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Licensed pesticide applicators who used chlorinated pesticides on more than 100 days in their lifetime were at greater risk of diabetes, according to researchers from the National Institutes of Health (NIH). The associations between specific pesticides and incident diabetes ranged from a 20 percent to a 200 percent increase in risk, said the scientists with the NIH’s National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute (NCI).

“The results suggest that pesticides may be a contributing factor for diabetes along with known risk factors such as obesity, lack of exercise and having a family history of diabetes,” said Dale Sandler, Ph.D., chief of the Epidemiology Branch at the NIEHS and co-author on the paper. “Although the amount of diabetes explained by pesticides is small, these new findings may extend beyond the pesticide applicators in the study,” Sandler said. Some of the pesticides used by these workers are used by the general population, though the strength and formulation may vary. Other insecticides in this study are no longer available on the market, however, these chemicals persist in the environment and measurable levels may still be detectable in the general population and in food products. For example, chlordane, which was used to treat homes for termites, has not been used since 1988, but can remain in treated homes for many decades. More than half of those studied in the National Health and Nutrition Examination Survey in 1999-2002 had measurable evidence of chlordane exposure. “This is not cause for alarm,” added Sandler “since there is no evidence of health effects at such very low levels of exposure.”

Overall, pesticide applicators in the highest category of lifetime days of use of any pesticide had a small increase in risk for diabetes (17 percent) compared with those in the lowest pesticide use category (0-64 lifetime days). New cases of diabetes were reported by 3.4 percent of those in the lowest pesticide use category compared with 4.6 percent of those in the highest category. Risks were greater when users of specific pesticides were compared with applicators who never applied that chemical. For example, the strongest relationship was found for a chemical called trichlorfon, with an 85 percent increase in risk for frequent and infrequent users and nearly a 250 percent increase for those who used it more than 10 times. In this group, 8.5 percent reported a new diagnosis of diabetes compared with 3.4 percent of those who never used this chemical. Trichlorfon is an organophosphate insecticide classified as a general-use pesticide that is moderately toxic. Previously used to control cockroaches, crickets, bedbugs, fleas, flies and ticks, it is currently used mostly in turf applications, such as maintaining golf courses.

“This is one of the largest studies looking at the potential effects of pesticides on diabetes incidence in adults,” said Freya Kamel, Ph.D., a researcher in the intramural program at NIEHS and co-author in the paper appearing in the May issue of the American Journal of Epidemiology. “It clearly shows that cumulative lifetime exposure is important and not just recent exposure,” said Kamel. Previous cross-sectional studies have used serum samples to show an association between diabetes and some pesticides.

Diabetes occurs when the body fails to produce enough insulin to regulate blood sugar levels or when tissues stop responding to insulin. Nearly 21 million Americans have diabetes. The cause of diabetes continues to be a mystery, although genetics and environmental factors such as obesity and lack of exercise appear to play roles.

To conduct the study, the researchers analyzed data from more than 30,000 licensed pesticide applicators participating in the Agricultural Health Study, a prospective study following the health history of thousands of pesticide applicators and their spouses in North Carolina and Iowa. The 31,787 applicators in this study included those who completed an enrollment survey about lifetime exposure levels, were free of diabetes at enrollment, and updated their medical records during a five-year follow-up phone interview. Among these, 1,171 reported a diagnosis of diabetes in the follow-up interview. The majority of the study participants were non-Hispanic white men.

Researchers compared the pesticide use and other potential risk factors reported by the 1,171 applicators who developed diabetes since enrolling in the study to those who did not develop diabetes. Among the 50 different pesticides the researchers looked at, they found seven specific pesticides — aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor and cynazine — that increased the likelihood of diabetes among study participants who had ever been exposed to any of these pesticides, and an even greater risk as cumulative days of lifetime exposure increased.

All seven pesticides are chlorinated compounds, including two herbicides, three organochlorine insecticides and two organophosphate pesticides.

“The fact that all seven of these pesticides are chlorinated provides us with an important clue for further research,” said Kamel. Previous studies found that organochlorine insecticides such as chlordane were associated with diabetes or insulin levels. The new study shows that other types of chlorinated pesticides, including some organophosphate insecticides and herbicides, are also associated with diabetes. The researchers also found that study participants who reported mixing herbicides in the military had increased odds of diabetes compared to non-military participants.

Genetic variation in the DNA of mitochondria – the “power plants” of cells – contributes to a person’s risk of developing age-related macular degeneration (AMD). The study is the first to examine the mitochondrial genome for changes associated with AMD, the leading cause of blindness in Caucasians over age 50.

“Most people don’t realize that we have two genomes,” said lead author Jeff Canter, M.D., M.P.H., an investigator in the Center for Human Genetics Research. “We have the nuclear genome – the “human genome” – that makes the cover of all the magazines, and then we also have this tiny genome in mitochondria in every cell.”

Canter teamed with Jonathan Haines, Ph.D., and Paul Sternberg, M.D., experts in AMD genetics and treatment, to examine whether a particular variation in the mitochondrial genome is associated with the disease. The genetic change occurs in about 10 percent of Caucasians, referred to as mitochondrial haplogroup T.

“We suspect that this variant will be one of a small group of important genetic variations that underlie AMD,” Canter said. “By knowing this, we have a better chance of predicting accurately who will get the disease.”

AMD affects as many as 10 million people in the United States, robbing them of the sharp central vision necessary for everyday activities like reading, driving, watching television, and identifying faces. The toll of the disease is expected to mount as the U.S. population ages.

The genetics of AMD has been a “hot” area lately, Canter said. Haines led a team that identified a variant in the Complement Factor H (CFH) gene as accounting for up to 43 percent of AMD. Variations in ApoE2 and a gene called LOC387715 on chromosome 10 have also been linked to the disease, and Haines and colleagues demonstrated an interaction between the chromosome 10 gene and smoking in raising AMD risk.

The current study also examined variation in these nuclear genes in 280 cases and 280 age-matched controls, and demonstrated that the mitochondrial genome variation was independent of the known nuclear factors.

“We’re at the stage where we can use genetic information to predict who is likely to develop AMD well before they actually develop it,” said Haines, director of the Center for Human Genetics Research. “Now we can conduct trials of preventive treatments – something’s that never been possible before.”

Sternberg, G.W. Hale Professor and Chairman of the Vanderbilt Eye Institute, is leading a trial to test preventive measures in AMD.

Variation in the mitochondrial genome reflects human migrations and different environmental exposures. Changes in the mitochondrial DNA can alter the efficiency of energy generation and lead to over-production of “reactive oxygen species” – free radicals that can damage the cell.

“By identifying genetic changes associated with the mitochondria, our results lend additional confirmatory evidence for the role of oxidative stress in AMD,” Sternberg said. “This supports study of interventions that attempt to bolster our antioxidant defenses.”

“I can see a day when physicians order genotyping on patients at a certain age to determine risk for AMD and put things in place – dietary changes, antioxidants, increased screening – that could prevent the disease,” Canter added. “This would be truly personalized medicine.”

Canter emphasized that variation in the mitochondrial genome has been linked to a wide variety of diseases including neurodegenerative diseases like Parkinson’s and Alzheimer’s as well as breast cancer and trauma survival.

“It’s important to realize that there’s another genome in the mitochondria, and even though there are not many genes there, they’re important,” Canter said.

Every year, an estimated 700,000 Americans have a first heart attack, with another 500,000 suffering a recurrent attack. About 40 percent of these people die as a result. However, many of these individuals might live if heart attack victims and bystanders recognize symptoms and call 911, said lead author Henraya McGruder, Ph.D., an epidemiologist at the Centers for Disease Control and Prevention (CDC).

In a survey of 33,059 adults, most ages 25 to 64, McGruder and co-authors found that while knowledge of heart attack symptoms is poor within the general population, it is especially poor among African-Americans and Hispanics yet heart attacks are more prevalent among these populations than among whites.

“Our research highlights the importance of targeting these groups with education, so they understand the signs of heart attack and know what to do,” she said. “The key to survival is knowledge and awareness of symptoms, because lifesaving treatments must be given within a certain time window.”

The study appears in the spring issue of the journal Ethnicity and Disease, the journal of the International Society on Hypertension in Blacks.

McGruder and CDC colleagues looked at data from the 2001 National Health Interview Survey, in which participants indicated their awareness of heart attack symptoms and the need to call 911 to get help fast.

Respondents indicated their ability to recognize the following five signs of cardiac distress: (1) chest pain or discomfort; (2) pain or discomfort in the jaw, neck or back; (3) pain or discomfort in arms and shoulders; (4) feeling weak, lightheaded, or faint; and (5) shortness of breath.

“Knowing the signs and symptoms — and knowing to call 911 — will decrease death and disability associated with heart attack,” McGruder said, noting also the importance of traveling to the hospital by ambulance.

“Research suggests that patients arriving by ambulance received quicker care and a shorter time to treatment, compared to those who arrived via personal transportation,” she said.

“This paper certainly adds ammunition to the argument that we need to build more culturally appropriate public information health campaigns,” said Brian Smedley, Ph.D., research director and co-founder of The Opportunity Agenda.

“This paper does an important service in pointing to the need for patient education,” Smedley said. “If we want to reduce the disproportionate burden of heart attack in communities of people of color, however, there are fundamental, structural issues we need to address. We also need sound public policies that can help to ensure that everyone has appropriate access to health care resources.”

One problem, Smedley said, is that many hospitals have closed in minority neighborhoods. Even with increased awareness of the symptoms of heart attack and knowing to call 911, minorities could still face longer travel times to get to an emergency room.

The developing nervous system makes far more nerve cells than are needed to ensure target organs and tissues are properly connected to the nervous system. As nerves connect to target organs, they somehow compete with each other resulting in some living and some dying.

Now, using a combination of computer modeling and molecular biology, neuroscientists at Johns Hopkins have discovered how the target tissue helps newly connected peripheral nerve cells strengthen their connections and kill neighboring nerves.

“It was hard to imagine how this competition happens because the signal that leads cells to their targets also is responsible for keeping them alive, which begs the question: How do half of them die?” says David Ginty, Ph.D., a professor of neuroscience and investigator of the Howard Hughes Medical Institute.

Target tissues innervated by so-called peripheral neurons coax nerves to grow toward them by releasing nerve growth factor protein, or NGF. Once the nerve reaches its target, NGF changes from a growth cue to a survival factor.  In fact, when some populations of nerve cells are deprived of NGF they die.  To further investigate how this NGF-dependent survival effect works the researchers looked for genes that are turned on by NGF in developing nerve cells.

They found hundreds of genes that respond to NGF genes, some of which are involved in enhancing NGF’s effect. With the observation that NGF seems to control genes that improve NGF effectiveness, Ginty’s team hypothesized that this could be the way in which nerve cells compete with one another for survival. To test this idea the team turned to colleagues at the Mind/Brain Institute at Hopkins who specialize in computer modeling of such problems.

The computer model they built assigns each nerve cell its own mathematical equation that take into account how much NGF the cell encounters or how effective NGF can be to simulate a cell’s drive to survive. When they plugged in the model, it showed that over time-about 100 days or so-about half of the cells manage to survive, while the other half die.

But, in the developing mouse embryo, nerve cells that die do so over the course of two to three days just before birth. “So then we considered whether these nerves compete like other systems in the body, where those with stronger connections punish the weaker ones,” says Ginty. The team turned their attention to other genes they found to be NGF dependent; two of which code for proteins that kill neighboring nerve cells and another is the receptor for these death proteins.

According to Ginty, nerves that connect to muscles undergo a similar process called synapse elimination where stronger connections stay connected and weaker ones are eliminated. The team wondered if this is also true of peripheral nerve cells competing for NGF availability and ultimate cell survival.  To test this idea they plugged these three additional genes into their computer model, assuming that the stronger connected nerve cell punishes its neighbors by releasing the two proteins capable of killing. The computer model showed again, that half the nerve cells die over time, but this time the death occurred over two to three days rather than 100 days, just as in living animals.

To confirm that the model is accurate, the team went back to genetically altered mice. They predicted that removal of the punishment signals should delay cell death as observed in their early computer simulations. Indeed, nerve cells in mice lacking the receptor protein for the death signals died much slower than in mice with the receptor protein intact.

“I never would have believed that these three genes could speed up competition so much,” says Ginty. “But there it was in front of us-it was amazing.”

The research was funded by the National Institutes of Health, a Woodrow Wilson Undergraduate Research Fellowship, and the Howard Hughes Medical Institute.

Authors on the paper are Christopher Deppmann,

A recent international study of heart attacks and gender finds women differing from men on everything from symptoms to treatment in both heart attack and severe chest pain.

One of the most striking findings was that women were twice as likely as men to have “normal” or “mild” results on an exam of their heart’s blood vessels, with no single blockage taking up more than 50 percent of any one blood vessel.  This was despite the fact that their other test results showed they were definitely having a heart attack, or a form of chest pain called unstable angina.
The study is being published online today in the journal Heart by a team led by researchers from the University of Michigan Cardiovascular Center. It’s based on data from 25,755 men and women in 14 countries who had a heart attack or chest pain episode between 1999 and 2006, and are included in the Global Registry of Acute Coronary Events.

All of the patients had an angiogram, which allows doctors to see blockages in the heart’s blood vessels – a major cause of heart attacks and chest pain. The lack of serious blockages may have something to do with other differences the researchers found: differences in how women were treated and how well they fared.

In all, among patients with the same level of coronary artery disease, women were significantly less likely than men to receive drugs called beta blockers, statins and ACE inhibitors — all of which are considered crucial to preventing further heart episodes. And no matter how serious their blockages, women were less likely to receive an angioplasty or a stent to open up their blood vessels.

By six months after their heart attack or angina attack, women with more advanced coronary artery disease were more likely than men to have died, or to have suffered another heart attack, a stroke or another problem that sent them to the hospital.

The researchers also found that the symptoms women reported when they first reached the hospital were often different from those the men complained of. While 94 percent of men and 92 percent of women reported they felt chest pain, women patients who didn’t cite chest pain were more likely to experience “atypical” symptoms such as nausea and jaw pain.

“We’ve made great strides in treating women with heart disease, but these data show there’s still much to be done – and that we need to find out whether women might have blockages that are ‘invisible’ on angiograms,” says senior author Kim Eagle, M.D., FACC, the Albion Walter Hewlett Professor of Cardiovascular Medicine.

Eagle, a director of the U-M Cardiovascular Center, is co-chair of the publication committee for GRACE, which was launched in 1999 and funded by unrestricted funds from Sanofi-Aventis. The company has no role in the collection, analysis or publication of data from the GRACE registry, which includes patients from hospitals in North and South America, Europe, the Middle East, Asia, Australia and New Zealand.

Says study co-author Lisa Jackson, M.D., MPH, an assistant professor of cardiovascular medicine at U-M, “We have two education challenges ahead, based on these data: educating women that they should seek immediate attention for both the classic heart attack symptoms and atypical sudden symptoms, and educating physicians that non-obstructive coronary artery disease is still disease and needs to be treated seriously.”

The findings echo data from earlier studies, which have found differences in the symptoms women experience during a heart attack, and the tests and treatments they receive during or after an attack.

The lack of serious blockages, or obstructions, on the angiograms of many women heart attack patients has led experts to suspect that women may have blockages in smaller blood vessels that can’t be seen on conventional angiograms. Or, their blockages may have been fleeting, disappearing before the images can be made.

Either way, these women still have issues serious enough to cause a heart attack or unstable angina, and those issues need to be addressed through preventive treatment, the authors say.

The under-treatment of women – and men – with non-obstructive coronary artery disease may set patients up for more heart attacks and other problems in the future, say Jackson and Eagle. In fact, both women and men with mild obstructions had similar outcomes six months after their heart attack or angina episode.

Part of the problem is that many patients and physicians don’t yet see coronary artery disease for what science has shown it to be: a whole-body problem that must be prevented or managed through lifestyle changes as well as medications and, for emergency cases, treatments such as angioplasty or bypass surgery.

Only through improvements in diet and exercise habits, quitting smoking, controlling blood pressure and blood sugar, and using medication when needed, will people with non-obstructive disease keep themselves from progressing to worse problems, says Jackson, who is part of the Women’s Heart Program at U-M. “We need a more comprehensive, whole-body approach to prevention,” she says.

GRACE, headquartered at the University of Massachusetts Medical School, is now completing two-year follow-up on patients. Analysis of further results will likely yield more insights into differences between men and women in cardiovascular disease. At the same time, Eagle and Jackson are now looking to data from a U-M registry of patients with heart attacks and chest pains to find more clues.

In addition to Eagle and Jackson, the new study’s authors include first author Sujoya Dey, M.D., a clinical lecturer in cardiovascular medicine at U-M, Marcus Flather of the Royal Brompton Hospital in London, Gerard Devlin of the Waikato Hospital in New Zealand, David Brieger of Concord Hospital in Australia, Enrique Gurfinkel of the ICYCC Favaloro Foundation in Argentina, Phillippe Gabriel Steg of Hopital Bichat in Paris, and Gordon FitzGerald of the University of Massachusetts.

Facts about U.S. women and heart disease:

• Every year, 459,000 women die of cardiovascular disease; it’s the leading cause of death for women.
• Every year in the U.S., 365,000 women have a heart attack, and another 180,000 suffer the chest pain of unstable angina. Heart attacks kill 64,200 women each year.
• Previous studies, and the new study published in Heart, have shown differences in how women experience heart disease symptoms, and how they are diagnosed and treated.

Written by: Kara Gavin, University of Michigan Health System

Being resistant to aspirin makes patients four times more likely to suffer a heart attack, stroke or even die from a pre-existing heart condition, according to a recent study. The study relates to patients who are prescribed aspirin long term as a way of preventing clots from forming in the blood.

Patients who are labelled “aspirin resistant” have blood cells (platelets) that are not affected in the same way as those of patients who are responsive to the drug, ie people who are “aspirin sensitive.”

There is currently no agreed method of accurately determining who is and isn’t aspirin resistant and the reasons why someone might be aspirin resistant are currently a cause of controversy.

Relatively few studies have looked at whether aspirin resistance has any impact on clinical outcome so the Canadian authors carried out a review of all the available data to better understand the relationship between the two.

They identified 20 studies, involving 2,930 patients with cardiovascular disease, all of whom had been prescribed aspirin as a way of preventing clots from forming in the blood. 28% were classified as aspirin resistant.

They found that all aspirin resistant patients, regardless of their underlying clinical condition, were at greater risk of suffering a heart attack, stroke or even dying. In particular they found that 39% of aspirin resistant patients compared to 16% of aspirin sensitive patients suffered some sort of cardiovascular event.

They also found that taking other drugs to thin the blood, such as Clopidogrel or Tirofiban, did not provide any benefit to these patients.

The authors conclude that there needs to be further studies on aspirin resistance to identify the most useful test to determine the condition. They also say aspirin resistance: “is a biological entity that should be considered when recommending aspirin as antiplatelet therapy.”

The study was published in the online edition of British Medical Journal.

Intensively targeting blood sugar to near-normal levels in adults with type 2 diabetes at especially high risk for heart attack and stroke does not significantly reduce the risk of major cardiovascular events, such as fatal or nonfatal heart attacks or stroke, but increases risk of death, compared to standard treatment.

Researchers from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) clinical trial compared a medical strategy aimed at near-normal blood sugar levels — below current recommendations — to a strategy to reach more standard blood sugar levels. Supported by the National Institutes of Health, the study evaluated the effects of intensively targeting blood sugar control among adults with established diabetes, high blood sugar levels, and pre-existing heart disease or at least two cardiovascular disease risk factors in addition to diabetes.

In February, 2008, the NIH’s National Heart, Lung, and Blood Institute (NHLBI) stopped the intensive blood sugar strategy after an average of 3.5 years of treatment, instead of the planned 5.6 years, due to safety concerns. The intensive strategy group had a 22 percent higher risk of death — or 54 more deaths — compared to the standard group. The increased risk began emerging within 1 to 2 years after the strategy began to aggressively lower the participants’ blood sugar levels. All participants now follow a medical strategy to reach the standard blood sugar levels while other components of the study continue.

“ACCORD is providing important evidence to help guide treatment recommendations for adults with established type 2 diabetes who have had a heart attack or stroke or who have two or more risk factors for cardiovascular disease in addition to diabetes,” said NHLBI Director Elizabeth G. Nabel, M.D. “For these individuals, intensively lowering blood sugar to near-normal levels appears to be too risky.”

The researchers caution that the results might not apply to patients who are at lower risk of cardiovascular disease than the ACCORD participants or to patients with more recently diagnosed type 2 diabetes. On average, ACCORD participants had been diagnosed with diabetes for 10 years at enrollment.

ACCORD’s ongoing studies of the effects of aggressively lowering blood pressure and treating multiple blood lipids (cholesterol and triglycerides) in high-risk diabetic patients are expected to continue through June 2009.

“Adults with type 2 diabetes are two to four times more likely than adults without diabetes to die from heart disease, so identifying the safest and most effective ways to help them lower their risk of heart disease, stroke, and death is critical,” Nabel noted. An estimated 21 million Americans have diabetes and 284,000 die from it each year. Sixty-five percent of deaths in persons with diabetes are from cardiovascular causes.

Conducted at 77 sites nationwide and in Canada, ACCORD randomly assigned 10,251 participants between the ages 40 and 79 (average age 62) to standard or intensive blood sugar treatment goals. Therapy in both groups included patient education and counseling, and treatment with any of the major classes of Food and Drug Administration-approved diabetes medications, as prescribed by their study clinician: metformin, thiazolidinediones (TZDs, primarily rosiglitazone), insulins, sulfonylureas, exanatide, and acarbose. Combinations of medications could be used as needed to reach the treatment goals.

Hemoglobin A1C levels, a standard measure of average blood sugar levels over the preceding two to three months, were used to monitor participants’ blood sugar. The standard strategy group (5,123 participants) aimed to lower blood sugar levels to an A1C of 7 to 7.9 percent — a target similar to what is achieved, on average, by individuals treated for type 2 diabetes in the United States. The intensive strategy group (5,128 participants) had an A1C blood sugar target of less than 6 percent — similar to that found in adults without diabetes. To join the study, participants needed to have an A1C level of 7.5 percent or higher; at study enrollment, one-half of the participants had an A1C level over 8.1 percent.

Half of the participants in the standard strategy group achieved an A1C less than 7.5 percent, and half of the intensive strategy group achieved an A1C less than 6.4 percent. On average, participants in both groups achieved these levels within the first year of the study and maintained them throughout the study.

After an average of 3.5 years, 257 people in the intensive strategy group died, compared to 203 participants in the standard strategy group. This difference of 54 deaths resulted in a 22 percent increased death rate in the intensive group. Causes of death were similar in each group, with about half from cardiovascular conditions, such as heart attack, sudden cardiac death, stroke, or heart failure. However, the intensive group had 41 more cardiovascular deaths than the standard group, resulting in a 35 percent higher cardiovascular death rate.

“Despite detailed analyses, we have been unable to identify the precise cause of the increased risk of death in the intensive blood sugar strategy group,” noted lead author Hertzel C. Gerstein, M.D., M.Sc. “Our analyses to date suggest that no specific medication or combination of medications is responsible. We believe that some unidentified combination of factors tied to the overall medical strategy is likely at play.” Gerstein holds the Population Health Research Institute Chair in Diabetes and is director of the Division of Endocrinology & Metabolism and Diabetes Care and Research Program at McMaster University and Hamilton Health Sciences, Hamilton, Canada.

To meet their more aggressive targets, participants in the intensive group used more medications, were more likely to use combinations of medications, and changed medications and/or doses of medications more frequently than those in the standard group. For example, 52 percent of participants in the intensive strategy group were on three oral medications plus insulin compared with 16 percent of participants in the standard strategy group. The intensive strategy was associated with more adverse side effects from medications, hypoglycemia (low blood sugar) events, weight gain, and fluid retention.

The researchers also studied whether participants’ characteristics at enrollment had an impact on their outcomes. They compared persons with and without existing cardiovascular disease, women and men, those older and younger than age 65, those with A1C levels lower and higher than 8 percent, and white and non-white participants. Death rates were consistently higher in the intensive strategy group regardless of baseline characteristics. However, compared to participants in the standard group, those in the intensive group who began the study with no history of heart attack or stroke, or with lower blood sugar levels (A1C level 8 percent or less) had fewer combined cardiovascular events — fatal and nonfatal heart attacks or strokes — during the study.

The increased risk of death from the intensive strategy surprised researchers and other experts because earlier studies had shown that blood sugar at near-normal levels was associated with lower cardiovascular disease risk in people with type 2 diabetes. However, these were observational studies, rather than randomized clinical trials, as they did not test treatments to reduce blood sugar. In addition, intensive blood sugar control has been shown in clinical trials to reduce microvascular complications from diabetes — including eye, kidney, and nervous system diseases — in people with type 1 or type 2 diabetes, and to lower cardiovascular disease risk in people with type 1 diabetes. However, the levels tested in other studies were not at as low as the level targeted in the ACCORD intensive treatment group.

The American Diabetes Association’s clinical guidelines recommend that most people with type 2 diabetes reach and maintain an A1C of less than 7 percent. The guidelines also state that treatment should be individualized. For example, a less stringent A1C goal should be considered for people with severe or frequent low blood sugar or with other medical conditions.

“The ACCORD results can now be considered when doctors are tailoring blood sugar strategies for adults with type 2 diabetes who are at especially high risk for cardiovascular disease,” said Denise G. Simons-Morton, M.D., Ph.D., a coauthor and NHLBI project officer for ACCORD.

Future analyses from ACCORD will determine the effects of the intensive blood sugar strategy on microvascular diseases, cognition, quality of life, and other outcomes in the study participants.

ACCORD is primarily funded by NHLBI, with additional funding and scientific expertise contributed by the National Institute of Diabetes and Digestive and Kidney Diseases. Other components of the NIH — the National Institute of Aging and National Eye Institute — as well as the Centers for Disease Control and Prevention, support substudies. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare Inc., GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals, Inc., Novo Nordisk, Inc., Omron Healthcare, Inc., and Sanofi-Aventis U.S.

Source: New England Journal of Medicine,

Many popular diet plans are based on changing the proportion of carbohydrates, proteins, and fats in the diet. There has been some controversy regarding the effectiveness of these diets. A new study accepted for publication in the Journal of Clinical Endocrinology & Metabolism (JCEM) examines the relative ability of different nutrient types to suppress ghrelin, which is secreted by the stomach and is the only known appetite-stimulating hormone. Circulating ghrelin levels increase shortly before meals and then decrease promptly after ingestion of food.

“We found that when fat is consumed, levels of ghrelin remain relatively high, which could in turn stimulate hunger,” said Dr. Karen Foster-Schubert of the University of Washington School of Medicine in Seattle, Washington. “Protein consumption resulted in the greatest suppression of ghrelin over a long period and, interestingly, consumption of carbohydrates resulted in a strong ghrelin suppression initially, although subsequent ghrelin levels rebounded well above baseline.”

Study subjects were given three beverages with widely varying compositions of macronutrients (carbohydrates, fats, and proteins). Blood samples were taken before the first beverage was ingested and every 20 minutes for six hours thereafter. Researchers then measured the ghrelin levels in each sample.

“These findings open the door to future research on the effectiveness of varying methods of dieting,” said Foster-Schubert. “Improving our understanding of the regulation of ghrelin by ingested macronutrients could facilitate rational design of weight-reducing diets.”

Other researchers involved in this study include Joost Overduin, Holly Callahan, and David Cummings of the University of Washington School of Medicine in Seattle, Washington; and Jianhua Liu, Bruce Gaylinn, Michael Thorner, and Catherine Prudom of the University of Virginia in Charlottesville, Virginia.

Source: Endocrine Society

A new study finds that a chemical found in the body is capable of promoting weight loss, improving insulin resistance and reversing diabetes in an animal model. The hormone is gastric inhibitory polypeptide (GIP) receptor blockade.

GIP is a peptide hormone that is secreted in response to food. It inhibits the secretion of acids stimulates the releases insulin as part of the digestive process in response to food. It is found in a variety of tissues, including the intestine, heart, stomach, brain and in adipose (fat).

While the significance of its action is largely unknown, its potent and prolonged stimulation after a high-fat diet has led researchers to speculate it may play a key role in metabolizing fat. Research has shown that high fat feeding results in elevated circulating GIP concentrations, traits often found in patients who are obese with diabetes. GIP also effects the growth of fat cells. Other studies have shown that mice injected with the GIP receptor antagonist – (Pro3)GIP – can reverse or prevent many of the metabolic abnormalities associated with obesity.

The Study: A new study examined whether prolonged GIP receptor antagonism using daily injections of (Pro3) GIP was able to reverse well established diet-induced obesity and related metabolic abnormalities.

Methodology: The researchers used a model for diet-induced obesity that has been used extensively alongside genetic models and has close parallels with obesity, increasingly found in humans who consume a high-fat, energy-rich diet. In this model, young (8-week old) male, age matched mice were age-divided into groups and housed individually in an air-conditioned room at 22±2°C with a 12 hour light: 12 hour dark cycle. Experimental animals had free access to drinking water and a high fat diet (45 percent fat, 20 percent protein and 35 percent carbohydrate; percent of total energy of 26.15kj/g). Age-matched control mice from the same colony had free access to a standard rodent maintenance diet (10 percent fat; 30 percent protein; 60 percent carbohydrate; percent of total energy of 12.99kj/g.). The two were used for comparison purposes.

Prior to the study, mice were maintained on a high fat diet for 160 days. In addition, a separate set of mice were maintained on a high fat diet for 112 days prior to measuring circulating GIP and GLP-1 levels. On both occasions, obesity and diabetes were clearly evident.

The mice which had previously been fed a high fat diet for 160 days received only daily injections of either saline or (Pro3)GIP over a 50-day period. Food intake and body weight were recorded daily while plasma glucose and insulin concentrations were monitored at 5-7 day intervals.

Blood was taken on day 50 to measure cholesterol, triglycerides, glucagon (the hormone involved in metabolizing carbohydrate), corticosterone (involved with carbohydrates in the liver) and circulating adipokines (which play a key role in obesity-related diseases). Glucose tolerance and insulin sensitivity tests were performed at the end of the study period. The metabolic response of both groups of mice was also analyzed.

Key Findings: Highlights of the research findings include the following:

• Compared with the standard rodent diet (control), the mice that were fed the high-fat diet for the previous 160 days exhibited increased body weight, energy intake, and circulating glucose concentrations. The levels remained elevated throughout the study. The cholesterol and triglycerides levels increased at day 50.
• consumption of the high fat diet resulted in progressive weight gain and elevations of plasma glucose and gyrated hemoglobin, leading to impaired insulin sensitivity and glucose intolerance by 10 days. Fat (adipose) tissue deposits were increased as were circulating cholesterol and triglyceride concentration levels.
• (Pro3)GIP was able to counter many of the detrimental effects of high fat diet on body weight and indices of glucose and lipid metabolism.

Conclusion: This study showed that blocking GIP activity using (Pro3)GIP in mice with established, high fat diet-induced obesity and diabetes results in significant weight loss, improvement of insulin resistance and amelioration of diabetes. These findings represent an interesting new approach to the treatment of obesity and metabolic disturbances.

According to the research team’s Nigel Irwin, Ph.D., “Interestingly, possible parallels exist with the benefits of Roux-en-Y surgery (gastric bypass surgery) in treating gross obesity and associated diabetes in people. In this procedure, nutrients surgically bypass the area of the small intestine, resulting in a deficiency of circulating GIP. We are looking to better understand how and why.”

The new study is entitled, “GIP Receptor Antagonism Reverses Obesity, Insulin Resistance, and Associated Metabolic Disturbances Induced in Mice by Prolonged Consumption of High-Fat Diet.” It was conducted by Paula L. McClean, Nigel Irwin, Roslyn S. Cassidy, Victor A. Gault and Peter R. Flatt, all of the School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK; and Jens J. Holst, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark. It is entitled The findings appear in the American Journal of Physiology – Endocrinology and Metabolism

High blood pressure appears to be associated with an increased risk for mild cognitive impairment, a condition that involves difficulties with thinking and learning, according to a report in December issues of Archives of Neurology

“Mild cognitive impairment has attracted increasing interest during the past years, particularly as a means of identifying the early stages of Alzheimer’s disease as a target for treatment and prevention,” the authors write as background information in the article. About 9.9 of every 1,000 elderly individuals without dementia develop mild cognitive impairment yearly. Of those, 10 percent to 12 percent progress to Alzheimer’s disease each year, compared with 1 percent to 2 percent of the general population.

Christiane Reitz, M.D., Ph.D., and colleagues at the Columbia University Medical Center, New York, followed 918 Medicare recipients age 65 and older (average age 76.3) without mild cognitive impairment beginning in 1992 through 1994. All participants underwent an initial interview and physical examination, along with tests of cognitive function, and then were examined again approximately every 18 months for an average of 4.7 years. Individuals with mild cognitive impairment had low cognitive scores and a memory complaint, but could still perform daily activities and did not receive a dementia diagnosis.

Over the follow-up period, 334 individuals developed mild cognitive impairment. This included 160 cases of amnestic mild cognitive impairment, which involves low scores on memory portions of the neuropsychological tests, and 174 cases of non-amnestic mild cognitive impairment. Hypertension (high blood pressure) was associated with an increased risk of all types of mild cognitive impairment that was mostly driven by an increased risk of non-amnestic mild cognitive impairment; hypertension was not associated with amnestic mild cognitive impairment, nor with the change over time in memory and language abilities.

“The mechanisms by which blood pressure affects the risk of cognitive impairment or dementia remain unclear,” the authors write. “Hypertension may cause cognitive impairment through cerebrovascular disease. Hypertension is a risk factor for subcortical white matter lesions found commonly in Alzheimer’s disease. Hypertension may also contribute to a blood-brain barrier dysfunction, which has been suggested to be involved in the cause of Alzheimer’s disease. Other possible explanations for the association are shared risk factors,” including the formation of cell-damaging compounds known as free radicals.

“Our findings support the hypothesis that hypertension increases the risk of incident mild cognitive impairment, especially non-amnestic mild cognitive impairment,” the authors conclude. “Preventing and treating hypertension may have an important impact in lowering the risk of cognitive impairment.”

This study was supported by grants from the National Institutes of Health; the Charles S. Robertson Memorial Gift for Research in Alzheimer’s Disease; and the Blanchette Hooker Rockefeller Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Source: Arch Neurol