RxPG News : Metabolic Syndrome

Single mechanism to explain metabolic syndrome

Mon, 30 Jun 2008 08:59:48 PST

( from http://www.rxpgnews.com ) Many of the 75 million Americans with essential hypertension also develop diabetes and other complications in addition to their high blood pressure, and researchers have discovered a common molecular mechanism in a strain of rat that explains why such metabolic disorders arise together in mammals.

The bioengineering researchers at UC San Diego’s Jacobs School of Engineering also showed that a drug developed for unrelated purposes in humans was effective in counteracting the underlying molecular mechanism in the spontaneously hypertensive rat (SHR), a strain predisposed to develop high blood pressure.

In a paper published June 30 in the online version of Hypertension, Frank DeLano, a research scientist at UC San Diego, and Geert Schmid-Schönbein, a professor of bioengineering, describe how they successfully reversed the SHR animals’ symptoms of high blood pressure, a pre-diabetes condition called insulin resistance, and immune suppression.

H. Glenn Bohlen, a professor in the Department of Cellular and Integrative Physiology at Indiana University Medical School, wrote in an accompanying editorial in Hypertension that the new study will likely be important to people suffering from obesity as well as hypertension. “With the national and international emphasis on obesity and its attendant cardiovascular problems, there is a tendency to forget that essential hypertension affects about the same percentage of humans as does serious obesity and an even higher percentage of the population than does type 2 diabetes mellitus,” wrote Bohlen. “The elegant study by Delano and Schmid-Schönbein points to a potentially very important overlap of an insulin resistance mechanism with hypertension in the spontaneously hypertensive rat (SHR).”

The SHR strain is a model for essential hypertension in humans because both the rodent and many humans with hypertension also develop a variety of other metabolic complications when high blood pressure strikes.

In the circulation of SHR rodents, Schmid-Schönbein and DeLano found significant levels of proteases, which are enzymes that break down proteins. Natural enzyme inhibitors found in normal healthy rats did not lower the level of protease activity in the SHR strain to normal levels.

“We were looking for a common cause of diverse but concurrent metabolic problems and we were testing our theory that enhanced proteolytic activity in the circulation may be the root cause,” said Schmid-Schönbein. “In the hypertensive rat we studied, enzymes cleave extracellular portions of several protein receptors, such as the insulin receptor, so that insulin can no longer bind and facilitate normal metabolism of glucose.”

Under normal conditions, the pancreas releases insulin in the bloodstream. The molecule then binds to insulin receptors on the cell-surface membrane, which signals the cells to absorb glucose, a main source of cellular energy. However, when a cell loses the binding site for insulin on the insulin receptors, it becomes “resistant,” or unresponsive to insulin and no longer absorbs glucose in healthy amounts on cue, which is the problem in type 2 diabetes.

The researchers showed that the SHR animals have protease activity in their circulation that cleaves more than just insulin receptors. In these animals, proteases also cleave significant numbers of CD18, an important binding receptor on the surface of infection-fighting leukocytes. CD18 gives these cells the ability to adhere to the walls of blood vessels as a way to home in on infections. With the loss of CD18 receptors, leukocytes of the SHR animals are unable to bind to the wall of blood vessels, resulting in a compromised immune system.

“These results point to a single mechanism that explains multiple and diverse cell dysfunctions encountered in hypertensive rats, and they also suggest that a similar mechanism may be operating in humans suffering simultaneously from hypertension, diabetes, and other metabolic conditions,” said Schmid-Schönbein.

The team went on to test whether administration of a protease-blocking drug could reverse the multiple metabolic complications in the rat strain. They administered doxycycline, a seemingly unlikely candidate to have such a beneficial effect. Infectious disease specialists often prescribe doxycycline, an antibiotic, to counter bacterial infections. However, in laboratory tests doxycycline also blocks the activity of certain proteases in the SHR strain of rat.

The researchers found that protein receptors on the surface of SHR cells become clipped off as the animals develop hypertension. They used a novel visualization technique to show that after several weeks of ingesting doxycycline in their drinking water, the SHR rats developed cells that again bristled with normal CD18 and insulin receptors. The animals’ metabolic conditions simultaneously improved; blood pressure normalized and symptoms of immune suppression disappeared.

“These studies indicate the first time that hypertension and cell dysfunctions associated with the metabolic syndrome may be part of an enzymatic auto-digestion process in which proteases in our body become uncontrolled and break down proteins,” Schmid-Schönbein said. “Our observations provide a conceptual framework in which we can start to understand how diverse complications in the metabolic syndrome arise.”

Schmid-Schönbein said his findings will likely spark follow-up studies of this mechanism in humans.

“Even if future studies only support the clear linkage of hypertension to insulin receptor cleavage in the current study of SHRs, this observation should lead to many studies of how these two problems perhaps interact,” wrote Bohlen in the Hypertension editorial. “To what extent this interaction is part of the cause or consequences of mechanisms associated with hypertension will remain controversial for some time to come. However, it is tempting to speculate that treatment of hypertension may be inadvertently improving insulin sensitivity and likely many other abnormalities associated with cell surface receptors that have been unknowingly damaged by protease activation associated with elevated blood pressure.”

Weight loss better than insulin therapy in type 2 Diabetes Mellitus

Tue, 11 Mar 2008 15:27:42 PST

( from http://www.rxpgnews.com ) Weight-loss and major lifestyle changes may be more effective than intensive insulin therapy for overweight patients with poorly controlled, insulin-resistant type 2 diabetes, according to a diabetes researcher at UT Southwestern Medical Center.

The National Heart, Lung, and Blood Institute of the National Institutes of Health recently halted part of an ongoing clinical trial on diabetes and heart disease after more than 250 people died while receiving intense treatment to drive their blood glucose levels below current clinical guidelines.

The evidence is compelling that when insulin levels are high, certain tissues are overloaded with fatty molecules, which leads to insulin resistance. And yet, the high blood glucose levels of many obese patients with insulin-resistant type 2 diabetes are being treated with increasing amounts of insulin in an attempt to overpower that resistance. While high doses of insulin may lower glucose levels, it will also increase the fatty molecules and may cause organ damage.

In a commentary in the March 12 issue of The Journal of the American Medical Association, Dr. Roger Unger, professor of internal medicine, wrote about the recent findings of his own and other labs that link insulin resistance to excess accumulation of fatty molecules in liver and muscle.

Dr. Unger, who has investigated diabetes, obesity and insulin resistance for more than 50 years said intensive insulin therapy is contraindicated for obese patients with insulin-resistant type 2 diabetes because it increases the fatty acids that cause diabetes. Instead, the most rational therapy eliminates excess calories, thereby reducing the amount of insulin in the blood and the synthesis of the fatty acids stimulated by the high insulin. Giving more insulin simply increases body fat.

“Evolution was unprepared for the change in the American diet to processed fast food and drive-through lanes,” he said. “There’s no way that our genes could evolve to gird themselves against the superabundance of very, very high-calorie foods that have flooded the U.S.”

Before the discovery of insulin, starvation was the only treatment for diabetes, said Dr. Unger, who is a member of the National Academy of Sciences.

“Today there are many treatment options, including bariatric surgery, if necessary, to lower the fat content in the body before you start giving insulin,” he said. “The fat is causing insulin resistance and killing the insulin-producing beta cells in the pancreas — that is what is causing type 2 diabetes.”

Giving more insulin simply channels the glucose into fat production. There is now a spectrum of therapies that improve diabetes by correcting the insulin resistance by reducing the body fat. Insulin treatment would be indicated only if all these fail.

Dr. Unger said insulin should be given to patients with insulin deficiency, but not if the insulin levels are already very high but ineffective. “Giving more insulin to an insulin-resistant patient is akin to raising the blood pressure of a patient with high blood pressure to overcome resistance to blood flow. Instead, you would try to reduce the resistance,” he said.

In the commentary, Dr. Unger said the increase in the number of patients with insulin-resistant type 2 diabetes can be traced to the epidemic of obesity that began in the U.S. after World War II, when food preparation was moved from the family kitchen to factories and companies that produce high-fat, calorie-dense foods, leading both men and women to consume substantially more calories on a daily basis. In addition, technological advancements such as televisions, computers and automobiles reduced the number of calories burned per day.

Type 2 diabetes occurs when the body is unable to make enough of the hormone insulin to compensate for insulin resistance. The condition affects between 18 million and 20 million people in the U.S.

Factors that increase the risk of type 2 diabetes include obesity, age and lack of exercise. Over a period of years, high blood sugar damages nerves and blood vessels, leading to complications such as heart disease, stroke, blindness and kidney disease.

Separate mechanisms in metabolic syndrome- Akt and atypical PKC

Sun, 14 May 2006 18:54:37 PST

( from http://www.rxpgnews.com ) Insulin uses two distinct mechanisms to control glucose and the metabolism of blood fats (lipids) in the liver, a new Joslin Diabetes Center-led study has discovered. Failures in each of these networks can lead to serious health problems: the breakdown of glucose metabolism that can lead to type 2 diabetes, and the malfunction of lipid metabolism contributing to metabolic syndrome, which is a cluster of conditions that puts people at increased risk of heart disease, vascular disease and type 2 diabetes.
The new study, led by C. Ronald Kahn, M.D., and Cullen Taniguchi, M.D., Ph.D., of Joslin Diabetes Center in Boston and their colleagues, is published in the May edition of Cell Metabolism. The findings open the door to the development of new treatments that one day may target directly the conditions that contribute to type 2 diabetes and the metabolic syndrome.

"Patients with the metabolic syndrome have high levels of both glucose and lipids in the blood. We now understand that insulin that controls the pathways that control glucose levels are different from those that regulate lipid levels. By targeting these specific pathways, we might be able to improve problems with glucose metabolism, lipid metabolism or both," says Dr. Kahn, President of Joslin Diabetes Center and Mary K. Iacocca Professor of Medicine at Harvard Medical School.

Diabetes affects an estimated 20.8 million children and adults in the United States -- 7 percent of the population. An estimated 14.6 million Americans have been diagnosed, leaving 6.2 million Americans unaware that they have the disease. In addition, 41 million Americans are thought to have pre-diabetes, or elevated blood glucose levels that put them at risk for developing type 2 diabetes. If untreated or poorly treated, diabetes can lead to blindness, kidney disease, stroke, nerve damage and circulation problems that can result in limb amputations.

Patients generally are diagnosed with metabolic syndrome if they have three or more of the following conditions: abdominal obesity; high cholesterol levels or triglycerides; low levels of good cholesterol; high blood pressure; and high blood glucose. The metabolic syndrome has become increasingly common in the United States, and according to a recent survey, is seen in 24 percent of all adult Americans above age 20 and in about 40 percent of those above age 60.

Exploring the role of the liver The liver is the body's primary chemical factory, and among its key roles is keeping glucose levels in the blood constant between meals. The liver also produces and packages cholesterol and triglycerides to send throughout the body. Insulin's activity in the liver controls both of these processes, but, until now, researchers have not understood how insulin does its job.

"In one of its roles, insulin tells the liver that you have just eaten, that it can stop producing glucose since the food you have just eaten will, for a while, supply an adequate amount," says Dr. Taniguchi, a postdoctoral fellow in Joslin's Section on Cellular and Molecular Physiology and lead author of the paper. "Insulin also is the trigger that tells the liver how to handle lipids. We have been trying for many years to understand how insulin provides these signals, and now we have shown that insulin controls each process differently."

Insulin drives the liver's metabolic functions by activating a molecule called phosphoinositide 3-kinase (PI3K), which then recruits other enzymes to carry out its orders. While researchers knew that the PI3K pathway was important to insulin's action, until now they didn't know how insulin uses PI3K to control either glucose or lipid metabolism.

Using mice bred to lack specific subunits of the PI3K pathway, the researchers discovered that mice that could not activate the protein kinase Akt had increased glucose production in the liver, impaired glucose tolerance, and increased levels of insulin in the blood, all contributors to type 2 diabetes. On the other hand, those mice with defects in the atypical forms of the enzyme protein kinase C (PKC) had decreased lipids in the blood and reduced levels of a protein called SREBP, which is critical for regulating fatty acid and cholesterol in the blood. (This particular form of the PKC enzyme is distinct from the form known as PKC-beta, which is activated by high blood glucose and is linked to many diabetic complications, including those of the eye and the blood vessels.)

"People used to think that Akt controlled both glucose and the lipids in the liver," says Dr. Taniguchi. "Now we know that Akt has nothing to do with the lipids. Akt controls the glucose part and the atypical PKC controls the lipids part." He explains that some patients with fatty liver disease don't have any glucose problems, while others with type 2 diabetes don't have problems with their lipids. "Now that we have uncovered the important molecules for each condition," says Dr. Taniguchi, "we can begin to look for ways to specifically target just the lipids or just the glucose."

New clinical team approach reduced cardiovascular risk for obese metabolic syndrome patients

Mon, 01 May 2006 00:46:37 PST

( from http://www.rxpgnews.com ) Obesity researchers at the Medical College of Wisconsin in Milwaukee found that a multidisciplinary clinical approach to caring for obese patients with metabolic syndrome could swiftly and significantly lower their risk for heart disease.

The research found that such care could lower their ten-year risk for cardiovascular disease by nearly 20 percent within six months. It will be presented in a poster session, at the American Association of Clinical Endocrinologists Annual Meeting, in Chicago, April 28.

The study was conducted by Safak Guven, M.D., assistant professor of medicine at the Medical College and clinical director of the Obesity/Metabolic Syndrome Clinic at Froedtert Hospital, a major teaching affiliate of the Medical College, in collaboration with the University of Wisconsin School of Pharmacy.

"This study highlights the benefits of a clinic that specializes in the needs of obese patients with metabolic syndrome" says Dr. Guven. "Metabolic syndrome affects approximately 24 percent of the US adult population; according to the Third National Health and Nutrition Examination Survey criteria. About 47 million people have metabolic syndrome, including 44 percent of those who are ages 50 and older. Metabolic syndrome (without type 2 diabetes) significantly increases the risk of coronary heart disease (CHD).

The research could also help establish national clinical standards of care for metabolic syndrome, and accreditation for clinics treating this rapidly emerging problem. "Studies have shown that patients with metabolic syndrome are 1.5 times at greater risk for CHD," says Dr. Guven. "On the other hand, women in reproductive ages with metabolic syndrome are prone to have polycystic ovarian syndrome, which also puts them at risk for fertility issues. In other words, your waistline now has a significant impact on your lifeline."

Metabolic syndrome is a dangerous constellation of problems occurring in abdominally obese, insulin-resistant patients, with or without type 2 diabetes, and having any of several conditions, including cholesterol abnormalities, hypertension, clotting, or inflammatory protein factors in their blood. This leaves them extremely vulnerable to cardiovascular diseases caused by plaque deposits. These include coronary and/or peripheral artery disease and strokes.

The team reviewed charts of over 480 patients treated in the recently-developed obesity and metabolic syndrome clinic at Froedtert Hospital and found 46 obese patients who met the criteria for the study.

Outcomes data on these patients revealed that, after six months of treatment, their collective body mass index dropped 4.4 percent, their waist size 4.3 percent, their triglycerides (harmful fatty acids) dropped 13.1 percent and their HDL (beneficial) cholesterol level rose 6.2 percent. As a result, their ten-year risk of developing cardiovascular disease, based on scoring criteria established by the National Heart Lung and Blood Institutes' landmark Framingham Heart Study,* was reduced by 19.5 percent.

Study warns of growing Metabolic syndrome epidemic in China

Sat, 15 Apr 2006 09:57:37 PST

( from http://www.rxpgnews.com ) As more people in China adopt Western diets and lifestyles, many are developing a cluster of cardiovascular disease risk factors, according to a new study in the April 18, 2006, issue of the Journal of the American College of Cardiology.

"The metabolic syndrome has become increasingly common in this Asian population and the prevalence is about to catch up with that in Western populations. That's a very dangerous sign in terms of cardiovascular disease," said Frank B. Hu, M.D., Ph.D. from the Harvard School of Public Health in Boston, Massachusetts.

The researchers, including lead author Yao He, M.D., Ph.D. from Harvard and also the Chinese PLA General Hospital in Beijing, China, interviewed and examined 2,334 people age 60 years or older who lived in the Beijing metropolitan area. Almost a third to almost half of the participants had metabolic syndrome. Metabolic syndrome is a cluster of five risk factors: central obesity defined by waist circumference, high blood pressure, low HDL ("good" cholesterol), high triglycerides, and high blood sugar.

"There have been some reports from developing countries, including China, on the prevalence of metabolic syndrome, but this is actually the first study to look at the urban elderly population in a systematic way and to document not only the prevalence of metabolic syndrome, but also its relationship with cardiovascular disease," Dr. Hu said.

According to the definition of metabolic disease from the U.S. National Cholesterol Education Program (NCEP), just over 30 percent of the participants had metabolic syndrome. However, 46 percent of the people in this study met the criteria for metabolic syndrome used by the International Diabetes Federation (IDF). The presence of metabolic syndrome was also associated with higher prevalence of cardiovascular disease.

"Using the IDF definition, the prevalence of metabolic syndrome increased substantially, because a lower cut-off point for central obesity was used. And what's interesting is that in this study it appears that metabolic syndrome as defined by the IDF is more strongly correlated with cardiovascular disease, including heart disease, stroke and peripheral artery disease, than the metabolic syndrome defined by the U.S. National Cholesterol Education Program criteria," Dr. Hu said. "This is not surprising given that Chinese people develop diabetes and cardiovascular disease at much lower BMI (Body Mass Index) compared to Caucasians."

Dr. Hu said the findings indicate that as the economy and lifestyles in China become more westernized, people in China are also developing "western" patterns of cardiovascular disease risk.

"So the population is undergoing the transition from under-nutrition to over-nutrition and from underweight to obesity. In the next several decades, I think the obesity problem will get worse and the prevalence of metabolic syndrome and also its consequences, such as diabetes and cardiovascular disease, will continue to increase. This will create a huge burden for the health care system," Dr. Hu said.

Dr. Hu pointed out that this study just took a snapshot of the health of a selected urban population. He said future studies should follow people in China over time to track metabolic syndrome and how well it predicts the development of diabetes and cardiovascular disease.

In the meantime, he urged clinicians to look beyond the diagnosis and treatment of individual risk factors, such as high blood pressure, and instead pay closer attention to preventing and treating the cluster of risk factors that make up the metabolic syndrome.

"Chronic non-communicable disease is increasingly becoming prevalent in China, especially in cities such as Beijing, due to changing of dietary patterns and lifestyle," he said. "The future burden from cardiovascular disease or other chronic disease in China will be substantial."

Dr. Chen pointed out that this study is just a first step toward understanding metabolic syndrome and cardiovascular disease in China.

"This study is relatively small and, as discussed in the paper, it is only a cross-sectional study. A large prospective study in China is needed to assess the relationship between metabolic syndrome and risk of cardiovascular disease mortality and incidence," he said.

Whole grains in diet reduce risk of metabolic syndrome

Tue, 07 Feb 2006 15:26:37 PST

( from http://www.rxpgnews.com ) With the recent revision of the Food Guide Pyramid, the Dietary Guidelines for Americans have for the first time provided the public with a quantitative recommendation for whole-grain intake. In a study published in the January issue of American Journal of Clinical Nutrition, researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (HNRCA) found that consuming a diet rich in whole-grain foods may lower an elderly person's risk for cardiovascular disease and reduce the onset of metabolic syndrome. Metabolic syndrome, which is a collection of risk factors, puts people at an increased risk of cardiovascular disease and type 2 diabetes.

The study, a collaborative effort that included Paul Jacques, DSc, director of the Nutritional Epidemiology Program at the HNRCA, Nicola McKeown, PhD, scientist in the same program, and others, examined the relationship between whole-grain intake and cardiovascular disease risk factors, metabolic syndrome, and the incidence of death due to cardiovascular disease in the elderly.

"Previous studies have found a link between whole-grain intake and reduced risk of metabolic syndrome in middle-aged populations. What's unique about our study," says McKeown, "is that we went back to data that was collected 20 years ago, using diet records that captured food intake, and found that whole-grain foods had a subsequent benefit in the elderly." The ability of researchers to differentiate whole grains from refined grains more accurately through the use of diet records is a major advantage when assessing dietary intake. "In past studies," states McKeown, "fixed food categories have made it difficult to accurately separate whole and refined grains for some food items â such as breads."

According to Jacques, who is also a professor at the Friedman School of Nutrition Science and Policy at Tufts, "consuming a high whole-grain diet is likely to have positive metabolic effects in elderly individuals, who are prone to greater insulin resistance and impaired glucose tolerance."

McKeown and Jacques found that, indeed, as whole-grain intake increased, fasting blood sugar levels were lower in these subjects. Refined grain intake, on the other hand, was associated with higher fasting blood sugar levels. Elevated fasting blood sugar levels can indicate impaired glucose tolerance and the presence of diabetes. In addition, people who consumed high amounts of refined grains had twice the risk of having metabolic syndrome than those people who consumed the fewest servings of refined grains.

"It is important to note," cautions McKeown, "that the subjects in the study were not a representative sample of the elderly, so we do not know the implications of applying these results to other populations. Based on the research, whole-grain intake is one modifiable dietary risk factor that may lead to substantial health benefits at the population level, even among an older population. Older adults should be encouraged to increase their daily intake of whole grain foods to three or more servings a day by substituting whole grains for refined grains."

Chronic stress at work and metabolic syndrome

Fri, 20 Jan 2006 15:18:37 PST

( from http://www.rxpgnews.com ) Stress at work is an important risk factor for the development of heart disease and diabetes, finds a study published online by the BMJ today.

Stress at work has been linked with heart disease, but the biological processes were unclear. This study provides new evidence for the biological plausibility of the link between work stress and heart disease.

Researchers examined the association between work stress and the metabolic syndrome (a cluster of factors that increases the risk of heart disease and type 2 diabetes) in 10,308 British civil servants aged between 35 and 55, over a 14 year period.

Work stress was measured on four occasions between 1985 and 1999. Components of the metabolic syndrome, such as obesity, high blood pressure, and high cholesterol levels, were measured between 1997 and 1999. Social position and health damaging behaviours, such as smoking, heavy alcohol consumption, and lack of exercise, were also recorded.

A dose-response relation was found between exposure to job stress and the metabolic syndrome, even after adjusting for other risk factors. For example, men with chronic work stress were nearly twice as likely to develop the syndrome than those with no exposure to work stress. Women with chronic work stress were also more likely to have the syndrome, but they formed a small group.

Both men and women from lower employment grades were more likely to have the syndrome, confirming previous reports that the syndrome has a social gradient.

The association between the metabolic syndrome and exposure to health damaging behaviours was stronger among men than women. Poor diet (no fruit and vegetable consumption), smoking, heavy alcohol consumption, and physical inactivity were all associated with higher odds of the syndrome.

Despite some study limitations, a dose-response relation exists between exposure to work stress and the metabolic syndrome, even after other risk factors are taken into account, say the authors.

One possible explanation is that prolonged exposure to work stress may affect the nervous system. Alternatively, chronic stress may reduce biological resilience and thus disturb the bodys physiological balance (homoeostasis).

This study provides evidence for the biological plausibility of psychosocial stress mechanisms linking stressors from everyday life with heart disease, they conclude.

Low-carb diet better at improving metabolic syndrome

Wed, 16 Nov 2005 19:24:38 PST

( from http://www.rxpgnews.com ) Diabetes and cardiovascular disease associated with it. In an article published today in the open access journal Nutrition & Metabolism, Jeff Volek and Richard Feinman review the literature and show that the features of metabolic syndrome are precisely those that are improved by reducing carbohydrates in the diet. Metabolic syndrome is a cluster of health signs that may occur together and indicate a risk for diabetes, stroke and heart disease. The markers of metabolic syndrome - high blood pressure, low HDL levels, high triglycerides, obesity, high blood glucose and high insulin levels are all improved by a low carbohydrate diet. By contrast, the evidence shows that they are not improved, and can even be worsened by low fat/high carbohydrate diets.

Previous research has never explicitly connected low carbohydrate intake and improvement of metabolic syndrome. The general recommendation to patients has been to focus on reducing fat intake. Volek et al. argue that the cause of metabolic syndrome is linked to insulin imbalance. Carbohydrates are the main stimulus for insulin, and reducing carbohydrate can be effective at restoring insulin responses. So reducing carbohydrate intake, not fat intake, should be the main aspect of treatment for metabolic syndrome, the authors argue. This is supported by data from previous research, which shows that carbohydrate reduction is more effective than fat reduction at improving all the components of metabolic syndrome.

Genetics affect the severity of metabolic syndrome

Tue, 25 Oct 2005 22:00:38 PST

( from http://www.rxpgnews.com ) Hereditary factors appear to make obese individuals more susceptible to metabolic syndrome, a disorder associated with excess fat around the abdomen that increases the chances of heart disease, stroke and diabetes.

"Our goal is to gain further understanding of the genetic events that contribute to the metabolic syndrome in obese individuals," said co-researcher Dr. Luigi Bouchard, Université Laval. "The knowledge of genes involved in that syndrome may have considerable public health implications."

Dr. Bouchard's research findings will be presented today at the Canadian Cardiovascular Congress, hosted by the Heart and Stroke Foundation of Canada and the Canadian Cardiovascular Society.

More specifically, metabolic syndrome is defined as a cluster of health conditions including: high blood pressure, high levels of blood fats, insulin resistance, abdominal obesity, and low levels of good cholesterol.

Increased death rate associated with obesity can be explained by the presence of several of these health conditions that define metabolic syndrome. However, a significant proportion of obese individuals can escape many of the health conditions defining this syndrome and remain healthy, whereas other obese individuals show little to many of the metabolic complications associated with metabolic syndrome.

The research team, funded by the Canadian Institutes of Health Research (CIHR) through the strategic initiative Obesity and Healthy Body Weight of the Institute of Nutrition, Metabolism and Diabetes, took a novel approach to the study of the severity of the metabolic syndrome in obese individuals. The study compared the gene expression profiles of the fat cells known as 'visceral adipose tissues' found within the abdominal cavity of obese men, with and without the metabolic syndrome.

"Obesity places a substantial burden on the health of Canadians," said Dr. Diane Finegood, Scientific Director, CIHR's Institute of Nutrition, Metabolism and Diabetes. "Understanding the biologic basis for obesity as a risk factor for co-morbidities such as cardiovascular disease and diabetes may lead to important new therapeutic approaches to preventing these devastating diseases."

"The work of Dr. Bouchard and his team could one day help us identify which obese individuals are most at risk of developing serious health complications", said Dr. Jacques Genest, a Heart and Stroke Foundation researcher and spokesperson.

The study found differences in the gene expression profiles between the study groups. Thereafter, a converging genomic approach was used to prioritize and increase our confidence in the proposed genetic targets that will be further studied. This approach compares differentially expressed genes to chromosomal regions that have been found to harbor metabolic syndrome-genes using a genome scan approach. In summary, this study shows that converging genomics is a powerful method to identify target genes for the metabolic syndrome.

"This kind of research is a perfect example of the multidisciplinary research environment encouraged at CIHR," said Dr. Bruce McManus, Scientific Director, CIHR's Institute of Circulatory and Respiratory Health.

Dr. Bouchard will be presented at the Congress with a Heart and Stroke Foundation/sanofi-aventis Fellowship Award for his work.

The Canadian Institutes of Health Research (CIHR) is the Government of Canada's agency for health research. CIHR's mission is to create new scientific knowledge and to catalyze its translation into improved health, more effective health services and products, and a strengthened Canadian health care system. Composed of 13 Institutes, CIHR provides leadership and support to close to 10,000 health researchers and trainees across Canada.

Potential metabolic effects of telmisartan in preliminary studies

Thu, 08 Sep 2005 01:33:38 PST

( from http://www.rxpgnews.com ) Preclinical studies show that the angiotensin II receptor blocker (ARB), Micardis® (telmisartan), has a beneficial effect on metabolic parameters including plasma glucose, insulin resistance and lipid abnormalities, in addition to its proven effect on high blood pressure, due to its partial activation of PPAR-gamma (peroxisome proliferator-activated receptor-gamma).1-4 PPAR-gamma is a hormone receptor known to have an important role in regulating carbohydrate and lipid metabolism, by increasing insulin sensitivity.1-5 High blood pressure, lipid abnormalities, insulin resistance and obesity are key components of metabolic syndrome, a common precursor of cardiovascular disease and type 2 diabetes.6 The implications of these findings were discussed today by leading experts at a meeting in Stockholm, Sweden, coinciding with the European Society of Cardiology Annual Meeting.

These preclinical findings are very exciting and suggest Micardis® may have a uniquely beneficial metabolic effect. We have effective treatments for some of the individual components of metabolic syndrome, such as high blood pressure, but we need to tackle the different risk factors concurrently, Professor Ted Kurtz, University of California, USA, commented. These are very early days but given the major impact of the metabolic syndrome on cardiovascular morbidity and mortality, any treatment that could tackle more than one of the components of metabolic syndrome would provide a huge advantage to patients and physicians in the fight against cardiovascular disease.

The Micardis® molecule is structurally similar to the PPAR-gamma activator, pioglitazone,3 which has been approved for the treatment of type 2 diabetes.7 Micardis® partially activates PPAR-gamma resulting in metabolic effects that differentiate it from other ARBs, according to preclinical data.1-4 These data demonstrate that Micardis® has a beneficial effect on insulin resistance and blood lipids, independent of its effect on the renin-angiotensin-aldosterone system (RAAS).1-4

Studies by Schupp et al and Kurtz et al showed Micardis® is a more potent PPAR-gamma activator compared to other commercially available ARBs.1-2 Furthermore, an in vitro and in vivo study reported by Benson et al showed Micardis® significantly reduced serum glucose levels (p<0<0<0

Possible drug targets for treating metabolic syndrome outlined

Thu, 11 Aug 2005 17:28:38 PST

( from http://www.rxpgnews.com ) Ongoing studies by researchers at UT Southwestern Medical Center and other institutions have uncovered the biochemical basis of many of the factors contributing to what is known as the metabolic syndrome, suggesting potential new drug targets for treating the condition.

The metabolic syndrome, which affects more than 47 million Americans, is a constellation of disorders of the body's metabolism - such as abdominal obesity, hypertension and insulin resistance - that increase one's risk of heart disease, dangerous plaque buildup in artery walls and non-insulin-dependent diabetes.

In a review article in the Aug. 11 issue of The New England Journal of Medicine, UT Southwestern's Dr. David Mangelsdorf, professor of pharmacology and biochemistry, and Dr. Andrew Shulman, a Medical Scientist Training Program fellow, examine how one category of proteins found in the cell's nucleus, called retinoid X receptor heterodimers, are promising novel drug targets for treating the metabolic syndrome.

"Our research has taught us that that these receptors are potentially legitimate therapeutic targets that show great promise," Dr. Mangelsdorf said. "But we also have learned that, as with any drug development, it is going to be a challenge to come up with the right drug or drugs to do the job."

The metabolic syndrome, sometimes referred to as syndrome X, is characterized by multiple risk factors, with the underlying causes being obesity, physical inactivity and genetic factors. The characteristic disorders present in the metabolic syndrome include: excessive fat tissue in and around the abdomen; high blood pressure; insulin resistance or glucose intolerance; blood fat disorders, mainly high triglycerides and low high-density lipoproteins, or "good" cholesterol; and abnormalities in blood clotting.

Any one of these disorders by itself is a risk for certain diseases, but in combination they can dramatically boost one's chances for developing life-threatening illnesses, said Dr. Mangelsdorf, a Howard Hughes Medical Institute investigator.

"One person may have a more severe case of type 2 diabetes, for example, or another person may not have hypertension, yet they may all have the syndrome," he said. "There's not one factor that overrides everything else.

Lipid, or fat, metabolism is an important component, however, and in fact, lipid metabolism may drive the syndrome. The question is, why?"

The answer may lie in research conducted by Dr. Mangelsdorf and others that identified the protein retinoid X receptor, or RXR, which play`s a key role in lipid metabolism. This protein can bind to several other so-called nuclear receptors to form distinct molecular complexes called heterodimers. Each complex then can go on to control certain genes involved in regulating lipid and cholesterol metabolism.

"When RXR is paired with a nuclear receptor called PPAR-gamma, for example, it activates one set of genes," Dr. Mangelsdorf said. "When RXR is paired with another receptor called LXR, it acts on a different set of genes. All of the genes, however, are involved with lipid metabolism."

Drugs that target RXR and its binding partners are already in clinical use or trials for the treatment of cancer, dermatological disorders, endocrine disorders and some aspects of the metabolic syndrome. In their review article, Drs. Mangelsdorf and Shulman outline promising research findings on how drugs that target RXR complexes may be used in the management of the metabolic syndrome.

One of the challenges to developing therapies targeting these receptors is that activating or blocking a given receptor can have both positive and negative effects on the body. The trick, Dr. Mangelsdorf said, is to develop drugs that selectively act on a particular receptor to activate only the good effects while dialing out the bad effects.

For example, activating the LXR receptor, which binds with RXR to modulate cholesterol levels, also has the effect of increasing fat synthesis, which is undesirable, Dr. Mangelsdorf said.

Some drugs that selectively modulate nuclear receptors have already proved successful as cancer drugs. For instance, tamoxifen citrate acts on estrogen receptors to selectively block the activity of estrogen in breast tissue while acting like estrogen in other tissues, where it slows bone loss and lowers blood cholesterol.

Metabolic syndrome increase risk of blocked arteries

Thu, 26 May 2005 18:46:38 PST

( from http://www.rxpgnews.com ) Now, researchers at Cedars-Sinai Medical Center have found that patients with metabolic syndrome and a moderate level of calcium in the coronary arteries had a greater chance of having blockage of those arteries, as detected on a stress imaging test. The findings, reported in the June issue of Diabetes Care, show that analyzing a patient's metabolic profile in relation to their coronary calcium levels will help physicians identify patients who need stress testing so that effective treatment measures can be taken.

"Metabolic syndrome is very similar to diabetes in accelerating heart disease," said Daniel Berman, M.D., the director of Cardiac Imaging at Cedars-Sinai Medical Center and senior author of the study. "Importantly, our findings reveal that patients with the metabolic syndrome who had only moderate amounts of calcium in their coronary arteries had a significantly greater chance of having ischemia too little blood flow to the heart during a stress test."

Coronary calcium indicates the presence of atherosclerosis plaque build-up in the arteries surrounding the heart. The amount of coronary calcium in the arteries, called a calcium score, is measured by using computed tomography (CT) scanning to obtain cross-sectional pictures of the heart and surrounding arteries. Even when patients have no symptoms, their coronary calcium score directly correlates with their long-term risk of cardiac events, such as a heart attack, or sudden death. Calcium scores of zero are the best scores; scores between one and 100 are considered mild and correlate with a low risk for any cardiac event over the ensuing five years. Patients with moderate calcium scores of 100 to 400 are at increased or intermediate risk for cardiac events, and patients with extensive coronary calcium (score over 400) are at even higher risk.

"Although coronary calcium scores provide an excellent measure of plaque build-up in the arteries, the presence of calcium doesn't mean that we will see evidence of ischemia or artery blockage when a patient does a stress test," Berman said. "In most patients, the calcium buildup causes the artery to expand outward, without blocking the vessel, and does not cause ischemia. This occurrence is associated with a low likelihood of a cardiac event over the next few years but a relatively high long-term risk. Regardless, the calcium scan correctly identifies these patients as needing aggressive medical treatment to reduce their risk for a cardiac event, but they don't need to be considered for angioplasty or bypass surgery."

Still, some patients with coronary calcium have arteries that are partially blocked, restricting blood flow to the heart muscle during stress. The most widely used approach to detect blocked coronary arteries is stress imaging, during which patients exercise on a treadmill or, if they can't, are given medication that causes the heart's arteries to dilate. Once the patient reaches "peak" stress, a small amount of radioactive imaging agent is given that concentrates in the heart according to blood flow, emitting signals that are captured by a special type of camera. The cardiac images show the parts of the heart which do not get enough blood flow during stress and is very effective in predicting short-term risk of a cardiac event and determining whether it is necessary to consider angioplasty or surgery at that time.

To test whether the presence of metabolic syndrome might help identify patients at highest risk for coronary artery blockage, the researchers evaluated 1,043 patients without any known heart disease who underwent a coronary calcium scan and stress imaging within a three-month time period. They found that metabolic abnormalities were present in a total of 313 or 30 percent of patients. Among these patients, 140 had diabetes, while 173 had metabolic syndrome without diabetes.

The investigators then compared coronary calcium scores and stress test results of the three groups of patients: those without metabolic syndrome, those with metabolic syndrome, and those with diabetes. They found that 15 percent of metabolic syndrome patients with moderate calcium scores between 100-399 (a level which is generally not considered high enough to require stress testing) had ischemia on stress imaging indicating blocked arteries. Importantly, these patients were also as likely to have these stress test abnormalities as were patients who had extensive calcification but no metabolic abnormalities. Similar findings were observed in patients with diabetes and those with the metabolic syndrome.

When coronary calcium scores were greater than 400, the amount of blockage identified on stress tests among patients with metabolic syndrome was significantly higher compared to those without the disorder, (23.4 percent vs. 13.6 percent). Among patients with calcium scores below 100, only about three percent had artery blockage that was detected by stress testing.

"Our findings suggest that patients' coronary calcium scans need to be interpreted in light of whether or not they have metabolic syndrome or diabetes, in order for us to best determine which patients need to be referred for stress testing. Contrary to previous thinking, our data show that patients with the metabolic syndrome or diabetes deserve earlier stress testing than patients without those metabolic abnormalities," Berman said. "If our findings are confirmed in additional clinical trials, the practice guidelines for stress testing are likely to be changed so that more patients with metabolic syndrome can be stress tested, allowing those with ischemia those who are at highest risk for heart attack to be identified and appropriately treated."

Metabolic syndrome - bad prognosis in MI

Thu, 26 May 2005 02:59:38 PST

( from http://www.rxpgnews.com ) Nearly half of heart attack patients also met criteria for metabolic syndrome, putting them at a higher risk for development of heart failure, according to an article in the May 23 issue of the Archives of Internal Medicine, one of the JAMA/Archives journals.

Metabolic syndrome is a group of risk factors in an individual that may precede type 2 diabetes mellitus, according to background information in the article. The definition for metabolic syndrome includes thresholds for waist circumference, concentrations of triglycerides, high-density lipoprotein (HDL) cholesterol (the "good cholesterol"), fasting blood glucose levels, and elevated blood pressure. A survey found that metabolic syndrome was prevalent in 25 percent of white Americans and 44 percent of people 50 years and older. The effect of metabolic syndrome after acute myocardial infarction (AMI, heart attack) has not yet been studied.

Marianne Zeller, Ph.D., from the University of Burgundy, Dijon, France, and colleagues examined the prevalence of metabolic syndrome in 633 patients hospitalized with AMI. Patients were enrolled if they were 18 years or older and were admitted to the hospital within 24 hours of the onset of heart attack symptoms. Participants were diagnosed with metabolic syndrome if they had three of five criteria: a waist circumference greater than 102 cm (40 inches) in men and 88 cm (35 inches) in women, high triglyceride levels, low HDL cholesterol levels, high blood glucose level, and high blood pressure.

The researchers found that 46 percent (n = 290) of patients met the criteria for metabolic syndrome. Patients with metabolic syndrome were older, more likely to be women, had a more frequent history of previous MI than patients without metabolic syndrome, and had a higher number of cardiovascular risk factors. The metabolic syndrome was associated with worse in-hospital outcomes, and an increased risk of heart failure. Examining the metabolic syndrome criteria independently, the researchers found that hyperglycemia (high blood glucose level) was a major determining factor associated with severe heart failure.

"Our study showed the high prevalence of metabolic syndrome among patients with AMI and highlights the detrimental impact of metabolic syndrome on short-term outcomes, particularly heart failure," the authors write. "Finally, our study suggests that, among metabolic syndrome components, hyperglycemia has the strongest relation to increased incidence of congestive heart failure in patients with metabolic syndrome and MI. Given the ever-increasing prevalence of metabolic syndrome worldwide, this finding has important clinical implications and confirms the importance of evaluating glycemic control during the acute phase of MI."

Effect of Plant Extracts on Metabolic Syndrome to be Investigated

Wed, 04 May 2005 18:16:38 PST

( from http://www.rxpgnews.com ) Rutgers University plant scientists are truly into something hot. They are working with a research laboratory named for the late Tabasco® Pepper Sauce heir, John S. McIlhenny, and built with a gift from the trust he established, the Coypu Foundation. The lab is part of the Pennington Biomedical Research Center, a campus of the Louisiana State University system. At this facility, researchers collaborating with Rutgers colleagues will investigate whether plant extracts can cut risk factors for heart disease, stroke, diabetes or other serious illnesses.

An $8 million, five-year botanical research grant from the National Institutes of Health (NIH) will enable Rutgers plant scientists to collaborate with Pennington researchers in forming the NIH Center for Botanicals and Metabolic Syndrome, one of five newly funded NIH dietary supplement research centers.

Center researchers will study the effects of plant extracts on metabolic syndrome, a collection of risk factors that predispose a person to potentially life-threatening disorders. Common risk factors include obesity, hypertension and high insulin levels. In combination, the risk factors can produce a whole the syndrome that is truly greater than the sum of its parts.

This center is one of five NIH dietary supplement research centers, jointly funded by the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, focusing on studies of botanical products.

With $1.4 million from the NIH grant and matching funds from Rutgers, research will be conducted in the laboratory of Ilya Raskin at the Biotechnology Center for Agriculture and the Environment on Rutgers' Cook College campus.

"We will grow most of the plants and use biochemistry to isolate the bioactive compounds," said Raskin, professor of plant science at Rutgers, The State University of New Jersey, and associate director of the new NIH center. "We will determine which chemical compounds in the plants have therapeutic potential and, with the assistance of the LSU Agricultural Center, learn how to best grow them to produce the highest concentrations of the compounds."

The "Tabasco contingent," led by Pennington's Dr. William Cefalu, NIH center director, will do the medical testing and, in the third and fourth years of the study, conduct the human clinical trials. Pennington, the largest academically based nutrition research center in the world, conducts both clinical and basic research and is acknowledged to be the premier institution in its field.

"Metabolic syndrome represents one of the most important public health problems facing our society as the prevalence is reaching epidemic proportions worldwide," Cefalu said.

The treatment of metabolic syndrome is a particularly promising area for botanicals because the complex syndrome has many different targets. Most botanicals derive their effectiveness from a mixture of active molecules, acting in concert. Multiple agents attacking multiple targets simultaneously present decided advantages over conventional drugs which are each based on one compound that produces one action, Raskin explained. "When you have a complex condition like metabolic syndrome in which so many things can go wrong, it will not be possible to deal with all of them with just one single chemical," he said.

Simple Actions Wipe Out Huge Higher Heart Risks For Asian Diabetics

Mon, 25 Apr 2005 19:40:38 PST

( from http://www.rxpgnews.com ) New research, to be revealed on Tuesday 26th of April at the launch of the University of Warwick Medical School's new Clinical Sciences Research Institute at the University Hospital campus at Walsgrave in Coventry, has shown that very simple interventions to target the health care of UK Asian diabetics can almost wipe out the 40% higher risks of heart disease linked to diabetes in that community.

Warwick Medical School researcher Dr Paul O'Hare will use the launch of the Clinical Sciences Research Institute to outline that diabetes is four times more common in the UK Asian population than it is among Caucasians. Onset of diabetes can also be over a decade earlier among Asian patients and Asian diabetics face a much higher risk of renal and heart complications leading to a 40% higher mortality rate compared with Caucasians.

The researchers also point out that, on top of these increased diabetes risk faced by the Asian population, cultural and communication differences make health care delivery much more challenging for this community group.

The researchers studied what the effect would be of a special effort to target and reach out to the Asian community on the issue of diabetic and related health care. This effort attempted to overcome the health care delivery challenges posed by that community and tried to address the substantially increased health risks they faced in this case. They observed the results of this special pilot package of diabetes health care outreach to over 500 UK Asians in Coventry and Birmingham. The simple package included the use of multi-lingual Asian health workers led by a community diabetes specialist nurse.

The researchers found this approach provided a number of benefits but one of the most significant was an average drop in blood pressure of around 4mmHg in the Asian patients - research has shown that such a drop in blood pressure leads to a 35% reduction in the risk of heart disease. The simple tools of this new pilot outreach effort to the UK Asians had thus, in just one parameter, almost completely wiped out the huge 40% increased risk of heart disease traditionally faced by that community.

The researchers have now scaled their research up to a study of around 2000 people that will consider a wide range of possible diabetes-related health effects and implications for the NHS.