-Up Study were supported by NIH grants. Lead author Gurol Tuncman is a recipient of a postdoctoral fellowship from the Iacocca Foundation to conduct this interdisciplinary project and was supervised by both Rimm and Hotamisligil.

Source: Harvard School of Public Health

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Scientists Make Major Finding on Potential Cure for Type 1 Diabetes

April 2006 - A major finding, which represents an important step toward a potential cure for type 1 (insulin-dependent) diabetes, has been made by a research team at the La Jolla Institute for Allergy & Immunology (LIAI). The team, led by Matthias von Herrath, M.D., an internationally recognized expert on the molecular basis of type 1 diabetes, used a combinatorial treatment approach in laboratory mice and found it reversed recent onset type 1 diabetes in the majority of animals tested.

The study, which combined two therapies (anti-CD3 antibody and proinsulin peptide) already being tested individually in human clinical trials, produced better efficacy, longer-lasting results and fewer side effects in the preclinical trials in mice than either therapy has shown alone in the human studies. The researchers hope to begin testing the combination therapy in human clinical trials later this year. Damien Bresson, a researcher in Dr. von Herrath's lab, contributed to the study. Kevan Herold, an Associate professor at Columbia University, and Jeffrey Bluestone, Director of the University of California, San Francisco Diabetes Center, were also contributors.

"The finding of increased efficacy of reversal of recent-onset type 1 diabetes in animals that received a combination of systemic anti-CD3 antibody and intranasal proinsulin peptide compared to therapy with the antibody alone is an exciting and important finding," said Richard A. Insel, M.D., Executive Vice President for Research at the Juvenile Diabetes Research Foundation.

The anti-CD3 antibody has been shown to temporarily reverse recent onset human type 1 diabetes in two independent clinical trials. The reversal was maintained for more than a year. "This combination approach is worth evaluating in human type 1 diabetes to increase both the overall efficacy of the treatment and the duration of the beneficial effect," Dr. Insel said.

The finding was published in the online version of the Journal of Clinical Investigation in a paper, "A novel combination therapy in recent onset autoimmune diabetes: synergy of anti-CD3 and nasal proinsulin to induce Tregs." Dr. von Herrath said the human clinical trials, which still require regulatory approval, would be directed at persons recently diagnosed with type 1 diabetes or who are already being treated for pre-diabetes.

George Eisenbarth, M.D., Ph.D., Executive Director of the Barbara Davis Center for Childhood Diabetes in Colorado, called the finding "a very important discovery, demonstrating synergistic efficacy of two therapies (anti-CD3 and proinsulin immunomodulation) that are in human studies for the prevention of type 1 diabetes."

Dr. von Herrath's approach focuses on teaching the immune system to tolerate, rather than attack, the insulin-producing beta cells of the pancreas. By injecting the anti-CD3 antibody, which calms the immune system and lessens the attack on the beta cells, along with a piece of the nasal proinsulin peptide, which acts like a vaccine and induces a special cell type called "regulatory cells" that can actively and highly specifically protect beta cells, Dr. von Herrath was able to stop the immune system's destruction of the beta cells in mice.

Combining the two therapies produced a "strong synergy," he said. "The combinatorial approach doubled the efficacy in laboratory mice -- with fewer side effects than using either one alone." The study represented the first time a combinatorial treatment approach using a vaccine strategy had ever been tried in type 1 diabetes. Dr. von Herrath added that the combined therapy also showed long-lasting results. "The diabetes never reoccurred in the lifespan of the mice."

Mitchell Kronenberg, Ph.D, LIAI President and Scientific Director, said the therapy is "particularly attractive because ? if successful in humans ? it could replace current insulin-injection treatments altogether, which often cannot prevent the long-term detrimental effects of diabetes." Type 1 diabetes, also called insulin-dependent diabetes or juvenile diabetes, occurs when the immune system mistakenly destroys the insulin-producing beta cells of the pancreas, which are key to controlling blood sugar levels. As a result, type 1 diabetes sufferers inject insulin daily to control blood sugar levels. However, complete control is difficult to achieve and damage to body organ systems can still occur. Complications from type 1 diabetes can include kidney failure, adult blindness and the need for amputations.

"Since the complications from high blood sugar levels (diabetes) worsen with time, we are hopeful that this therapy can reverse the disease in patients before they have too much multi-organ damage," Dr. von Herrath said.

Source: La Jolla Institute for Allergy and Immunology

Study Reveals Findings on How Insulin-Producing Beta Cells Grow and Function

April 2006 - A new Joslin Diabetes Center-led study has shown conclusively that two receptors in the insulin-producing beta cell do not affect developmental growth, refuting a long-held hypothesis in diabetes research. This finding is helping scientists in their efforts to isolate the growth factors that do stimulate beta cell growth and understand the defects in insulin production and secretion that cause diabetes.

These two receptors have been a major focus of research on beta cell development as scientists seek to find ways to promote the growth of these essential insulin-producing cells in diabetes patients. This latest research will appear in an upcoming issue of Nature Genetics and is published online on the journal's Web site, http://www.nature.com/ng.

In two previous Joslin studies, insulin receptor, a protein that mediates the action of insulin, and the receptor for insulin-like growth factor I (IGF-I), a hormone, which were suggested as critical for mediating islet/beta cell development and growth, were individually "knocked out" in beta cells in genetically altered mice. Researchers were surprised to discover that the beta cells developed and grew normally without these receptors, according to Rohit N. Kulkarni, M.D., Ph.D., Investigator at Joslin Diabetes Center and Assistant Professor of Medicine at Harvard Medical School, who led the latest study and was lead author in the two previous Joslin studies.

"When you knock out one receptor at a time, the remaining receptor can compensate for the other since both are so similar," says Dr. Kulkarni. "In this study, we knocked out both at the same time and still didn't see a defect in the developmental growth of beta cells. Our conclusion is that there are growth factors and pathways independent of IGF-I and insulin that are necessary for the development of beta cells."

Beta cell function, or lack of it, is critical in both type 1 and type 2 diabetes. Type 1 diabetes occurs when the beta cells in the pancreas are attacked by a malfunctioning immune system, while in type 2 diabetes, the beta cells function but do not produce enough insulin to meet the body's needs or do not respond appropriately to the insulin that is produced. Long viewed as an autoimmune disease, type 1 diabetes may instead be caused by an underlying dysfunction in insulin/IGF-I signaling and increased vulnerability of beta cells to stress during the weaning period, a hypothesis currently being investigated by Dr. Kulkarni's laboratory. Recent research suggests that type 2 diabetes includes a variety of diseases caused by multiple defects in the insulin-production, insulin-signaling and insulin-using system.

Older studies using traditional techniques did suggest that IGF-I affected beta cell growth. Using more precise genetic engineering techniques, the Joslin studies have revealed that the absence of receptors for IGF-I or insulin don't affect development but do play a critical role in insulin secretion by regulating the glucose-stimulated insulin release from the beta cell. Without the receptors, there were insufficient levels of two proteins -- the enzyme glucokinase and the specific glucose transporter of the beta cell, Glut2 -- instrumental in glucose sensing by the beta cell. The study provides further evidence to explore the role of the insulin receptor in insulin secretion, which may lead to a greater understanding of why beta cells in type 2 diabetes cannot secrete insulin.

In the study, the "knockout" mice without the receptors were born with the same number of beta cells as the control group. At two weeks, however, they had abnormally small mass of beta cells and developed diabetes at three weeks. They died at five to six weeks; the normal mouse lifespan is two years. Compared to the mice that had only one receptor knocked out, these mice developed more severe diabetes.

"Without the activation of proteins necessary for survival provided by the "knocked-out" receptors, the beta cells became susceptible to cell death as the mice aged," says Dr. Kulkarni.

Dr. Kulkarni's laboratory in the Section on Cellular and Molecular Physiology at Joslin is currently conducting experiments using mice that lack both receptors and exploring what growth factors are altered. "It will give us a clue about which growth factors are critical for development of beta cells in the absence of the two receptors," says Dr. Kulkarni. "If we can understand how the beta cells grow, we can think of ways to promote growth that would aid diabetes treatment."

If the exact growth factor is identified, it could be used to promote beta cell growth. Another treatment option is growing beta cells outside the body and transplanting them into patients with type 1 or type 2 diabetes. The body needs a large number of beta cells to function normally.

Other researchers participating in the study include: C. Ronald Kahn, M.D., President of Joslin Diabetes Center and Mary K. Iacocca Professor of Medicine, Harvard Medical School; Kohjiro Ueki, M.D., Ph.D., Terumasa Okada, M.D., Ph.D., Jiang Hu, M.D., Chong Wee Liew, Ph.D., and Anke Assmann, M.D., of Joslin; Gabriella M. Dahlgren, Ph.D., Jennifer L. Peters, Ph.D., Jonathan G. Shackman and Robert T. Kennedy, Ph.D., of the University of Michigan; Min Zhang, Ph.D., and Leslie S. Satin, Ph.D., of the Virginia Commonwealth University Medical Center; Isabella Artner, Ph.D., and Ronald Stein, Ph.D., of Vanderbilt University Medical Center; and Martin Holzenberger, M.D., Ph.D., of the Hopital Saint-Antoine, France. Funding for the study was provided by the National Institutes of Health.

Source: Joslin Diabetes Center

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Diabetes Reversed: FDA Authorizes Human Trials
posted 04/21/2006

After successfully demonstrating that a groundbreaking treatment strategy can reverse type 1 diabetes in animal studies, the FDA has given the go-ahead for researchers from the University of Pittsburgh Medical Center to begin a phase I trial evaluating the treatment in humans.

Source: Diabetes In Control

The FDA approved the start of a clinical trial to evaluate the safety and feasibility of the treatment. The trial is expected to begin sometime this spring and will include at least 15 patients over the age of 18, with type 1 diabetes.

The treatment involves specific modification of dendritic cells. University of Pittsburgh researcher Dr Massimo Trucco and his team found that by removing dendritic cells from the blood during a two-to four-hour procedure, some 20 million dendritic cells can be harvested.

Dendritic cells are cells found in the bloodstream and normally function as one of nature's most efficient immune function cells. The cells identify foreign substances such as cancer cells, process these foreign substances, and then jumpstart the immune response by bringing these foreign substances to the attention of T cells.

Once harvested, researchers then combine the dendritic cells with specific blockers of molecules, known as CD40, CD80 and CD86, all of which can be synthesized in a laboratory. This treatment strategy was found to inhibit the interaction and destructive effect of T cells on the insulin-producing beta cells of the pancreas, a process that is known to be a critical part of how diabetes occurs.

Subcutaneous injection of dendritic cells into the abdominal/pelvic area near the pancreas and lymph nodes, blocks the T cells as they travel to the pancreas to destroy beta cells.

"We did this in mice, giving them six injections over the course of several weeks. The injections interrupted the T cell and beta cell interaction, allowing the beta cells in the pancreas to regenerate. This enabled the pancreas of the mice to begin producing insulin again," said Dr Trucco. "The injections proved capable of stopping this vicious cycle, and through this process curing type 1 diabetes in a mouse."

Low-Carb Diet Controls Diabetes Without Weight Loss Or Insulin Use
posted 04/21/2006

A new study released in the scientific journal Nutrition & Metabolism found that type 2 diabetes can be managed and controlled simply by minor changes in the diet alone without the need for weight loss or the use of insulin medications.

Source: Diabetes In Control: Nutrition & Metabolism 2006, 3:16

Dr. Mary C. Gannon and Dr. Frank Q. Nuttall, both from the Center For Diabetes Research at the University of Minnesota, Minneapolis, wanted to test a theory that you can bring about improvements in patients with type 2 diabetes that do not require weight loss or insulin to control the blood glucose concentration. What they wanted to know was if it was possible to do this by changing the KIND of foods eaten rather than the AMOUNT of food consumed.

For the study, they looked at the protein:carbohydrate:fat ratios of three groups of patients with untreated type 2 diabetes over a 5-week period.

One group had a 15:55:30 ratio (commonly known as the low-fat diet), another group had a 30:40:30 ratio (which closely resembles The Zone diet), and the final group had a 30:20:50 ratio (you know as livin' la vida low-carb).

The 30:40:30 ratio diet saw a moderate but significant decrease in 24-hour integrated blood glucose area and percentage of total glycohemoglobin (%GHb). But, even more exciting, was the 30:20:50 ratio diet group (low-carb) which saw an amazing 38 percent drop in the 24-hour glucose area, which was a reduction in fasting glucose that resemble close to "normal" readings and the %GHb fell more than two percentage points from 9.8% to 7.6%. The 30:30:40 ratio diet saw similar results.

Based on these results, Dr. Gannon and Dr. Nuttall concluded that changes in diet alone could indeed help control diabetes without the need for weight loss or medication.

"Altering the diet composition could be a patient-empowering method of improving the hyperglycemia of type 2 diabetes without weight loss or pharmacologic intervention," the researchers explained.

Take away notes:
“The protein in the low-carb diets that aided the production of insulin in the study participants because protein actually stimulates the production of insulin.”

"If you increase insulin, then you decrease glucose," Dr. Gannon explained at the conference.

“Fats can delay the digestion of carbohydrates which is why consuming fat is so important as part of a healthy eating plan, especially for diabetics who want to control their blood glucose levels.

Since starchy foods are 100% glucose, they are directly responsible for raising blood glucose levels to dangerous levels for type 2 diabetics.”

In type 2 diabetes patients who are treated with metformin alone, those who achieve low levels of glycosylated hemoglobin level (HbA1c), a common measure of blood sugar, in the first year have a longer period of drug effectiveness, investigators report.

Because diabetes is a progressive disease, patients typically undergo a succession of drug therapy adjustments, Dr. Gregory A. Nichols and his associates point out. If drug effectiveness is maximized at each disease stage, treatment flexibility will be increased and blood glucose levels will be reduced in the long term, they add.

To identify predictors of metformin response, Nichols' group evaluated the records of patients treated between 1996 and 2003 at Kaiser Permanente Northwest HMO in Portland, Oregon. They identified 1,547 patients with diabetes whose first drug was metformin.

According to their report in Diabetes Care, the most important factor predicting long-term success with metformin was the reduction of HbA1c achieved during the first year.

For example, about half of the patients whose lowest blood sugar level was between 7 and 7.9 percent in the first year had to switch drugs or have another drug added within 36 months. In contrast, patients whose blood sugar was less than 6 percent in the first year did not require a switch or another drug for 84 months.

Another important factor that predicted response to metformin was weight loss. The authors found that patients who needed to add or switch drugs lost an average of 1.9 kg, (4.2 lbs) compared with an average loss of 5.0 kg (11.0 lbs) among those who remained on metformin monotherapy.

"Our results indicate that if glycemic control is achieved initially with metformin monotherapy, it can be successfully maintained for several years," Nichols and his associates conclude.

DATE: March 10, 2006

Researchers are closer to learning the root cause of insulin resistance, which is what leads to diabetes, by studying the healthy children of those with diabetes.

Monty Littlejohn, a 28-year-old medical student at SUNY Buffalo, is young, fit, and active. But because both of his grandmothers have diabetes, the family history of the disease has him concerned. Diabetes is usually associated with obesity, aging and lack of exercise, but as a medical student Littlejohn knows that diabetes also has a strong genetic component. "It is a little bit scary to think that no matter what I do, this is sort of looming over me in my future," he reflects.

Now researchers hope that studying the exceptions to the rule can provide insight into the underlying biological mechanisms of the disease. Physiologist Gerald Schulman and his colleagues at Yale University studied 20-year-olds whose parents are diabetic. Despite being young, healthy and lean, all of the test subjects had high levels of insulin resistance. Insulin resistance is often referred to as "pre-diabetes" because it's the first sign that the body is not processing sugar properly.

After eating a meal, the digestive system breaks most food down into units of glucose, a simple sugar that is one of the basic energy sources for the body. Insulin is a hormone made by the pancreas, which triggers cells to absorb the glucose and use it. Once inside the cell, small energy factories called mitochondria convert the glucose sugar into a chemical called ATP. ATP powers every cellular and bodily function, from thinking to moving. When someone is insulin resistant, his or her cells aren't able to absorb sugar from the bloodstream to make ATP, which leaves the cells starving for energy even though it's right there just outside the cell wall. Another thing that these young patients with family histories of diabetes had in common is that despite being lean, they actually had more fat inside their cells. And as Shulman says, "Fat inside the muscle cell causes insulin resistance; so the real question becomes, 'Why is the fat building up?'"

One of the goals of the team's research was to figure out exactly what was happening on a cellular level to cause this fat buildup. Shulman says there were two possible explanations, "So it became a question of, are there defects in the fat cells in the body, releasing more fat to liver and muscle, causing the buildup? Or are there defects in the mitochondria… the factories in all the cells of our body that produce energy?" His group designed several experiments that used a technology called Nuclear Magnetic Resonance (NMR) spectroscopy to actually measure different things inside the volunteers' cells. One kind of NMR allowed them to directly measure the amount of fat both inside and outside the muscle cells. They also developed two other kinds of NMR spectroscopy — one to measure the activity of the mitochondria inside the cells and another to quantify how quickly the mitochondria were making ATP. "So we use all three NMR tools here to get an integrated picture of metabolism in human skeletal muscle," Shulman explains. They found that compared to normal volunteers, the insulin-resistant group had much less mitochondrial activity. So it was, in fact, the mitochondria that were to blame for the fat building up inside the cells and not a defect in fat cells.

Shulman says that discovering that reduced mitochondrial activity is to blame is a key step in coming up with treatments and prevention. "I'm very excited about this because, really, if you understand the mechanisms to the disease, this will allow us to develop pharmacologic interventions to correct the disease or ideally prevent it," he says. In an even more recent study published in the Journal of Clinical Investigation, Shulman's team revealed that the lower mitochondrial activity in these insulin-resistant patients is actually due to the fact that they have fewer mitochondria. As a result, the team is also focusing on identifying the genes that might be responsible for this reduced mitochondria count. Until treatments are available, though, Shulman says there's a lot we can do to keep the risk of diabetes at bay. In another study, his team actually observed a total reversal of insulin resistance as a consequence of — you guessed it — regular exercise. "We've taken the same group of individuals and had them exercise four times a week on a stairmaster, and have totally reversed the insulin resistance in skeletal muscle," he says.

Monty Littlejohn is doing his best to take this advice to heart by eating a healthy diet and exercising almost daily. Shulman's recommendation is that we all do the same, "Try to watch [your] weight, stay lean, and more importantly, stay active." Shulman's work was funded by the National Institutes of Health, the American Diabetes Association, the United States Public Health Service, and the Yamanouchi USA Foundation.

Study: Effect Of Diabetes On Heart May Differ By Ethnicity

Diabetes strongly increases the risk of heart failure in all ethnic groups, but early effects of diabetes on the heart may differ depending on whether the subjects are white, African-American, Hispanic or Chinese. These results emerged from the Multi-Ethnic Study of Atherosclerosis (MESA) when the investigators focused on heart mass – the weight of the heart muscle as measured by MRI, according to Alain Bertoni, M.D., M.P.H., at Wake Forest University School of Medicine.

"People with diabetes are recognized as having an increased risk of heart failure," Bertoni said. "We sought to better understand why.

We were especially interested in the role atherosclerosis may play."

In a report in the March issue of Diabetes Care, the researchers compared people with diabetes or impaired fasting glucose (which means their blood sugar levels were too high) with those who had normal blood sugar levels.

The investigators particularly looked at the muscle mass of the left ventricle, the part of the heart that pumps the blood through the aorta and out into the circulatory system. They measured the left ventricle itself, not the blood in it.

They also measured the volume of the ventricle when filled with blood just before it pumps the blood out. A lower volume indicates less blood is able to enter the ventricle, and suggests increased heart stiffness, said Bertoni.

"Increased left ventricular muscle mass suggests the future possibility of developing heart failure," he said. "We also think that if you have a stiffer heart, that could be an early indication that you have a propensity for developing heart failure."

MESA measured "subclinical" atherosclerosis – atherosclerosis that has yet to produce symptoms – through CT scans measuring the amount of calcium in the coronary arteries and ultrasound measuring the wall thickness of the carotid artery in the neck. Both are indications of atherosclerosis.

"Every ethnic group seems to have a set of abnormalities related to diabetes. While we think those with diabetes from all ethnic groups are at increased risk for heart failure, perhaps there is a different mechanism in play in each of the ethnic groups," Bertoni said.

"We found evidence that in whites, African-Americans, and Hispanics with diabetes there was increased heart muscle mass over those without diabetes," he said. In whites, the increased left ventricular mass was completely explained by subclinical atherosclerosis and high blood pressure, he said. With partial blockage of the coronary arteries, some areas of the heart muscle are getting less blood flow and are weakened, which means the rest of the heart muscle has to bulk up, he said.

In African-Americans and Hispanics, the increased mass was not fully explained by these factors. Among Chinese participants no differences in mass were observed.

In contrast, lower volumes, suggestive of increased stiffness, were seen in whites, blacks, and Chinese participants with diabetes, but not Hispanics.

Bertoni stressed that none of the MESA participants actually had heart failure. "We did not see any significant difference in the function of the heart, the squeeze of the heart."

"Other studies have in fact suggested that the incidence of heart failure is similar between whites and African-Americans with diabetes, but somewhat lower among Hispanics and Asians with diabetes."

The MESA investigators intend to follow the participants at least until 2008, with some participants in a sub-study called MESA Air being followed at least until 2012. If the measurements do predict heart failure, "they would help us target preventive therapies," Bertoni said.

"Further investigation will be required to determine whether there are differences in the incidence of heart failure by ethnicity in this [group], and if so, whether the observed differences at baseline will be predictive of the future risk of heart failure," the researchers said in Diabetes Care.

Other investigators at Wake Forest include David C. Goff Jr., M.D., Ph.D., Ralph B. D'Agostino Jr., Ph.D., and W. Gregory Hundley, M.D. The team also includes Kiang Liu, Ph.D., of Northwestern University, Joao A. Lima, M.D., and Moyses Szklo, M.D., Dr.P.H., of Johns Hopkins University, Joseph F. Polak, M.D., M.P.H., of Tufts-New England Medical Center, Mohammed F. Saad, M.D., M.R.C.P., of Stony Brook University, Russell P. Tracy, Ph.D., of the University of Vermont and David S. Siscovick, M.D., M.P.H., of the

Now is the time to read our abstracts. The Medical Letter on Drugs and Therapy is published by The Medical Letter, Inc. Volume 48, January 30, 2006 highlighted Pioglitazone/Metformin combination for type 2 diabetes. This information is important so we are bringing it you for your edification. For some patients, taking one medication to fight hyperglycemia does not do the job. The FDA has approved a fixed-dose combination of two popular medications called Actoplus met—Takeda. It is made up of metformin (Glucophage) and thiazolidinedione pioglitazone (Actos). It is suggested for patients already being treated with both of these medications or as a second-line therapy for those not adequately controlled with either medication alone. Rosigilitazone, another thiazolidinedione, is also available in a fixed-dose combination with metformin. The two medications work differently. Thiazolidinediones such as pioglitazone improve sensitivity to insulin in muscles, adipose tissue, and the liver. Metformin acts primarily by reducing hepatic glucose production, but also improves peripheral glucose uptake and utilization. Studies have shown that the fixed-dose combination is equivalent to the same doses of the individual drugs taken at the same time. The clinical efficacy and safety of Actoplus met have been established only I studies of pioglitazone and metformin taken concurrently. Adverse side effects of metformin include gastrointestinal difficulties including metallic taste, nausea, abdominal pain, and diarrhea as well as modest weight loss. Pioglitazone patients often gain weight, but the fixed-dose combination lowers that median weight gain from 2.6 kg for pioglitazone alone to 1.8 kg with the combined fixed-dose medication. The article reports on Adverse Effects including Lactic Acidosis, Heat Failure, Hepatotoxicity, Pregnancy, Drug Interactions, Dosage and Administration and concludes that the fixed-dose combination of these two medication in Actoplus met could be more convenient and less expensive than taking the drugs separately, but the limited number of tablet strengths could reduce flexibility in dosing. Whether the new fixed-dose combination offers any advantage over rosiglitazone/metformin remains to be established.

An increasing incidence of type 2 diabetes could bring a rise in death and disability caused by stroke according to a Canadian study of more than 12,000 newly diagnosed type 2 diabetics. These findings were presented to the American Stroke Association annual stroke conference by Dr. Thomas Jeerakathil, an assistant professor of neurology and medicine at the University of Alberta. His group found that people newly diagnosed with type 2 diabetes have a double risk of stroke, and those under 55 years of age are at greatest risk to be admitted to a hospital for stroke. Of the study population more than 9% were admitted to the hospital for stroke in the first five years after diagnosis. This finding “argues for very aggressive cardiovascular risk factor control". The researchers suggest advising diabetics to pay attention to cholesterol and blood pressure, to stop smoking, exercise, and eat a diet high in whole grains and vegetables. Concern was noted that when people are diagnosed they think they have years until complications kick in. “In fact there is real risk of stroke even in the first few years after being diagnosed."

Diabetes Care 29:312-316, 2006 has an interesting article titled Sexual function and endocrine profile in fertile women with type 1 diabetes by Andrea Salonia, MD et al. The researchers assessed sexual function and endocrine profile among fertile type 1 diabetic women during the follicular and luteal phrases of the menstrual cycle, to compare these results with those obtained among healthy luteal women who served as control subjects, and to explore the correlations between sexual function and endocrine milieu among patients and control subjects during the follicular and luteal phases of the menstrual cycle. Fifty fertile women with type 1 diabetes and 47 healthy control subjects completes a semi-structured medical interview and filled in self-administered validated instruments to evaluate sexual function, depression, and sexual distress. The results indicate that type 1 diabetic women had decreased sexual function and increased sexual distress compared with control subjects during the luteal, but not the follicular, phase of the menstrual cycle. During the follicular phase, patients had lower estrogenic tone, lower “weak" androgen production, and lower free-triiodothyronine and free-thyroxine levels compared with control subjects. During the luteal phase, total testosterone levels were the higher in patients than control subjects, while 17ß-estradiol and progesterone levels were lower in patients than in control subjects. They concluded that among type 1 diabetic women, sexual function and sexual distress vary according to the phase of the menstrual cycle. The finding has implications on the clinical assessment of sexual function in type 1 diabetic women.

March shines with the beginning of Spring and holidays that bring us together with family and friends so we as people with diabetes need to once again continue our commitment to health. We read and learn to make sure we are up to date and even out front so that we know what we need to do to keep our diabetes under control. Do look up recipes for Easter and Passover on our web sites so you can enjoy these holidays. We certainly have menus for these family events. Take care, dear readers and remember to let us know what you are interested in reading about so we can research you interests. We begin with headlines and then as each month, we bring you an interesting articles and abstracts. We share an update on fixed-dose medication for those of you with type 2 diabetes, research on stroke and newly diagnosed type 2 diabetics, and finally sexual function and endocrine profile in type 1 diabetic women. Get your coffee or tea hot again and here we go.

Let’s start with our headlines. Whole grains and foods low in the glycemic index may help those of us with diabetes as well as those in the general population. Here are two headlines that will attest to this. Diabetes Care, Feb., 2006 reports that women with type 2 diabetes who incorporate more whole grains, bran, and cereal fiber into their diets may reduce their risk of heart disease. What’s more, low-glycemic index foods may also help curb early signs of heart trouble. The study written by Dr. Lu Qi at Harvard School of Public Health found that women who ate the higher fiber diet tended to have lower levels of two markers of blood vessel inflammation that are linked to heart disease—CRP and TNF-R2. The researcher recommends that women with diabetes “consume whole grain bread and cereals and less refines grains. In addition, a meal with low glycemic components such as bean, cruciferous vegetables, low-fat unsweetened yogurt, grapefruit, apples, tomatoes will also help."

The American Journal of Clinical Nutrition has an article which found that diets rich in whole grains can lower the risk of diabetes and heart disease. The study examined the diet records and blood samples of nearly 1,000 healthy middle-aged adults and measured levels of insulin and hemoglobin A as an index of diabetes risk, as well as homocysteine and cholesterol concentration to gauge coronary heart disease. The authors concluded that while there appears to be a lowered risk of diabetes and heart disease among individuals who consume higher levels of whole grains, the reasons for how this works is unclear. However, whole grains are rich in fiber, minerals, vitamins, and antioxidants. “These compounds all may have important biological functions which as a whole are an important contribution to reductions in diabetes and ischemic heart disease". The authors speculated also that slower digestion is likely a key factor as well.

One more abstract about heart disease will hopefully help all of us to rededicate ourselves to a heart healthy life style. Circulation, Feb.7, 2006 has an article written by Dr. David C. Goff from Wake Forest University School of Medicine. This article concludes that people who are at highest risk for cardiovascular disease generally have the lowest level of control of high cholesterol levels. They conclude that since cardiovascular disease is a public health problem in the US and there is a known benefit of using lipid-lowering therapy for primary prevention, “…efforts to improve the treatment and control of (high cholesterol) and to eliminate disparities…should be considered among our highest national healthcare quality improvement priorities."

Diabetes Care, February 2006 has an article that will again have all of us using intensive therapy in treating our diabetes. This study involved 1,257 subjects who were enrolled in the Diabetes Control and Complications Trial who were randomly assigned to receive intensive or conventional diabetes therapy. The intensive approach involved at least three injections of insulin per day, while the conventional approach involved no more than two. After following the subjects for an average of 6.5 years, all the subjects were encouraged to use the intensive therapy. The patients were then evaluated annually for neuropathy and other complications. Patients who received intensive therapy were 64 percent and 45 percent less likely to have symptoms and signs, respectively, of neuropathy compared to those who received conventional therapy. The benefit persisted fro at least 8 years after the end of trials. The researchers concluded the relationship between blood sugar control and neuropathy suggests that interventions have durable effect on neuropathy similar to what has previously been noted in diabetic eye disease and kidney.

New Test Predicts Damage from Diabetes


New test has the potential to be as significant to health care as measuring cholesterol levels.

Merlin Thomas, of Melbourne's Baker Heart Research Institute, is in the process of refining a blood test aimed at predicting the likelihood of organ damage in those with elevated blood-sugar levels, particularly patients with diabetes.

The test is based on determining the level of advanced glycation end-products (AGEs) in the body, which form when sugar damages proteins.

Associate Professor Thomas says the process is much the same as what happens when brown sugar and butter are mixed together to make caramel but when it occurs in the body, the result is nowhere near as sweet.

AGEs are known to be involved in hardening of the arteries, Alzheimer's disease, ageing of the skin and kidney disease. Basically, they contribute to the ageing process, slowly "caramelizing" us through time, Prof Thomas says. They cause tissue to become stiffer - the same process as what makes mutton tougher than lamb. Although AGEs are present in everybody, they accumulate much more quickly when sugar concentration is high, one of the reasons why strong sugar control is so important for those with diabetes.

The process means people with diabetes are at increased risk of heart attacks, strokes, kidney failure and blindness at an earlier age.

Already Baker scientists have successfully trialed a "crude" test for AGEs on more than 1,000 patients with diabetes, finding it to be an accurate predictor of the likelihood of complications.

But Prof Thomas said much more work needed to be done before general practitioners could use it." We need to refine it, make it even more precise," he said."

Prof Thomas said if doctors could reduce AGEs levels in the body, along with current strategies to control sugar, cholesterol and blood pressure, then it may be possible to avoid the complications of diabetes, including damage to the kidneys, eyes and heart vessels.

"What we're wanting to do with AGEs is the same thing that's been done with cholesterol," Prof Thomas said in an interview. "We want to establish what increases AGEs in the body and what is the best way to reduce them." Some medications to treat AGEs already exist.

But others are being developed, including international human trials of a novel drug, known as alagebrium, which aims to break down pre-existing AGEs and make hardened tissue supple again.

"It'll be a couple of years before we have the full results but our preliminary studies have been extremely positive," Prof Thomas said. "The key to reducing the impact of diabetes is to break the link between high sugar levels and the damage they cause. AGEs are one of those links and this will provide an important advance to their care."

Case Study: DKA in Type 2

By Brian J. Welch, MD, and Ivana Zib, MD

Many people think that diabetic ketoacidosis (DKA) occurs only in people with type 1 diabetes. Here are two cases of people with type 2 diabetes and DKA. (Their names have been changed.)

Mr. Williams is a 25-year-old African American. He was diagnosed with type 2 diabetes five years ago. He was prescribed oral medications for his diabetes, which he took for one month. He didn't get the prescription refilled.

He came to our hospital because he'd had an upset stomach and been vomiting for five days. Over the previous two weeks, he had been very thirsty and had to go to the bathroom a lot, and he had lost 10 pounds without trying. He also said that he'd had pain in his lower back for five days.

His lab work showed:

Blood glucose: 314 mg/dl
A1C of 13.5 percent.
Blood pH of 7.14. A normal blood pH is 7.35-7.45. His blood was
more acidic than it should be.
His urine was positive for ketones.
He was in DKA. We admitted him to the hospital and gave him IV fluids and insulin.
Mr. Williams's white blood cell count was very high (over 20,000), which meant he had an infection somewhere. Bladder infections are common, but tests showed Mr. Williams did not have a bladder infection.

Mr. Williams still had back pain, and it was getting worse. His legs became numb and weak. We called a neurologist for help. During the neurology exam, Mr. Williams lost control of his bladder. An MRI showed an abscess was pressing on his spine. Emergency surgery was done to drain the abscess.

Case 2
Mr. Hillman, a 39-year-old white man with mild mental retardation, was diagnosed with type 2 diabetes four years ago. He took diabetes
pills for a month but couldn't afford to have the prescription refilled.

He came to our hospital because he'd been drinking and urinating a lot for three weeks, he had pain in this left hip and had begun to use a cane to walk, and he felt that he couldn't empty his bladder completely.

Mr. Hillman's heart rate and blood pressure were high. He was very thin and dehydrated. His lab worked showed:

Blood glucose 322 mg/dl
A1C of 12.6 percent
Blood pH of 7.24
Urine positive for ketones
White blood cell count of 22,200
We suspected Mr. Hillman had a bladder infection and, because of his hip pain, an infection in the bone there. We were surprised when the MRI showed an abscess in the prostate gland. He also had an uncommon complication of diabetes called myonecrosis, where some muscle tissue in the sore area of his hip had died.

After surgery to drain the abscess and a long course of IV antibiotics, Mr. Hillman recovered.

What You Can Learn From These Cases

DKA does occur in people with type 2 diabetes. A recent study
showed that out of 138 admissions for DKA, 22 percent of the patients
had type 2 diabetes.
Most times, DKA is triggered by an infection.
The infection may be hard to find, so your doctor should keep looking.
.

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THURSDAY, Feb. 16 (HealthDay News) -- The increasing incidence of type 2 diabetes could bring a rise in death and disability caused by stroke, new research warns.

Stroke risk in people newly diagnosed with type 2 diabetes is double that of the general population, and those under age 55 are at greatest risk, according to two studies to be presented Thursday at the American Stroke Association's annual stroke conference, in Kissimmee, Fla.

One Canadian study of more than 12,000 newly diagnosed type 2 diabetics found that, "in the first five years, more than 9 percent were admitted to the hospital for stroke," according to lead researcher Dr. Thomas Jeerakathil, an assistant professor of neurology and medicine at the University of Alberta in Edmonton, Alberta.

What's not known, because it was beyond the scope of this study, is whether those who experienced stroke were even less likely to keep risk factors such as diabetes or blood pressure under control.

The new findings add much to what experts knew -- or didn't know -- about diabetes and its relation to stroke, Jeerakathil said.

"The usual thought is that complications don't develop for several years," he said. "We were interested in looking at the risk soon after diagnosis. Most of the studies that have looked at this in the past have looked at risk of stroke after five, 10 or more years."

His team used health records from the Canadian province of Saskatchewan to track the stroke incidence of more than 12,000 people with newly diagnosed type 2 diabetes.

The researchers found that the risk of stroke over a follow-up of about five years was double for the new diabetics vs. that of the general population.

The finding "argues for very aggressive cardiovascular risk factor control," Jeerakathil said. He advises diabetics to "pay attention to cholesterol and blood pressure, stop smoking, lead an active lifestyle and eat a diet high in whole grains and vegetables."

Right after a type 2 diabetes diagnosis, "I think people tend to think they can relax, that complications are far in the future," Jeerakathil said. "In fact, there is a real risk even in the first few years after being diagnosed of having a stroke."

The study did have its limitations, Jeerakathil noted. "We had to define 'new-onset' [diabetes] as those who got a new prescription for diabetes medication. The five years [follow-up] started when they got their first prescription, and the limitation is that some may have been diet-controlled [at first], and may have had the diagnosis longer than five years. But most people are started on medication soon after diagnosis," he said, so the limitation may not be significant.

In the second study, Dr. Brett Kissela, an associate professor of neurology at the University of Cincinnati, found that diabetes is one of the most important risk factors for stroke, and that the risk is greatest in patients under age 55.

"What we found is that risk is not uniform across all the different age groups," he said. "In fact, people who get diabetes at a younger age have a substantially increased risk of stroke."

His team evaluated more than 2,400 cases of strokes occurring in 1999 in the Cincinnati area, comparing the incidence of stroke in those with type 2 diabetes to those without. According to the researchers, 33 percent of the patients were diagnosed with diabetes before the stroke occurred.

Kissela's team broke down the cases by age and race.

They found that people under age 55 with type 2 diabetes had a risk of stroke that was five to nine times higher than that of similarly aged nondiabetics. And before age 45, black Americans with diabetes had a seven to nine times greater risk of stroke than those without diabetes of the same ages and race.

"Diabetes is an important risk factor for stroke across the life span, but it's very high for those who have been diagnosed at a young age," Kissela concluded.

Dr. John Buse, vice president of the American Diabetes Association, welcomed both studies. He pointed out that there's been a paucity of research focused on diabetes and stroke risk alone, rather than all types of cardiovascular disease.

The findings should help get the message out that those with diabetes need to pay close attention to cardiovascular risk factors, he added.

"The American Diabetes Association did a survey a few years ago of people with diabetes," Buse said. "Even though 80 percent of people with diabetes eventually die of heart disease or stroke, most patients with diabetes, about 70 percent, said they did not feel at risk of heart disease or stroke."

TORONTO (CP) - Taller diabetics may be at higher risk of lower-leg amputation due to peripheral sensory loss than diabetics of shorter stature, underscoring the need for careful monitoring to pick up early signs of the complication, a study suggests.

The Taiwanese study, appearing in Tuesday's issue of the Canadian Medical Association Journal, suggests taller diabetics may be at greater risk for peripheral sensory loss - and, hence, infections that lead to amputation - because their longer nerve fibres may be more vulnerable to external injury and the vascular complications of the disease.

"Because peripheral sensory loss with the development of foot ulcers is the most common indication for lower-extremity amputation among diabetic patients, taller patients may be at increased risk of such a procedure," says the study led by Dr. Chin-Hsiao Tseng of National Taiwan University Hospital.

While diabetes accounts for up to half of all lower-limb amputations in Taiwan, "the procedure is much less common among Taiwanese people of shorter stature than among white people who are much taller," the authors write. "The reason for the difference in rates between ethnic groups is unknown, but height may be a factor."

The 1995-2002 study involved phone interviews with more than 93,000 patients with either Type 1 (3.5 per cent) or Type 2 (96.5 per cent) diabetes. The detailed questionnaires determined 1.7 per cent of those with Type 1 and 0.8 per cent with Type 2 had undergone lower-limb amputation.

Researchers found that for every 10-centimetre increment of height, there was a 16 per cent rise in the risk of leg amputation. While the rate of removal was roughly equal for men and women with Type 1 (insulin-dependent) diabetes, far more men than women with Type 2 (insulin-resistant) diabetes lost a leg due to the disease.

Donna Lillie, vice-president of research and professional education at the Canadian Diabetes Association, would not comment on specifics of the research, but she called the results "interesting information."

"And it really does emphasize for us the overriding issue that the physician has to understand the whole patient and the risk for individual patients," she said Monday.

Lillie said diabetics are at great risk for foot and leg ulcers because of diabetic neuropathy - nerve damage that stops them from feeling pain or irritation that would warn of the presence of infection.

"And if you also run into problems with poorer circulation in your lower limbs, you get that combination of the blood flow not moving as well around an area and then you're not feeling it.

"That's why you've got to look," she said, advising that diabetics must check their feet daily for any breaks in the skin, redness or swelling. Feet should also be kept clean and moisturized to prevent cracking that could expose them to infection.

Infections left untreated can eventually become gangrenous, which would require a life-saving amputation of the affected limb.

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What is a placebo?

A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness. In some studies, the participants in the control group will receive a placebo instead of an active drug or treatment.

What is a control or control group?

A control is the standard by which experimental observations are evaluated. In many clinical trials, one group of patients will be given an experimental drug or treatment, while the control group is given either a standard treatment for the illness or a placebo.

What are the different types of clinical trials?

Treatment trials test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.
Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
Screening trials test the best way to detect certain diseases or health conditions.
Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.

What are the phases of clinical trials?

Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions:

In Phase I trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase II trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase III trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

What is an "expanded access" protocol?

Most human use of investigational new drugs takes place in controlled clinical trials conducted to assess safety and efficacy of new drugs. Data from the trials can serve as the basis for the drug marketing application. Sometimes, patients do not qualify for these carefully-controlled trials because of other health problems, age, or other factors. For patients who may benefit from the drug use but don't qualify for the trials, FDA regulations enable manufacturers of investigational new drugs to provide for "expanded access" use of the drug. For example, a treatment IND (Investigational New Drug application) or treatment protocol is a relatively unrestricted study. The primary intent of a treatment IND/protocol is to provide for access to the new drug for people with a life-threatening or serious disease for which there is no good alternative treatment. A secondary purpose for a treatment IND/protocol is to generate additional information about the drug, especially its safety. Expanded access protocols can be undertaken only if clinical investigators are actively studying the new treatment in well-controlled studies, or all studies have been completed. There must be evidence that the drug may be an effective treatment in patients like those to be treated under the protocol. The drug cannot expose patients to unreasonable risks given the severity of the disease to be treated.

Some investigational drugs are available from pharmaceutical manufacturers through expanded access programs listed in ClinicalTrials.gov. Expanded access protocols are generally managed by the manufacturer, with the investigational treatment administered by researchers or doctors in office-based practice. If you or a loved one are interested in treatment with an investigational drug under an expanded access protocol listed in ClinicalTrials.gov, review the protocol eligibility criteria and location information and inquire at the Contact Information number.

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The ethical and legal codes that govern medical practice also apply to clinical trials. In addition, most clinical research is federally regulated with built in safeguards to protect the participants. The trial follows a carefully controlled protocol, a study plan which details what researchers will do in the study. As a clinical trial progresses, researchers report the results of the trial at scientific meetings, to medical journals, and to various government agencies. Individual participants' names will remain secret and will not be mentioned in these reports (See Confidentiality Regarding Trial Participants).

What should people consider before participating in a trial?

People should know as much as possible about the clinical trial and feel comfortable asking the members of the health care team questions about it, the care expected while in a trial, and the cost of the trial. The following questions might be helpful for the participant to discuss with the health care team. Some of the answers to these questions are found in the informed consent document.

What is the purpose of the study?
Who is going to be in the study?
Why do researchers believe the new treatment being tested may be effective? Has it been tested before?
What kinds of tests and treatments are involved?
How do the possible risks, side effects, and benefits in the study compare with my current treatment?
How might this trial affect my daily life?
How long will the trial last?
Will hospitalization be required?
Who will pay for the treatment?
Will I be reimbursed for other expenses?
What type of long-term follow up care is part of this study?
How will I know that the treatment is working? Will results of the trials be provided to me?
Who will be in charge of my care?

What kind of preparation should a potential participant make for the meeting with the research coordinator or doctor?

Plan ahead and write down possible questions to ask.
Ask a friend or relative to come along for support and to hear the responses to the questions.
Bring a tape recorder to record the discussion to replay later.
Every clinical trial in the U.S. must be approved and monitored by an Institutional Review Board (IRB) to make sure the risks are as low as possible and are worth any potential benefits. An IRB is an independent committee of physicians, statisticians, community advocates, and others that ensures that a clinical trial is ethical and the rights of study participants are protected. All institutions that conduct or support biomedical research involving people must, by federal regulation, have an IRB that initially approves and periodically reviews the research.Does a participant continue to work with a primary health care provider while in a trial?

Yes. Most clinical trials provide short-term treatments related to a designated illness or condition, but do not provide extended or complete primary health care. In addition, by having the health care provider work with the research team, the participant can ensure that other medications or treatments will not conflict with the protocol.

Can a participant leave a clinical trial after it has begun?

Yes. A participant can leave a clinical trial, at any time. When withdrawing from the trial, the participant should let the research team know about it, and the reasons for leaving the study.

Where do the ideas for trials come from?

Ideas for clinical trials usually come from researchers. After researchers test new therapies or procedures in the laboratory and in animal studies, the treatments with the most promising laboratory results are moved into clinical trials. During a trial, more and more information is gained about a new treatment, its risks and how well it may or may not work.
Who sponsors clinical trials?

Clinical trials are sponsored or funded by a variety of organizations or individuals such as physicians, medical institutions, foundations, voluntary groups, and pharmaceutical companies, in addition to federal agencies such as the National Institutes of Health (NIH), the Department of Defense (DOD), and the Department of Veteran's Affairs (VA). Trials can take place in a variety of locations, such as hospitals, universities, doctors' offices, or community clinics.

What is a protocol?

A protocol is a study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants following a protocol are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.

An Introduction to Clinical Trials

Choosing to participate in a clinical trial is an important personal decision. The following frequently asked questions provide detailed information about clinical trials. In addition, it is often helpful to talk to a physician, family members, or friends about deciding to join a trial. After identifying some trial options, the next step is to contact the study research staff and ask questions about specific trials.

What is a clinical trial?

A clinical trial (also called clinical research) is a research study in human volunteers to answer specific health questions. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments. Observational trials address health issues in large groups of people or populations in natural settings.

Why participate in a clinical trial?

Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research.

Who can participate in a clinical trial?

All clinical trials have guidelines about who can participate. Using inclusion/exclusion criteria is an important principle of medical research that helps to produce reliable results. The factors that allow someone to participate in a clinical trial are called "inclusion criteria" and those that disallow someone from participating are called "exclusion criteria". These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. Before joining a clinical trial, a participant must qualify for the study. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy participants. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study.

What happens during a clinical trial?

The clinical trial process depends on the kind of trial being conducted (See What are the different types of clinical trials?) The clinical trial team includes doctors and nurses as well as social workers and other health care professionals. They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed.
Some clinical trials involve more tests and doctor visits than the participant would normally have for an illness or condition. For all types of trials, the participant works with a research team. Clinical trial participation is most successful when the protocol is carefully followed and there is frequent contact with the research staff.

What is informed consent?

Informed consent is the process of learning the key facts about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study to provide information for participants. To help someone decide whether or not to participate, the doctors and nurses involved in the trial explain the details of the study. If the participant's native language is not English, translation assistance can be provided. Then the research team provides an informed consent document that includes details about the study, such as its purpose, duration, required procedures, and key contacts. Risks and potential benefits are explained in the informed consent document. The participant then decides whether or not to sign the document. Informed consent is not a contract, and the participant may withdraw from the trial at any time.

What are the benefits and risks of participating in a clinical trial?

Clinical trials that are well-designed and well-executed are the best approach for eligible participants to:

Play an active role in their own health care.
Gain access to new research treatments before they are widely available.
Help others by contributing to medical research.
There are also risks to clinical trials:

There may be unpleasant, serious or even life-threatening side effects to treatment.
The treatment may not be effective for the participant.
The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements.

What are side effects and adverse reactions?

Side effects are any undesired actions or effects of drug or treatment. Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems. Experimental treatments must be evaluated for both immediate and long-term side effects.

How is the safety of the participant protected?

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Restless legs syndrome and quality of sleep in type 2 diabetes, by L.A. Lopes and colleagues. Diabetes Care 28:2633-2636, 2005.

Restless legs syndrome is an overwhelming urge to move the legs because of uncomfortable or unpleasant sensations in the legs. The sensations occur during periods of inactivity and become more sensitive in the evening and at night, making it difficult to sleep. Restless legs syndrome is temporarily relieved by moving the legs and may cause involuntary jerking of the limbs during sleep and sometimes during wakefulness.

Restless legs syndrome is a neurologic condition, meaning that is has to do with the nerves or the nervous system. Diabetes is a common cause of nerve damage, and some studies have found that sleep disturbances are common in people with diabetes.

The researchers wanted to look at the quality of sleep and how common restless legs syndrome was among people with type 2 diabetes.

One hundred patients with type 2 diabetes who regularly went to the diabetes clinic at the University Hospital of the Federal University of Ceará, Brazil.

The researchers used established indexes and criteria to measure the patient's quality of sleep and to find out if they had restless legs syndrome.

Twenty-seven percent of the patients had restless legs syndrome, and 45% suffered from poor sleep quality. Poor sleep quality was linked with age, nerve damage, and restless legs syndrome. Excessive daytime sleepiness was also linked with restless legs syndrome.

Excessive daytime sleepiness can be caused by many things, and this study was not designed to find out the exact causes of the daytime sleepiness.

Restless legs syndrome is commonly found in people with type 2 diabetes and can lead to poor sleep quality in these patients. Restless legs syndrome is linked with nerve damage, and physicians should actively ask their patients about the quality of their sleep.

Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome, by L. Azadbakht and colleagues. Diabetes Care 28:2823–2831, 2005.

The metabolic syndrome (a cluster of symptoms that include high blood pressure, large waist size, high levels of fats in the blood, and the body's inability to handle glucose) increases a person's chances of getting cardiovascular disease (disease of the heart and blood vessels).

The researchers wanted to see if following a specific eating plan, called a Dietary Approaches to Stop Hypertension (DASH) eating plan, could help lower the risk of getting the metabolic syndrome.

A total of 116 patients (34 men and 82 women) from Tehran, Iran, who were overweight or obese and had the metabolic syndrome.

The patients went on one of three diets for six months: a control diet, a weight-reducing diet that emphasizes healthy food choices, and the DASH diet. The DASH diet emphasizes reduced calories and more servings of fruit, vegetables, low-fat dairy, and whole grains. Compared to the other diets, the DASH eating plan is lower in saturated fat, total fat, cholesterol, and sodium.

The DASH diet resulted in higher HDL cholesterol (the good cholesterol) and lower triglycerides (fats in the blood), blood pressure, weight, and blood glucose levels, as compared to the other two diets, in both men and women.

The weight-reducing diet also resulted in benefits, but the benefits were greater among those who were on the DASH eating plan.

In this study, it was not possible to determine if one part of the DASH eating plan was the cause of the beneficial effects, or if the combined parts of the eating plan were responsible for the benefits.

It was not possible to report the soluble and insoluble fiber intakes, or the trans fatty acid intakes, separately in the three different groups.

The patients in each group were responsible for providing their own food.

Following the DASH eating plan (or one that is lower in fat, cholesterol, and sodium and contains more servings of whole grains, vegetables, and fruit) can help lower the risk for the metabolic syndrome in both men and women.

Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women, by S. Liu and colleagues. Diabetes Care 28:2926–2932, 2005.

The metabolic syndrome (a cluster of symptoms that include high blood pressure, large waist size, high levels of fats in the blood, and the body's inability to handle glucose) increases a person's chances of getting cardiovascular disease (disease of the heart and blood vessels) and type 2 diabetes.

Recent studies have shown that dairy can help prevent the metabolic syndrome and type 2 diabetes.

Both calcium and vitamin D are found in dairy products. Calcium helps to prevent becoming overweight, high blood pressure, and heart disease. Vitamin D has been shown to improve the body's ability to use insulin and the function of -cells, which produce insulin; a lack of vitamin D in the body has been shown to lead to higher chances of getting type 2 diabetes. Despite these findings, however, there is not enough evidence to prove that dairy, and calcium and vitamin D in particular, can help prevent the metabolic syndrome.

To gather more evidence to see how calcium and vitamin D intake are related to the metabolic syndrome and type 2 diabetes in middle-aged and older women from the U.S.

The researchers studied 10,066 female health professionals who were at least 45 years old and took part in the Women's Health Study.

The women in the study were given a survey that asked questions about how often they ate certain foods and how much of those foods they ate. To determine the amount of nutrients each woman got from the foods, the researchers multiplied how often each woman ate the different foods and that food's nutritional content based on the recommended portion size. Dairy products were grouped as low-fat dairy products, including skim or low-fat milk, sherbet, yogurt, and cottage/ricotta cheese; high-fat dairy products, including whole milk, cream, sour cream, ice cream, cream cheese, and other cheese; and total dairy products, including all of the above. The researchers also took into account whether the women were taking calcium or vitamin D supplements, as well as whether they smoked, exercised, drank alcohol, or had a history of heart attack in their family.

The metabolic syndrome was defined from the criteria of the Adult Treatment Panel III of the National Cholesterol Education Program. Women with three or more of the following conditions were said to have the metabolic syndrome: 1) high triglycerides (or fats in the bloodstream), 2) low HDL (“good”) cholesterol, 3) high blood pressure, 4) overweight or obese, and 5) high blood glucose levels.

The researchers found that women who had more calcium in their diets were more likely to not have the metabolic syndrome. These women were also slightly older and thinner and were less likely to smoke, drink alcohol, or have a history of high blood pressure, and they were more likely to exercise and use multivitamins. Calcium was also linked with lower fat and lower cholesterol in these women. These results were similar for vitamin D; however, vitamin D was not related to having lower cholesterol. Overall, the women who had more calcium and vitamin D in their diets had a lower chance of having any one of the five symptoms of the metabolic syndrome. Women with lower amounts of calcium and vitamin D in their diets were more likely to have high glucose levels and diabetes, and lower amounts of vitamin D were shown to affect the body's ability to produce and secrete insulin.

There were three main limitations to this study. First, a questionnaire can produce inaccurate results. Second, the design of the study cannot show the long-term effects that calcium has on the symptoms of the metabolic syndrome. Third, the women in this study were mainly white and do not reflect the general U.S. population.

There is evidence of the positive effects of calcium and vitamin D on preventing the metabolic syndrome and diabetes. However, more studies need to be conducted in order to say for certain that taking more calcium and vitamin D is a good way to prevent diabetes and its complications.

Effects of acute starvation on insulin resistance in obese patients with and without type 2 diabetes mellitus, by F. Duska and colleagues.  Clin Nutr 24:1056–1064, 2005.

While losing weight and increasing physical activity can help reduce the chance of getting diabetes, some people try drastic diets, such as fasting (or not eating for a long period of time). Little is known about how fasting or a starvation diet affects the body's ability to handle glucose in the blood.

The researchers wanted to study the effects of a short-term starvation diet on people with and without diabetes.

The study included 10 people with type 2 diabetes and 10 obese people without diabetes. All the participants were volunteers.

After eating a standardized meal for a few days before the study, participants fasted for 60 hours, consuming only water or weak unsweetened tea.

A 60-hour fast actually worsened the body's ability to handle insulin and glucose in both people with diabetes and obese people without diabetes. People who were severely impaired in their ability to handle insulin improved slightly, but overall the effects were negative.

Only 20 people were researched, so the findings may not apply to a larger population. People with diabetes were taking medication during the study, so it may not apply to people with less severe forms of diabetes. Also, the time before the fast was rather brief, so there may have been important differences in the participants at the beginning of the study.

Fasting is not a healthy way of dieting for people who are obese or who have type 2 diabetes.

Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes, by D.M. Nathan and colleagues. N Engl J Med 353:2643–2653, 2005.

Diabetes has many harmful effects on the body. Among the most serious is cardiovascular disease (disease of the heart and blood vessels), which often leads to heart attack and stroke.

The researchers wanted to see if intensive long-term management of diabetes lowered the chances of people getting heart and blood vessel disease.

The study included 1,441 people with type 1 diabetes who participated in the Diabetes Control and Complications Trial (DCCT), a large study sponsored by the National Institutes of Health.

First, participants had a physical exam, including having blood drawn for A1C (a measure of long-term blood glucose control) and tests that measured their general health.

Half of the participants received their usual diabetes care, while the other half received intensive diabetes care. Intensive diabetes care consisted of three or more daily injections of insulin or treatment with an insulin pump, with doses based on at least four glucose self-monitoring measurements throughout the day.

Participants were followed for an average of 17 years, during which time researchers kept track of illnesses and deaths related to heart and blood vessel disease.

Intensive diabetes care reduced the chances of heart and blood vessel disease by 42% and the chance of heart attack, stroke, or heart and blood vessel disease-related death by 57%.

The total number of heart and blood vessel disease-related events was low, which could make the results misleading.

Intensive diabetes care lowers the chances of getting heart and blood vessel disease in people with type 1 diabetes.

Study: 2M Adolescents Have Pre-Diabetes

CHICAGO - Roughly 2 million U.S. children ages 12 to 19 have a pre-diabetic condition linked to obesity and inactivity that puts them at risk for full-blown diabetes and cardiovascular problems, government data suggest.

Researchers from the federal Centers for Disease Control and Prevention and the National Institutes of Health examined the prevalence of abnormally high blood sugar levels after several hours without eating, a condition called impaired fasting glucose, or IFG, that is measured in a blood test.

One in 14 boys and girls in a nationally representative sample had the condition. Among the overweight adolescents, it was one in six.

Affected adolescents were more likely than those with normal fasting glucose measurements to have other symptoms suggesting they might be on the road to heart problems: Average levels of bad cholesterol and blood fats called triglycerides were higher in youngsters who had the pre-diabetic condition.

"The numbers are definitely concerning," said co-author Dr. Venkat Narayan, a CDC diabetes researcher.

The study appears in November's Pediatrics, being published Monday. It is based on data involving 915 youngsters who participated in a 1999-2000 national health survey. Narayan said the researchers will examine whether rates of pre-diabetes have increased since then.

About 20 million Americans have diabetes, most of them adults with type 2 diabetes, which impairs the body's ability to properly use the blood sugar-regulating hormone insulin. This form of the disease is strongly linked to being overweight and inactive.

Of the roughly 177,000 Americans under age 20 with diabetes, most have type 1, or juvenile onset diabetes, in which the body produces little or no insulin. But type 2 diabetes among youngsters has increased.

Dr. Francine Kaufman, head of the diabetes center at Children's Hospital in Los Angeles, said about 25 percent of the diabetic children treated there have type 2 diabetes, compared with just 4 percent a decade ago.

Both types involve abnormally high blood sugar levels that can damage blood vessels, the heart and other organs.

For the study, the researchers used American Diabetes Association criteria that defines impaired fasting glucose as blood sugar levels of at least 100 milligrams per deciliter; above 125 is considered diabetes.

The average level was 89.7, within the normal range, but 7 percent of the children in the study were in the pre-diabetic range, translating to about 2 million U.S. youngsters. Roughly 16 percent of the youngsters studied were obese, about the same as recent national estimates.

Elevated fasting glucose "has no symptoms but it signifies an advanced metabolic problem, which will in most cases progress to type 2 diabetes over time," said Dr. David Ludwig, director of the obesity program at Children's Hospital in Boston, who was not involved in the study.

"Intensive lifestyle interventions" including physical activity and improving diet can help prevent pre-diabetes from progressing in adults and it's likely the same can happen in children, the researchers said.

Ludwig said systematic societal changes are needed, too, including more healthful school lunches.

"It's just not enough to tell people to exercise and eat right," he said.

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Landmark hypertension study launches extensive physician and patient education program
Researchers in the largest high blood pressure clinical trial ever conducted are launching a comprehensive outreach program to improve high blood pressure control nationwide. About 150 physicians in 34 states and Washington, DC, have completed training to educate other physicians in their communities. Their goal: to help doctors and patients prevent and better treat high blood pressure.
The new $3.7 million, three-year educational effort is a follow-up to the landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and is being implemented in collaboration with the National High Blood Pressure Education Program (NHBPEP). Funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, the ALLHAT blood pressure study compared the effects of four major classes of medications to treat high blood pressure. More than 42,000 patients ages 55 and older participated. The main results were published in the Journal of the American Medical Association in December 2002 and played a central role in NHBPEP's revision of the clinical practice guidelines on high blood pressure released in May 2003 (Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure).

"It often takes years for the results of major studies to become part of standard health care," notes NHLBI director Elizabeth G. Nabel, MD. "The results of ALLHAT and the clinical guidelines could have an enormous impact on the health of millions of Americans. We are confident that by playing a more active role in sharing the information, we will be able to put the results into action more quickly and more effectively."

An estimated 65 million American adults – nearly one in three -- have high blood pressure. But, for more than two-thirds of them, blood pressure remains out of control. High blood pressure leads to more than half of all heart attacks, strokes, and heart failure cases in the United States each year, and it increases the risk of kidney failure and blindness. Clinical guidelines recommend that physicians work with patients to keep blood pressures below 140/90 mmHg, even lower for people with diabetes or kidney disease, and encourage all their patients to make healthy lifestyle changes, such as losing excess weight, becoming physically active, limiting alcoholic beverages, and following a heart-healthy eating plan, including cutting back on salt and other forms of sodium, and not smoking.

ALLHAT researchers reported in 2002 that, overall, diuretics are more beneficial than calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, or alpha blockers as initial treatment to lower blood pressure and to protect against adverse effects of high blood pressure. For patients with diabetes or with mildly elevated fasting glucose--a sign of pre-diabetes--diuretics are at least as effective, and in some cases more beneficial, than the other two classes of medications, according to ALLHAT findings published in June 2005.

In general, diuretics are well tolerated by patients, with few side effects. Sometimes called "water pills," diuretics reduce the amount of fluid in the body by helping the kidneys flush excess water and salt from the body.

The other medications lower blood pressure differently. Calcium channel blockers keep calcium from entering the muscle cells of the heart and blood vessels, causing the blood vessels to relax. ACE inhibitors prevent the formation of a hormone called angiotensin II, which normally causes blood vessels to narrow. Alpha blockers allow blood to pass more easily by reducing nerve impulses to blood vessels. However, ALLHAT found that participants taking alpha blockers had 25 percent more cardiovascular events and were twice as likely to be hospitalized for heart failure as those taking the diuretic. Because of these findings, the alpha blocker arm of the study was stopped early.

"Based on the results, the ALLHAT investigators recommend that in addition to lifestyle changes, diuretics should be the drug of choice for first line blood pressure treatment," says William C. Cushman, MD, chair of the ALLHAT Dissemination Committee and chief of Preventive Medicine at the Veterans Affairs Medical Center in Memphis. "Because most patients require more than one drug, diuretics should generally be part of any antihypertensive regimen."

Cushman cites another advantage for using diuretics. "They are much less expensive than the other two drug classes. For those stretching their budgets, taking a medicine which costs less than $100 a year is a very good thing."

In the past 20 years, however, prescriptions for newer, more costly medications began replacing diuretics. The newer drugs were shown to lower blood pressure and heart disease risk compared to placebo, but how the drugs compared to each other was unknown until ALLHAT. Analyses of prescribing trends suggest that prescriptions for diuretics have slowly begun to rise since the study ended and clinical guidelines have encouraged the use of diuretics either alone or in combination with other blood-pressure lowering medications.

"The guidelines were simplified and strengthened to emphasize the most effective ways to control blood pressure – starting with lifestyle changes and including diuretics when medication is needed," notes Jeffrey Cutler, MD, NHLBI senior advisor and ALLHAT project director.

The ALLHAT Dissemination Plan includes materials for investigator educators to lead small, interactive educational sessions with physician peers. Educators are asked to make at least one presentation per month. The sessions include discussions of the study results, current hypertension treatme  [report anonymous abuse]

Study using new imaging technology detects subtle brain changes in patients with Type 1 diabetes
 

Although people with diabetes are twice as likely as the general population to develop depression, the cause of this increased risk is not well understood. Now, a Joslin Diabetes Center-led collaboration has documented for the first time subtle changes in the gray matter of the brain of type 1 diabetes patients compared to control subjects who did not have diabetes. They made these observations using voxel-based morphometry (VBM), a relatively new magnetic resonance imaging (MRI) technology that allows researchers to take very sensitive measurements of small regions in the brain. For the first time, doctors have reason to ask if the increased risk of depression could in fact be due to changes in brain.

"We have known for a long time that diabetes can damage the nerves that control the extremities and those that control internal organs like the heart and the intestine," says the study’s principal investigator, Alan M. Jacobson, M.D., head of Behavioral and Mental Health Research at Joslin Diabetes Center. "This research helps document diabetes-related changes to the central nervous system. People tended to assume that the stress of dealing with a severe chronic illness and its complications was the sole source of depression. That still is an important issue, but now we have evidence that something else might be at work."

Equally important, by showing the effectiveness of VBM for observing and evaluating changes in brain structure that appear to be related to diabetes, the study opens up whole new approaches to understanding the central nervous system in diabetes. This technology creates three-dimensional images of magnetic resonance imaging data, which researchers can then use to observe and evaluate structural changes, in this case, in the brain.

"We’ve used this technology to look at patients with bipolar disorder or with classic neurodegenerative disorders, but this is the first study to use VBM to investigate brain changes in patients with diabetes," says co-investigator Perry Renshaw, M.D., Ph.D., who directs the Brain Imaging Center at McLean Hospital in Belmont, Mass.

For the study, the researchers measured gray matter densities in areas of the brain responsible for memory, language processing and attention. When they compared the images of 82 patients who had type 1 diabetes for 15 to 25 years with minimal complications to those of 36 age-matched control subjects who did not have diabetes, they discovered lower levels of gray matter density in the group with diabetes. Among that group, they also found that these lower levels in density were associated with poorer glycemic control and higher frequency of hypoglycemic events that led to unconsciousness.

"This study definitely does not mean that everyone who gets type 1 diabetes will suffer from clinically significant brain damage," Dr. Jacobson emphasizes. Indeed, he explains that in fact they observed little difference in cognitive function when patients with diabetes were compared to the participants in the control group. What is important, however, is the new tool researchers now have to examine what changes do occur, what drives them, and how they may affect brain functions, including those that lead to depression.

Understanding changes in brain structure becomes particularly critical as more and more people with type 1 diabetes are living longer lives, explains co-investigator Gail Musen, Ph.D., also of Joslin. "We want to be able to understand how the metabolic changes of diabetes affect the risks these patients face so we can find ways to minimize them as they go on to live 50 or more years with this disease."

Dr. Jacobson and his colleagues will continue now to follow the patients in the study to observe if and how the changes progress over time and whether high or low blood glucose influences that progression. Because they can also use MRI to measure the brain’s response to stimuli like cognitive or emotional tests, they will also start looking at functional changes.

"Now that we’ve identified unexpected structural changes in the brains of people with diabetes, we need to understand more about how these relate to changes in brain function," says Dr. Renshaw. "The more we understand the problem, the better solutions we can find."

   
More information: www.joslin.harvard.edu
 

 Carbohydrates Helps Improve Insulin ControlPainless Diabetes Meter - Successful Clinical Trial and Funding
Lein Applied Diagnostics Ltd, a Berkshire-based company, is developing a revolutionary new product to measure blood glucose levels diabetics. It has successfully completed clinical tests of its advanced prototypes and secured further investment from Seven Spires Investments, a member of Thames Valley Investment Network (TVIN).

The funding will enable Lein to accelerate the development programme for its non-invasive optical instrument.

In recent clinical tests, an advanced prototype of the instrument, which uses an innovative optical measurement technique to track the amount of glucose in the eye, produced well correlated readings of blood glucose levels when tested on volunteers with widely varying ages. Successful tests have also been performed on volunteers with contact lenses.

Dr Dan Daly, Director of Lein Applied Diagnostics, explained: “We are delighted with the excellent results from our clinical tests, and pleased that Seven Spires Investments have provided us with further investment, following on from the initial funding secured after we presented at a TVIN meeting. Having achieved our clinical and technical goals, we are now ready to accelerate our development programme.

Source: Innovations Report

On people previously randomized to more intense glucose control, were similar to those seen during the trial
In people previously randomized to tight blood pressure control, tended to be less than those seen during the trial
In overweight people previously randomized to first line therapy with metformin, had diminished, but remained significant for the primary endpoints, mortality and cardiovascular disease.
In addition, the apparently increased case fatality rate, which was observed in the sulphonylurea/metformin sub study, had decreased substantially and was no longer statistically significant.
They concluded that the benefits of improved glucose control obtained during the UKPDS trial appear to persist in the longer term whereas those obtained with improved blood pressure control were maintained to a lesser extent, once the study protocol was discontinued.

UK PROSPECTIVE DIABETES STUDY

The UKPDS is the largest and most comprehensive study of type 2 diabetes that has been undertaken. It was undertaken after the results of the DCCTs for type 1 diabetes were recognized. It was set up in 1977, initially as a pilot scheme involving five centers in England, Scotland and Northern Ireland. The study was subsequently extended to 23 centers. In 1987, the study of treatment of hypertension was started. UKPDS recruited 5100 patients who were allocated to various treatment groups. From the point of view of their age and racial mix, these people were representative of the typical British patients with type 2 diabetes. UKPDS closed at the end of 1997 and the results published in 1998.

The initial results indicated that intensive blood glucose control policy decreased the risk of diabetic complication. It also found that tight blood pressure control decreased the risk of diabetic complications.

The 5-year Post Study Monitoring (DSM) program for the UK Prospective Diabetes Study ran from 1997 to 2002. Its main objectives were: 1. to observe the glycemic and blood pressure levels achieved after the trial stopped, 2. to determine the degree to which glycemia and blood pressure related risk reductions obtained during the trial remained evident, 3. to examine the impact on macrovascular outcomes with extended follow up of improved glucose control, and, in overweight patients, of metformin therapy, and 4. to re-evaluate the apparent increased case observed in the sulphonylurea/metformin study. Careful monitoring for the predefined UKPDS clinical outcomes continued with collection of detailed documentation and adjudication by the UKPDS Endpoint Committee, exactly as during the trial. In addition, patients were seen annually in UKPDS clinics where possible to continue standardized collection of clinical and biochemical measurements.

The results:

Mean HbA1c levels rose in patients randomized previously to an intensive glucose control policy such that by year three, mean HbA1c levels were indistinguishable from those for patients randomized previously to a conventional glucose control policy. After year three, mean HbA1c levels improved in both groups.
Mean systolic blood pressure rose in patients randomized to a tight blood pressure control policy so that by year two, mean blood pressure levels were indistinguishable from those for patients randomized previously to a less tight blood pressure control policy. After year two, mean systolic and diastolic blood pressure levels improved in both groups.
Given that:

Patients returned to routine diabetic care
Mean HbA1c levels converged by three years
Mean BP levels converged by two years
Initial analyses presented on the Tuesday 27th August 2003 qt the IDF meeting in Paris suggest that the risk reductions seen five years after the end of the study:

Studys

THE STENO DIABETES STUDY This study was a randomized, open, parallel trial at the Steno Diabetes Center in Denmark and offers us a comparison of the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on risk factors for cardiovascular disease in type 2 diabetes. It was done by Gaude P, et al. The results can be found in the New England Journal of Medicine 348:383-393, 2003. Eighty patients with type 2 diabetes and microalbuminuria were assigned to receive conventional treatment in accordance with national guidelines, and another eighty assigned to receive intensive treatment with stepwise implementation of behavior modification and pharmacological therapy that treated hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with aspirin. The endpoints were death from CVD, nonfatal MI, nonfatal stroke, revascularization, and amputation.
People with diabetes have a two to three times risk of CVD than those without diabetes. Effective treatments are available to treat macro-and microvascular complications of diabetes. In particular, there is evidence of benefit of single-factor interventions: intensive glucose, lipid, and blood pressure control; treatment of microalbuminuria; and the use of regular aspirin. There is, however, scant literature on the effectiveness of multifactorial interventions, as would be applied in clinical practice, on CVD among people with diabetes.

The Steno study attempted to close this gap in evidence by testing an intensive multifactorial intervention against conventional treatment. The intensive intervention consisted of step-wise introduction of lifestyle and pharmacological interventions aimed at keeping glycated hemoglobin <6.5%, blood pressure <130/80mmHg, total cholesterol <175mg/dl, and triglycerides <150mg/dl. The lifestyle component of the intensive intervention included reduction in intake dietary fat, regular exercise, and smoking cessation. Participants receiving intensive intervention were also advised to take aspirin. A dietary supplement consisting of vitamins E and C, folic acid, and chromium picolinate were given as a angiotensin-converting enzyme (ACE) inhibitor, regardless of blood pressure.

After 7.8 years of follow-up, 44% of patients in the conventional arm, but only 24% in the intensive, multifactorial arm, developed CVD, representing a 53% reduction in risk. One CVD event was prevented for every five patients treated for 7.8 years with intensive, multifactorial intervention. The risks for nephropathy, retinopathy, and autonomic neuropathy were also lower in the multifactorial treatment group by 61, 58, and 63% respectively.

Reviewers of the study say that from a study such as this one, it is not possible to tease out the effects of each component of the multifactorial intervention, nor was this the purpose of the study. The authors were justified, based on existing evidence of CVD benefit, in including smoking cessation, physical activity promotion, lipid and blood pressure control, aspirin therapy, and ACE inhibitor therapy. Strong evidence for microvascular benefits from glycemic control exists and, although not unequivocally established, glucose control may also have positive benefits on CVD. On the other hand, CVD benefits from routine vitamin or mineral supplementation have not been established, and their inclusion in a multifactorial intervention to prevent CVD is thought by some reviewers to be premature.

Despite these limitations, the Steno study provides evidence that an aggressive multifactorial intervention which can be delivered in a real-life clinical practice situation can lower the risk of CVD among people with diabetes and microalbuminuria by 50%. The quality of diabetes care remains suboptimal in the United States and elsewhere, despite the availability of effective treatments to prevent CVD. The Steno study shows us the benefits of multifactorial interventions in practice and gives us strong reason to believe that evidence-based guidelines can be translated into clinical practice. The potential benefit to be accrued, in terms of CVD prevention, from systematic application of current knowledge, is enormous.