Bolstering a Link Between Alzheimer’s Disease and Lead Exposure.


Lifelong hazard. Infants exposed to lead from peeling paint and other sources may be more susceptible to Alzheimer’s-like brain abnormalities as adults, according to a study in macaques spanning 23 years.Shaiith/iStockphoto/Thinkstock; (inset) Paul StevensonLifelong hazard. Infants exposed to lead from peeling paint and other sources may be more susceptible to Alzheimer’s-like brain abnormalities as adults, according to a study in macaques spanning 23 years.

Researchers striving to understand the origins of dementia are building the case against a possible culprit: lead exposure early in life. A study spanning 23 years has now revealed that monkeys who drank a lead-rich formula as infants later developed tangles of a key brain protein, called tau, linked to Alzheimer’s disease. Though neuroscientists say more work is needed to confirm the connection, the research suggests that people exposed to lead as children—as many in America used to be before it was eliminated from paint, car emissions, water, and soil—could have an increased risk of the common, late-onset form of Alzheimer’s disease.

Even in small doses, lead can wreak havoc on the heart, intestines, kidneys, and nervous system. Children are especially prone to its pernicious effects, as it curbs brain development. Many studies have linked early lead exposure with lower IQs. Researchers estimate that one in 38 children in the United States still have harmful levels of the metal in their systems, but evidence linking this exposure to dementia later in life has been tenuous.

A team led by toxicologist Nasser Zawia, however, has vigorously pursued the lead hypothesis. In one early study, from 2008, the group showed that plaques, insoluble globs of a protein called β-amyloid, marred the brains of five macaques that had consumed a lead-enriched formula as infants. The researchers had compared the preserved brain tissues from those macaques, sacrificed in 2003 at age 23 in a National Institutes of Health lab, with four similarly aged monkeys who had had lead-free formula. The amyloid plaques closely resembled those in the brains of adults with Alzheimer’s disease that are thought to contribute to the dementia.

Now, Zawia’s team has used brain samples from the same five macaques that received lead-enriched formula to find clear evidence of another structural change strongly linked to Alzheimer’s: tangles of tau protein. It’s not certain how, or even if, these tangles promote dementia, but when tau proteins decompose into crumpled strands inside a neuron, the cell’s vital transport system can become blocked. The researchers analyzed frontal cortex tissues to show that the lead-exposed monkeys had three times more irregular tau protein in their brain cells than the monkeys who drank normal formula as infants. Moreover, the genetic instructions that assemble the tau proteins were altered, suggesting that early lead exposure epigenetically reprogrammed the monkeys’ DNA.

“This is very strong evidence that early [lead] exposure can determine what happens in old age,” says Zawia, of the University of Rhode Island, Kingston. The team’s results appear in the December issue of NeuroToxicology.

The brain physiologies of macaques and humans are close enough that dementia researchers should pay attention to the findings, says neuroscientist Marc Weisskopf of the Harvard School of Public Health in Boston. “This study adds another important piece to this link between early-life lead exposure and Alzheimer’s-like pathology.”

While Weisskopf says he is “intrigued” that the researchers could find macaques that lived a full life after infant lead exposure, he is cautious. “As far as I can tell, there’s only one group putting this story out,” he says. “We [would] like to see that this is replicable, but that’s hard. It’s just a difficult study to wait that long and have that kind of data.”

Understanding how lead might interfere with DNA’s instructions to promote brain degeneration later in life will take much more work, Weisskopf adds. Correlating the lead exposure of human infants to a disease that doesn’t manifest until people are in their 60s, 70s, and 80s is challenging, he says.

Current lead regulations in the United States should suffice to prevent such long-term neurological harm, Zawia believes. However, children in many other countries still face this hazard—as do adults in the United States who grew up in densely populated areas much more contaminated by lead. “This study is a good indicator to not forget people who were exposed in the past before [lead] awareness and regulations,” he says. “Their risk [of developing dementia] might have been increased.”


Completely Blind People Still Able To React To Light.

Photo credit: gun4hire

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Humans need light for a variety of reasons. Beyond allowing us to perceive our environment with sight, light also activates activity in the brain. A recent study has unexpectedly shown that even individuals who are completely blind are influenced by the presence of light. The presence or absence of light controls many bodily functions, including heart rate, attentiveness, mood, and reflexes. The study will be published in an upcoming edition of Journal of Cognitive Neuroscience. The work is a collaboration between a research team at the University of Montreal and the Brigham and Women’s Hospital in Boston.

The experiment was performed by exposing people who are completely blind to a blue light. The light was turned on and off and the participants were asked whether the light was on or off. The participants were shown to have a non-conscious response to the light, despite not being able to see it. There were more positive identifications made than could be explained by chance alone, though the awareness was non-conscious. This light perception comes from ganglion cells in the retina, which are different from the rod and cone cells that process light for sight.

Next, researchers tested if attentiveness was affected by the presence of light. For this activity, participants had to match sounds with lights on or off. Even though the participants could not visualize the light, they showed an increased attentiveness when light was shining into their eyes.

Finally, the test participants completed a brain scan with functional MRI (fMRI) to measure alertness, memory, and cognition recognition while performing tasks of matching sounds. Across the board, the tasks were completed more efficiently when light was present.

Because of these results, the researchers are speculating that light perception is part of the default mode network. This is the name for the brain activity that occurs non-consciously in the background, while other tasks take priority. They speculate that the ability to perceive light even without actively converting it into images is done to continually pay attention to and monitor the environment. If this is correct, it might help explain why cognitive performance is improved in the presence of light.

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Experimental Drug Shows Promise for Rare Genetic Disorder.

A new medication appears to be highly effective in combating a heredity-based form of the organ-damaging genetic disorder known as amyloidosis, according to researchers.

Amyloidosis refers to a family of more than a dozen diseases in which different types of abnormal proteins called amyloids lodge in major organs and nerves. These amyloids build up to the point that they cause damage and, ultimately, organ failure.


The new therapy caused a marked decline in blood-borne levels of an amyloid protein called transthyretin, or TTR, in 32 patients suffering from amyloidosis during one of the two Phase I drug trials, said the study’s co-author, Dr. Akshay Vaishnaw, chief medical officer for Alnylam Pharmaceuticals, which developed the medication and funded the trials.

“We can dramatically reduce the levels of TTR protein,” Vaishnaw said. “In fact, we can reduce them by 94 percent. One shot a month will produce this reduction.”

The study findings are published in the Aug. 29 issue of the New England Journal of Medicine.

Amyloidosis is a very rare disease. Between 1,500 and 2,500 Americans a year are diagnosed with AL amyloidosis, the disorder’s most common form, according to Harvard Medical School. Heredity-based forms of amyloidosis, most of which are related to transthyretin, are even rarer.

People suffering from TTR amyloidosis eventually become wheelchair-bound as the buildup of abnormal proteins along the nerves causes painful neuropathy in their arms and legs, Vaishnaw said. Transthyretin amyloids also lodge in the heart, causing heart disease that can lead to irregular heartbeat and heart failure.

Nearly all transthyretin amyloids are produced by the liver and, up to now, liver transplant has been the only effective treatment for TTR amyloidosis, Vaishnaw said.

The new medication – tested in the trials in two versions, called ALN-TTR01 and ALN-TTR02 – is delivered via an intravenous infusion and works by inhibiting the genetic process that prompts the creation of transthyretin. Blocking transthyretin production in the liver causes blood levels of the amyloid to drop.

The drug produced no major side effects in the patients tested, Vaishnaw said, noting that one patient did suffer an infusion reaction unrelated to the drug.

“This is a very exciting report, but it’s also a very early report,” said Dr. Raymond Comenzo, director of the Blood Bank and Stem Cell Processing Laboratory at Tufts Medical Center in Boston. “There was clear-cut evidence of safety and of effectiveness in reducing circulating levels of transthyretin.”

However, more research will need to be done to show that the drug not only reduces TTR amyloid levels but also helps improve amyloidosis symptoms in patients, Comenzo added.

“One has to wonder what the road ahead is, how will the clinical development process work its way out,” Comenzo said. “The [U.S. Food and Drug Administration] is going to want to see a benefit that’s measured in terms more than just levels of circulating TTR.”

For example, he added, regulators will want to see a reduction in organ damage or an overall improvement in survival rates.

Vaishnaw said he expects to be able to show those kinds of results, given that previous studies have shown that amyloid deposits will begin flushing from a person’s organs if the levels of amyloid in the bloodstream decrease dramatically.

“It’s allowing the organs to clear the deposits that are already there,” Vaishnaw said. “We’re hoping that over time we’ll allow clearing of the existing deposits, which has been seen in other amyloidosis disorders.”

However, it will likely be years before the medication passes through drug trials and receives FDA approval, he added.


Cocoa, Even With Few Flavonoids, Boosts Cognition.

Drinking cocoa, whether rich in flavonoids or not, appears to boost the effect of blood flow on neuronal activity in the brain, known as neurovascular coupling (NVC).

A new study shows not only that drinking flavonoid-rich or flavonoid-poor cocoa improves NVC but also that higher NVC is associated with better cognitive performance and greater cerebral white matter structural integrity in elderly patients with vascular risk factors.

As researchers search for ways to detect dementia at the earliest possible stage, the study results could pave the way for using NVC as a biomarker for vascular function in those at high risk for dementia, said lead author Farzaneh A. Sorond, MD, PhD, Department of Neurology, Stroke Division, Brigham and Women’s Hospital, Boston, Massachusetts.

“Our study shows that NVC is modifiable and can be enhanced with cocoa consumption,” said Dr. Sorond.

Tight Correlation

The double-blind proof-of-concept study included 60 community-dwelling participants, mean age 72.9 years. About 90% of the participants were hypertensive, but with well-controlled blood pressure, and half had diabetes mellitus type 2 with reasonably good control. Three quarters were overweight or obese.

Participants were randomly assigned to 2 cups a day of cocoa rich in flavonoids (609 mg per serving) or cocoa with little flavonoids (13 mg per serving). Diets were adjusted to incorporate the cocoa, each cup of which contained 100 calories. Participants were also asked to abstain from eating chocolate.

Researchers measured cerebral blood flow in these participants using transcranial Doppler ultrasonography. Among other things, they documented changes in the middle cerebral artery and blood flow velocity at rest and in response to cognitive tasks (NVC).

The study showed that NVC was tightly correlated with cognition; scores for Trail making Test B, a test of executive function, were significantly better in those with intact NVC (89 seconds vs 167 seconds; P = .002). Participants with intact NVC also had significantly better performance on the 2-Back Task, a test for both attention and memory (82% vs 75%; P = .02).

“The higher you increase your blood flow during a cognitive task, the better your cognitive performance,” commented Dr. Sorond, adding that this is something that has never been shown before.

NVC was also correlated with cerebral white matter structural integrity. Higher NVC was associated with overall less white matter macro- and micro-structural damage. In general, those with intact NVC had a greater volume of normal white matter and smaller volume of white matter hyperintensities, higher fractional anisotropy, and lower mean diffusivity in the normal white matter and WMH.

Therapeutic Target

These results suggest that NVC could be an important therapeutic target. But before NVC can be considered a biomarker, it has to be shown to be changeable, and the clinical importance of the modification must be shown.

To that end, the study authors opted to use cocoa. They could have chosen many other potential modifiers but chose cocoa because the literature has shown the beneficial effects of cocoa on brain health and also because it’s something that many people enjoy, said Dr. Sorond.

The study found that blood pressure, blood flow, and change in NVC were not significantly different between the 2 cocoa groups. In the combined cocoa groups, 30-day blood pressures were not significantly different from baseline (P > .5).

In contrast, response to cocoa differed significantly depending on NVC status. Cocoa had a significant effect on NVC in those with impaired (<5%) coupling at baseline. Of those with impaired NVC, 89% responded to 30 days of cocoa consumption and increased NVC compared with only 36% of those with intact NVC (P = .0002). In those with impaired baseline coupling, cocoa consumption was associated with an 8.3% (P < .0001) increase in NVC at 30 days.

The effect of cocoa consumption on Trail B scores was also significantly dependent on NVC status.

The authors were surprised at the lack of effect of flavonoids because previous research had indicated a dose-response with respect to cognitive performance. It could be something other than flavonoids in the cocoa, possibly caffeine, that improves NVC, or it could be that the 13 mg in the low-flavonoid cocoa group was enough to have an effect.

“I think there are effects of flavonol on brain blood flow no matter how low it is,” said Dr. Sorond, adding that perhaps only a tiny amount is needed to activate an enzyme or some other trigger.

It’s important to identify the component or mechanism, whatever it is, because just telling patients to drink cocoa could be risky, said Dr. Sorond. “Patients with diabetes or hypertension really don’t need the extra sugar, extra calories, and extra fat that come with it.”

Dr. Sorond thinks NVC could be measured in high-risk patients seen in the clinic. “I think this could be an easy, in-clinic quick test of vascular brain function that pertains to cognitive performance.”

The ideal next step would be to carry out a larger study in patients with mild cognitive impairment that includes more detailed cognitive profiles and more control groups. “We need a cocoa arm; we need a caffeine arm; we need maybe other arms, to make sure that we understand this, and maybe look at some of the metabolites in the blood as a result of cocoa consumption that correlates with these things,” said Dr. Sorond.

Remarkable First Step

In an accompanying editorial, Paul B. Rosenberg, MD, associate professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, and Can Ozan Tan, PhD, Harvard Medical School, Boston, write that in many ways, the study represents a “remarkable first step.”

For one thing, it demonstrates the practical utility of a simple, inexpensive, and noninvasive technique for measuring NVC that has several advantages over functional MRI and other means of measuring blood brain flow during cognitive tasks.

In demonstrating a link between NVC and cerebral white matter structural integrity, the study provides an important validation for the association between vascular and cognitive function, according to Dr. Rosenberg.

The study demonstrates that NVC “hangs together” as a measure of vascular function, which could be used in studies targeting vascular interventions, said Dr. Rosenberg in an interview with Medscape Medical News. In this way, he added, the study is “promising for the development of new treatments for vascular dementia.”

The study suggests that the vascular effects of cocoa are not due to its flavonol content, noted Dr. Rosenberg.”It could be a placebo effect.”

Dr. Rosenberg pointed out several strengths of the study, including its relatively large size for a pilot study and its “well-chosen” measures.

Among its weaknesses are that it’s not a placebo-controlled study and the hypothesis that flavonoid-rich cocoa would work better than flavonoid-poor cocoa didn’t pan out. The study may also not have been long enough, said Dr. Rosenberg. “It’s nice to see a drug work for 30 days, but you really need a longer study.”

The study didn’t include patients with mild cognitive impairment who are at risk of developing dementia, which Dr. Rosenberg sees as another weakness. “It’s one thing to show an effect in cognitively healthy older people; it’s a very different thing to show an effect in people who have a brain disease,” he said.

The Alzheimer’s Association also sees weaknesses in the study. Not only is it a very small and very preliminary study, but it was also not well designed as a test of an intervention or therapy because it didn’t include a control group for comparison with the group that drank cocoa, said Maria Carrillo, PhD, Alzheimer’s Association vice president of medical and scientific relations.

Further, said Dr. Carrillo, it didn’t appear that other factors that could possibly affect brain blood flow and/or cognition were controlled for, tracked, or accounted for in the study.

“There is no information on what else the 18 people with impaired cerebral blood flow did during the trial that might have improved their cerebral blood flow or cognitive performance: exercise, for example. A well-designed intervention trial anticipates, tracks, and accounts for these possible confounding factors to help ensure the credibility of the findings.”

Source: Neurology


Diet Soda, Aspartame Shown to Destroy Kidney Function.

In an 11-year study by scientists at the Brigham and Women’s Hospital in Boston, there was a strong positive correlation found between degeneration of kidney function and consumption of aspartame-containing diet soda.

Diet Soda, Aspartame Shown to Destroy Kidney Function - Aspartame - Aspartate - Phenylalanine - Methanol
Published in the Clinical Journal of the American Society of Nephrology, the study followed 3,318 women for a number of years as they consumed diet soda containing artificial sweeteners like Aspartame.

cientists took into account each participant’s age, blood pressure, smoking habits (when applicable), and pre-existing conditions like heart disease or diabetes, and administered food frequency questionnaires in 1984, 1986, 1990, 1994, and 1998. Two or more diet drinks daily, it was found, led to a doubled risk in fast-paced kidney decline.

A separate study published in the American Journal of Clinical Nutrition showed that, contrary to safety claims made by the manufacturers of aspartame, health-related concerns including non-Hodgkin lymphoma and leukemia still abound. While study authors at Brigham and Women’s Hospital and Harvard Medical School admitted that there were other variables to consider, such as the sex of the consumer in that particular case, they remained troubled by the risks associated with diet soda.

It’s worth noting that diet soda is also high in sodium—and in greater amounts than found in sodas sweetened with sugar or corn starch (which were not examined in either study).

Corruption: a Brief History of Aspartame

Is diet soda really that bad for you? This is neither the first nor will it be the last time diet soda and artificially sweetened goods will come under fire from the scientific community. The Food and Drug Administration quickly approved aspartame, called “NutraSweet,” in 1974 in use for limited foods, but only after examining studies provided by G. D. Searle Co.. Yes, the inventor of aspartame.

It was only after a research psychiatrist concluded that aspartic acid—a key ingredient in aspartame—made holes in mice brains that the FDA rounded up a task force to investigate Searle’s claims. The investigation unveiled a series of falsified claims, corrupted study results, and information that simply wasn’t there. Although the FDA moved for further investigation of Searle by grand jury, US Attorney Thomas Sullivan and Assistant US Attorney William Conlon didn’t lift a finger to help. Conlon, however, found a job at the law firm representing Searle.

Since then, the genetically modified creation, aspartame, has been implicated in a number of studies aspotentially causing tumors, seizures, brain holes, and reproductive problems. But the mainstream media won’t report on the aspartame-cancer link.

Other Sweeteners, the Good and the Bad

Other artificial sweeteners, like sucralose (supposedly “made from sugar”), have been implicated in other health problems like changing the gut flora environment and preventing proper nutrient absorption, according to the January 2008 issue of the Journal of Toxicology and Environmental Health.

Thus far, Stevia has drawn little fire comparative to artificial sweeteners, although excessive use might be cautioned as with anything. Stevia is, however, safer to use than artificial or GMO sugar, especially for diabetics.

Source: Nature

Nocturnal melatonin secretion associated with insulin resistance

Higher nocturnal melatonin secretion was associated with greater insulin sensitivity and a lower prevalence of insulin resistance in a study analyzing the data of more than 1,000 women without hypertension, type 2 diabetes or obesity, according to researchers.

Previous studies suggest that melatonin may play a role in glucose metabolism, according to Ciaran J. McMullan, MD, of the renal division in the department of medicine at Brigham and Women’s Hospital in Boston, and colleagues.

The researchers measured the main melatonin metabolite, 6-sulfatoxymetaltonin, through urine concentrations to estimate an association between endogenous nocturnal melatonin secretions.

The researchers included women aged 32 to 52 years (n=1,075) from the Nurses’ Health Study II (1997 to 1999) without diabetes, hypertension, or malignancy in their analysis.

According to data, adjustments were made for age, BMI, smoking, physical activity, alcohol intake, dietary glycemic index, family history of diabetes, blood pressure, total cholesterol, uric acid and estimated glomerular filtration rate (eGFR). After these adjustments, the OR for insulin resistance among women in the highest quartile of urinary 6-sulfatoxymelatonin:creatinine ratio was 0.45 (95% CI, 0.28-0.74) compared with women in the lowest quartile, researchers wrote.

These data indicate that higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance.

“Nocturnal melatonin secretion has been shown to be disrupted by sleep disorders. Thus, our finding that lower nocturnal melatonin secretion is associated with insulin resistance may be a potential mechanism explaining the previously described relationship between disruption of normal sleep pattern and incidence of diabetes,” McMullan and colleagues wrote.

However, due to the observational nature of this study, the researchers suggest further studies to confirm this association.

Source: Endocrine Today

Rare Gene Mutations Suggest One More Path to Obesity.

New research suggests that people with rare mutations of a gene linked with regulating metabolism may be highly susceptible to becoming obese.

The gene involved is known as Mrap2 in mice and as MRAP2in humans. It’s expressed predominantly in the brain, in some of the regions that regulate energy balance. The gene encodes a protein that apparently is linked with increasing metabolism and decreasing appetite.


To examine the gene’s effect on weight gain, researchers at Boston Children’s Hospital first inactivated Mrap2 in mice. The mice appeared normal until they were about a month old. Then they started to gain more weight, became excessively hungry, and ate more than their siblings with Mrap2 intact.

Even when their food was restricted to the same amount as their normal siblings, mice with the inactivated gene still gained more weight. They didn’t gain weight at the same rate as their siblings until they ate 10% to 15% less food. Mice with both copies of Mrap2 inactivated gained the most weight, but even mice with 1 working copy of the gene gained more weight and had bigger appetites than the normal mice.

When allowed to eat freely, mice with the inactivated gene ate almost twice as much as their siblings. They had more visceral fat, which surrounds organs deep in the abdomen and is linked with cardiovascular disease, diabetes, and colorectal cancer. They also had more fat in their liver, according to the results published online today in the journal Science

“These mice aren’t burning the fat; they’re somehow holding on to it,” the study’s lead investigator, Joseph Majzoub, MD, said in a statement.

Majzoub, chief of endocrinology at Boston Children’s, noted that he and his collaborators found similar mutations in obese participants in the Genetics of Obesity Study, an international effort to determine why some people become severely obese at a young age. They found 4 rare MRAP2 mutations in 500 obese study participants, all who had 1 working copy of the gene.

Rare MRAP2 mutations lead to obesity in fewer than 1% of people with such severe weight problems, the researchers said. But they suspect that other, more common mutations occur in the gene and may interact with various genetic and environmental factors to cause more widespread forms of obesity. They plan to expand the scope of their research to examine that possibility.



New hormone stimulates pancreatic β-cell proliferation.

Diabetes affects more than 360 million people worldwide and its prevalence is increasing, with 552 million diabetics predicted worldwide by 2030. Scientists recently discovered a hormone that could improve future diabetes management by stimulating replenishment of insulin-producing β cells in the pancreas.

The hormone, which has been named betatrophin, was discovered in studies of a mouse model of severe insulin resistance in which chemical blockade of insulin receptors induced pancreatic β-cell proliferation. Betatrophin was identified in murine liver and fat, and its stimulatory effect on cellular replication was limited to β cells. Its expression was also reported in human liver tissue.

Betatrophin treatment of mice increased proliferation of pancreatic β-cells by an average of 17-fold within a few days, causing an expansion of β-cell mass and increased insulin concentrations in the pancreas.

Betatrophin’s discovery “is a very exciting new development, and is only the beginning of the story”, says C Ronald Kahn (Joslin Diabetes Center, Boston, MA, USA). He adds that unanswered questions include whether “action on islets is direct or indirect. We don’t know how betatrophin works; is it only one growth factor or one of many? There is a lot of future work to be done”.

Senior author Douglas Melton (Harvard University, Cambridge, MA, USA) said: “It’s not often that one finds a new hormone, so it opens up all kinds of possibilities for new treatments”.

The most immediate application for betatrophin is for the “millions of prediabetics who are on their way to getting type 2 diabetes. If these individuals still have β cells, this hormone could give them more β cells and alleviate the need for insulin injections”, Melton continued. Betatrophin may also prove beneficial in type 1 diabetes, which is initiated by an autoimmune process. “If the disease is just starting, one could give an immunosuppressant and this hormone to forestall the onset of type 1 diabetes.”

Melton cautions that results from human studies should not be expected quickly. “We are currently working with our collaborators Evotec and Janssen to make the human betatrophin protein. This will take more than a year.” Results from studies in humans might be available “2—3 years from now, if all goes well”.

Source: Lancet

Fat Cells Feel the Cold, Burn Calories for Heat.

Transforming fat cells into calorie-burning machines may sound like the ultimate form of weight control, but the idea is not as far-fetched as it sounds. Unexpectedly, some fat cells directly sense dropping temperatures and release their energy as heat, according to a new study; that ability might be harnessed to treat obesity and diabetes, researchers suggest.


Fat is known to help protect animals from the cold—and not only by acting as insulation. In the early 1990s, scientists studying mice discovered that cold temperatures trigger certain fat cells, called brown adipose tissue, to release stored energy in the form of heat—to burn calories, in other words. Researchers have always assumed this mechanism was an indirect response to the physiological stress of cold temperatures, explains cell biologist Bruce Spiegelman of Harvard Medical School, Boston. The activation of brown fat seems to start with sensory neurons throughout the body informing the brain of a drop in temperature. In response the brain sends out norepinephrine, the chief chemical messenger of the sympathetic nervous system, which mobilizes the body to cope with many situations. In experimental animals, stimulating norepinephrine receptors triggered brown adipose tissue to release its energy and generate heat, while animals bred to be missing these receptors were unable to mount the same fat cell response.

People also have brown adipose tissue that generates heat when the body is cold. And unlike white fat, which builds up around the abdomen and contributes to many disorders including heart disease and diabetes, this brown fat is found in higher proportions in leaner people and seems to actively protect against diabetes.

In brown fat, the heat-generating process depends on a protein called UCP1; the protein is also thought to be central in brown fat’s ability to prevent diabetes. Researchers are now exploring ways of activating this molecular pathway. But in trying to figure out exactly how fat cells respond to the body being cold, Spiegelman and colleagues discovered that plain old “white” fat cells have a few surprises left. In a study appearing online today in the Proceedings of the National Academy of Sciences, the researchers exposed various kinds of fat cells to cold temperatures directly. “We were a little surprised that no one had tried this before,” Spiegelman says.

The researchers cooled several types of lab-grown human fat cells—brown, white and “beige” (white adipose tissue with some brown cells mixed in)—to temperatures between 27˚ and 39˚C for four hours, eight hours, or up to ten days. White fat cells and beige cells responded to cooling in dramatic fashion. In these cells, levels of the UCP1 were doubled by 8 hours after the treatment. The change in UCP1 also proved to be reversible: Its levels returned to normal once the cells’ temperature was lowered to 37 degrees. But in brown fat cells, no induction of the protein was observed, indicating that cold temperatures don’t mobilize these cells by flipping this particular switch.

The researchers also found that white fat cells obtained from mice lacking receptors for norepinephrine were still able to respond to cooling by turning on UCP1—showing that the heat-generating pathway is both specific to those fat cells and independent of the sympathetic nervous system .

The finding won’t lead to an antifat pill any time soon, Spiegelman says, but it does give scientists new avenues to explore. “It’s a piece of the basic science, adding to an evolving awareness that fat cells have many lives that we never knew about. Now we know they can sense temperature directly. The next question is, how do they do it, and can that ability be manipulated?”

“The paper is filling in an emerging picture that adipose tissue can be a more flexible, adaptive organ than we once thought,” says Sven Enerbäck, a physician and adipose tissue researcher at the University of Gothenburg in Sweden. “The finding raises the question of whether this new pathway has widespread effects on the animal as a whole.”

Finding that white fat cells directly detect and react to cold is a surprising development, notes cell biologist Peter Tontonoz of the University of California, Los Angeles, because it shows that the sympathetic nervous system isn’t the whole story when it comes to heat generation by adipose tissue. He’s curious whether the heat-generating pathway in white fat is a routine part of everyday temperature regulation. “Even if it isn’t,” he adds, “it could still be targeted by small molecules or other drugs.”




HbA1c Inadequate to Assess Diabetes Care Across Specialties.

New findings suggest that simply using HbA1clevels to assess the performance of individual physicians or healthcare systems in diabetes management may be misleading or inaccurate.

Endocrinologists typically see more complex patients who require more time to improve their glycemic control, which makes their performance look worse when judged solely by HbA1c levels.

But new data reported here at the American Diabetes Association 2013 Scientific Sessions show that when diabetes patients are grouped by medication use — a proxy for complexity and stage of disease — HbA1c levels for patients cared for by endocrinologists are the same as or better than those for individuals seen by general internists.

Lawrence S. Phillips, MD, professor of medicine in the division of endocrinology at Emory University, Atlanta, Georgia, who reported the findings in a poster at the meeting, said looking at patients by medication group shows there is very little difference between the performance of specialists and generalists.

“The message is really for the payers and the government… They need to do something like this. They need to have some conservative way to give the provider a chance to improve things, and then they need to compare apples to apples. Just looking at A1c is not sufficient,” Dr. Phillips told Medscape Medical News.

Poster session moderator Sanjeev Mehta, MD, MPH, director of quality at Joslin Diabetes Center, Boston, Massachusetts, agrees. “Dr. Phillips’s data demonstrated that endocrinologists, in the practice setting he evaluated, were seeing patients with higher HbA1c levels. While this suggests appropriate referrals by primary-care physicians to optimize glycemic control, it also supports Dr. Phillips’s conclusion that an outcome-based quality measure [such as HbA1c] may be inadequate when assessing the quality of diabetes care across all providers, especially endocrinologists,” he said.

Dr. Mehta noted that the Agency for Healthcare Research and Quality (AHRQ) has endorsed theadoption of more sophisticated quality metrics, including linked action measures such as appropriate medication use, which would assess outcomes in the context of the care provided.

“I strongly believe this is the direction that all stakeholders in the diabetes community need to be [following to evaluate] high-quality diabetes care,” he told Medscape Medical News.

Comparing Apples to Apples Is Best Approach

Dr. Phillips and colleagues obtained Emory Healthcare data for a total of 5880 diabetes patients cared for by 8 endocrinologists and 8 general internists over a 24-month period. The proportion of patients whose most recent HbA1c was 7% or above was higher for the endocrinologists than for the general internists, 51% vs 38%.

Subsequent analysis was restricted to the 3735 patients who had been seen 3 or more times in the past 24 months and at least once in the prior 12 months. This group was divided into 3 groups by medication use: Those using only oral medications and/or incretin-based drugs (1880), those using basal insulin (with or without oral medications/incretins, 324), and those also using mealtime insulin in addition to basal insulin, with or without other medications (1531). The latter group included patients with type 1 diabetes, Dr. Phillips told Medscape Medical News.

Overall control was poorer among the insulin-using patients, with HbA1c levels of 7% or higher in 66% of those using mealtime insulin and 55% of individuals using basal insulin, compared with just 21% of those not using insulin (P < .0001 for trend). And endocrinologists had more patients on insulin than did the general internists, with 53% vs 22% using mealtime insulin (P < .0001), 10% vs 7% using basal insulin (P = .02), and 37% vs 71% not using insulin (P < .0001), respectively.

When examined by treatment group, however, the non–insulin-using patients of the endocrinologists actually had better HbA1cs: 18.8% of their patients had levels at or above 7% vs 23.4% of the general internists’ patients.

For the 2 insulin treatment categories, there was no significant difference between the endocrinologists and the internists. In both groups, just over half of the patients had HbA1cs 7% or above (= .6) as did about two thirds of those using mealtime insulin (= .9).

New Models Needed for Evaluating Care

Dr. Mehta told Medscape Medical News:”I think this poster highlighted the importance of adopting more sophisticated quality metrics, such as linked action measures, and the importance of ongoing collaboration with specialists and specialty centers in the care of adults with diabetes.

“Specialists and specialty centers may have an opportunity to translate best practices to their referring primary-care physicians, who will continue to care for the majority of adults with diabetes in the United States,” he added.

And specialists should be rewarded, not penalized, for their particular patient mix. “Those providers and practices that care for more complex patients need to be recognized, even reimbursed, for their ability to make meaningful improvements in health outcomes in high-risk patients,” he observed.

Dr. Phillips told Medscape Medical News that “diabetes is a heavy-duty proxy for healthcare systems as a whole, because a lot of people have diabetes, and it’s an expensive disease.”

He believes his “apples-to-apples” comparison could have implications for other areas of medicine as well. “I think it’s an important concept. You would think it applies to blood pressure, cholesterol, all the things that doctors do. We think this is a model for how you evaluate care.”