Endocannabinoids trigger inflammation that leads to diabetes


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For Immediate Release: Monday, August 19, 2013

NIH scientists identify possible treatment target for type 2 diabetes

Researchers at the National Institutes of Health have clarified in rodent and test tube experiments the role that inflammation plays in type 2 diabetes, and revealed a possible molecular target for treating the disease.
The researchers say some natural messenger chemicals in the body are involved in an inflammatory chain that can kill cells in the pancreas, which produces insulin.

A report of the finding appears online in Nature Medicine.

“This study is a significant milestone in an ongoing exploration of the endocannabinoid system’s role in the metabolic complications of obesity,” says Kenneth R. Warren, Ph.D., acting director of NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA), which led the study.

Endocannabinoids are natural messengers in the body that help regulate many biological functions. They are chemically similar to the active compound in marijuana. Recent studies have tied endocannabinoids to the metabolic problems that lead to diabetes.  Researchers also have recognized that inflammation appears to play an important role in the pathology of diabetes. 

“The identities of the molecular and cellular actors in the inflammatory processes that underlie type 2 diabetes have remained elusive,” explains senior author and NIAAA scientific director George Kunos, M.D., Ph.D.  “Our study connects endocannabinoids to an inflammatory cascade leading to the loss of beta cells in the pancreas, which is a hallmark of type 2 diabetes.”

Working with a strain of genetically obese rats that serve as a model for human type 2 diabetes, Dr. Kunos and his colleagues used a combination of pharmacological and genetic tools to show that endocannabinoids trigger receptors on macrophages in the pancreas.  Macrophages are immune system cells, present in all tissues that rid the body of cellular debris and pathogens.

“Like various other peripheral tissues, such as the liver, skeletal muscles, pancreas, and fatty tissue, macrophages have receptors for endocannabinoids,” explains Dr. Kunos.

The researchers demonstrated that endocannabinoid activation of macrophages in the pancreas leads to activation of a protein complex within macrophages called the Nlrp3 inflammasome.  The inflammasome, in turn, releases molecules that cause the death of pancreatic beta cells and the progression of type 2 diabetes in the rats.

“When we treated the rats with compounds that deplete macrophages or block all peripheral cannabinoid receptors, inflammasome activation and type 2 diabetes progression was slowed,” noted Dr. Kunos.

In test tube experiments, the researchers showed that macrophages from humans and mice produced the same inflammasome response when they were incubated with endocannabinoids.  However, mouse macrophages that were genetically altered to lack cannabinoid receptors or inflammasomes generated no such response.

Most notably, the researchers showed that by selectively blocking the expression of cannabinoid receptors on macrophages, they could protect and restore beta cell function in the genetically obese rats, which delayed the development and reduced the severity of their diabetes.

The authors conclude that the findings point to a key role in type 2 diabetes for endocannabinoid-induced inflammasome activation in macrophages, and identify cannabinoid receptors on macrophages as a new therapeutic target.

“To understand type 2 diabetes, a public health threat that affects young and old alike, we need to consider all the factors at play,” said Monica Skarulis, M.D., staff clinician at National Institute of Diabetes and Digestive and Kidney Diseases and co-author. “We hope that what we’ve learned from this research will help us develop new strategies to prevent and treat the condition.”

In addition to Dr. Kunos’ team of NIAAA scientists and Dr. Skarulis, co-authors on the study included researchers from the University of Colorado Medical Campus, Aurora, and the University of Massachusetts Medical School, Worcester.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at http://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Jourdan, T, et al. Nature Medicine. 2013 August 18. [Epub ahead of print]


Type 2 Diabetes More Common Among Low-Income Families

Diabetes Finger Blood Test

CREDIT: Jim Delillo | Dreamstime

Being born into a low-income family may mean worse health later in life. Research has shown that those with low incomes are more likely to develop Type 2 diabetes than their richer peers, but the reason for this link has remained unclear.

Now, a new study finds that inflammation may be the key behind this connection, and that genetics plays a role.

“We’ve shown … there might be a link going from socioeconomic status to inflammation, through gene regulation, and that finally leads to increased risk of diabetes,” said lead author Silvia Stringhini, of the University Hospital of Lausanne in Switzerland.

Type 2 diabetes, which tends to develop in adults rather than children, occurs when body cells stop responding to insulin and become unable to use sugar in the blood.

The condition has been linked to excess weight and physical inactivity, but studies have shown that people who experienced socioeconomic adversity during their childhood tended to have a higher risk of developing this disease later in life, even when they didn’t suffer from obesity and an unhealthy diet. Stringhini and her team wanted to determine why  childhood poverty would have such a far-reaching effect.

The researchers used data from the Whitehall II study, which tracked clinical and social information from more than 10,000 people in London between 1991 and 2009. Every six years, all participants took an oral glucose test, and the researchers tracked which people developed Type 2 diabetes. They also took blood samples to measure key inflammatory proteins in the blood. To gather socioeconomic data, the researchers asked participants their job title, how much education they had and their father’s occupation. [How Inflammation Affects Your Health]

Participants who had overall low socioeconomic scores were almost twice as likely to develop Type 2 diabetes over the course of the study than those whose scores were high. Furthermore, people whose life trajectories either started or ended in a lower class had an increased risk of developing diabetes as adults.

While this finding may not be immediately surprising, Stringhini pointed out that typical diabetes risk factors, such as being overweight, physically inactive and eating poorly “explain about half of the socioeconomic status differences in the Type 2 diabetes,” she said.

The other half was tied to inflammation, regardless of a person’s weight or physical activity. People who had more disadvantaged lives overall had chronically higher levels of inflammatory proteins in their blood.

While obesity, lack of exercise, smoking and poor diet certainly contribute to chronic inflammation, the study points out that these lifestyle factors aren’t the only culprits.

“The stress related to financial adversity — that of living in poor, unsafe and polluted neighborhoods, experiencing more stressful life events, or experiencing abuse and violence — [may contribute to] an exacerbated inflammatory responses in adult life,” Stringhini said.

This discovery may point to new approaches to tackling the growing problem of Type 2 diabetes. “While this does not mean that we should stop trying to improve lifestyle behaviors in the most disadvantaged sections of society, we might try to recommend medications targeting directly inflammation,” Stringhini said.

Other experts are not so sure. “Type 2 diabetes is a very complex disease,” said Dr. Joel Zonszein, professor of clinical medicine at Albert Einstein University in New York.

“There is no question that it is an inflammation-based disease,” Zonszein said. But, he cautioned that the analysis of the data in the new study was not definitive enough to conclude that inflammation was a cause of Type 2 diabetes. “There is an interrelationship, but I don’t believe it’s a cause-and-effect relationship.”

More research is needed to determine the role of inflammation in Type 2 diabetes, he said.

The study is published today (July 2) in the journal PLoS Medicine.

Follow LiveScience @livescience, Facebook  Google+. Original article on LiveScience.com.

White blood cell enzyme contributes to inflammation and obesity

Imbalance between an enzyme called neutrophil elastase and its inhibitor causes inflammation, obesity, insulin resistance, and fatty liver in mice and humans—providing a new therapeutic target for these health conditions

Many recent studies have suggested that obesity is associated with chronic inflammation in fat tissues. In a new study, researchers discovered that an imbalance between an enzyme called neutrophil elastase and its inhibitor causes inflammation, obesity, insulin resistance, and fatty liver disease. This enzyme is produced by white blood cells called neutrophils, which play an important role in the body’s immune defense against bacteria.

The researchers found that obese humans and mice have increased neutrophil elastase activity and decreased levels of α1-antitrypsin, a protein that inhibits the elastase. When the team reversed this imbalance in a mouse model and fed them a high-fat diet, the mice were resistant to body weight gain, insulin resistance (a precursor to type 2 diabetes), and fatty liver disease. Their study appears April 2 in Cell Metabolism.

“The imbalance between neutrophil elastase and its inhibitor, α1-antitrypsin, is likely an important contributing factor in the development of obesity, inflammation, and other health problems. Shifting this balance—by either reducing one or increasing the other—could provide a new therapeutic approach to preventing and treating obesity and several obesity-related conditions,” said Zhen Jiang, Ph.D., assistant professor at Sanford-Burnham and senior author of the study.

What happens when you reduce neutrophil elastase levels

This study began when Jiang and his team noticed that neutrophil elastase levels are particularly high and α1-antitrypsin levels are low in a mouse model of obesity. Then they saw the same thing in blood samples from human male volunteers.

To further probe this curious neutrophil elastase-obesity relationship, the researcher turned once again to mouse models. They found that mice completely lacking the neutrophil elastase enzyme don’t get as fat as normal mice, even when fed a high-fat diet. Those mice were also protected against inflammation, insulin resistance, and fatty liver. The same was true in a mouse model genetically modified to produce human α1-antitrypsin, which inhibits neutrophil elastase.

Normal mice on a high-fat diet were also protected against inflammation, insulin resistance, and fatty liver when they were given a chemical compound that inhibits neutrophil elastase. This finding helps validate the team’s conclusions about neutrophil elastase’s role in inflammation and metabolism and also suggests that a medicinal drug could someday be developed to target this enzyme.

Mechanism: how neutrophil elastase influences inflammation and metabolism

How do high neutrophil elastase levels increase inflammation and cause weight gain and other metabolic problems?

Jiang and his team began connecting the mechanistic dots. They discovered that neutrophil elastase-deficient mice have increased levels of several factors, including adiponectin, AMPK, and fatty acid oxidation. These are known for their roles in increasing energy expenditure, thus helping the body burn excess fat.


This research was funded by a Sanford-Burnham start-up fund, the American Diabetes Association (grant 7-11-BS-72), U.S. National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK094025), and U.K. Medical Research Council (grant U117512772).

Original paper:

Mansuy-Aubert, V., Zhou, Q., Xie, X., Gong, Z., Huang, J., Khan, A., Aubert, G., Candelaria, K., Thomas, S., Shin, D., Booth, S., Baig, S., Bilal, A., Hwang, D., Zhang, H., Lovell-Badge, R., Smith, S., Awan, F., Jiang, Z. (2013). Imbalance between Neutrophil Elastase and its Inhibitor α1-Antitrypsin in Obesity Alters Insulin Sensitivity, Inflammation, and Energy Expenditure Cell Metabolism, 17 (4), 534-548 DOI: 10.1016/j.cmet.2013.03.005


Literature Review Shows Inflammation Links Obesity and Gum …

Newswise — Blood on your toothbrush can be a warning sign of gum disease. And, if you are overweight, it can indicate other serious health issues, such as diabetes, heart disease and high blood pressure.

Don’t wait. Get to the dentist, advise two faculty members from Case Western Reserve University School of Dental Medicine’s Department of Periodontics Charlene B. Krejci, DDS, MSD, and Nabil F. Bissada, DDS, MSD.

After reviewing previous research on gum disease and obesity, they found an association between both health problems, which they describe in the Journal of General Dentistry article, “Obesity and periodontitis: a link.”

“Healthcare professionals need to be aware of the complexity of obesity and the role periodontitis has in overall health,” said Bissada, professor and chair of the Department of Periodontics.

Periodontitis, commonly called gum disease (and gingivitis in its milder form), affects nearly half the U.S. population over age 30, according to the American Academy of Periodontology. The disease ignites an inflammatory response as the body begins to fight off bacteria present in the dental plaque. If not treated, the inflammation eventually erodes the jawbone and loosens teeth. In severe cases, patients lose their teeth. The bacteria can also cause ulcers in the pocket surrounding the involved teeth and eventually enter the blood and settle in other parts of the body.

Being overweight can compound the problem, the researchers warn. Belly fat contains about 50 bioactive substances, which can set off inflammatory responses that reduce the body’s ability to suppress appetite or use insulin to regulate glucose levels—both of which are linked to diabetes.

Adipose tissue (fat) can also increase production of the C-reactive protein (CRP) involved in the inflammation process and linked to cardiovascular disease.

Bissada first reported the obesity and gum disease link from animal studies in 1977. Several studies have since verified this link in humans.

“Whether gum disease or obesity came first is yet to be determined,” said Krejci, an associate clinical professor at the school of dental medicine who also has a private practice. “What has emerged from the literature is that the association between obesity and gum disease is chronic inflammation.”


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Diabetes may originate in your gut

Scientists have suggested that problems controlling blood sugar – the hallmark of diabetes – may begin in the intestines.

The finding may upend long-held theories about the causes of the disease. Because insulin is produced in the pancreas and sugar is stored in the liver, many scientists have looked to those organs for the underlying causes of diabetes.

In the new research, scientists at Washington University School of Medicine in St. Louis studied mice that are unable to make fatty acid synthase (FAS) in the intestine.

FAS, an enzyme crucial for the production of lipids, is regulated by insulin, and people with diabetes have defects in FAS. Mice without the enzyme in the intestines develop chronic inflammation in the gut, a powerful predictor of diabetes.

“Diabetes may indeed start in your gut,” said principal investigator Clay F. Semenkovich, MD.

“When people become resistant to insulin, as happens when they gain weight, FAS doesn’t work properly, which causes inflammation that, in turn, can lead to diabetes,” he explained.

First author Xiaochao Wei, PhD, and Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, collaborated with specialists in gastroenterology and genome sciences to determine what happens in mice that can’t make FAS in their intestines.

“The first striking thing we saw was that the mice began losing weight. They had diarrhea and other gastrointestinal symptoms, and when we looked closely at the tissue in the gut, we found a lot of inflammation,” stated Wei, a research instructor in medicine.

Wei explained that the mice got sick because of a defect in fatty acid synthase. The mice without fatty acid synthase had lost the protective lining of mucus in the intestines that separates the microbes from direct exposure to cells. This allowed bacteria to penetrate otherwise healthy cells in the gut, making the mice sick.

In a further collaboration with Nicholas O. Davidson, MD, director of the Division of Gastroenterology, the researchers found gastrointestinal effects resembling some features of inflammatory bowel disease. Other investigators studying humans with ulcerative colitis had previously made the unexplained observation that colon biopsies from these patients have low amounts of fatty acid synthase.

“Fatty acid synthase is required to keep that mucosal layer intact. Without it, bad bacteria invade cells in the colon and the small intestine, creating inflammation, and that, in turn, contributes to insulin resistance and diabetes,” Wei added.

Inflammation and insulin resistance reinforce each other. Inflammatory substances can cause insulin resistance and inhibit the production of insulin, both of which interfere with the regulation of blood sugar. In turn, insulin resistance is known to promote inflammation.

Further study showed that the ability to build the thin, but important, layer of mucosal cells was hindered by faulty FAS.

That the gut is so important to the development of diabetes makes sense because many people with the condition not only have faulty FAS, but they also frequently develop gastrointestinal difficulties, Semenkovich continued.

“Abdominal pain and diarrhea are some of the most common problems we see in people with diabetes. We could only connect these ‘dots’ because other experts at the university could help us link what we observed in these mice to what occurs in patients with diabetes and inflammatory bowel disease,” he said.

Semenkovich and Wei say much more study is needed, but they say that FAS and a key component of the intestinal mucosa called Muc2 may be potential targets for diabetes therapy. They now plan to study people with diabetes to see whether FAS is altered in a similar way, producing damage to the mucosal layer in the intestines.

The findings have been reported in the journal Cell Host and Microbe.

Radiotherapy ups the risk of cardiovascular disease

A recent study has found that radiotherapy, which is used for treating cancer, increases the chances of cardiovascular disease. According to www.medicalnewstoday.com, radiotherapy tends to change the pattern of genes which result in constant inflammation in the arteries which helps patients fight cancer. However, later in life this persistent inflammation leads to the development of cardiovascular disease in the survivors of cancer. The research was conducted by the researchers at the Karolinska Institutet.

Previous studies have established that radiotherapy furthers the chances of cardiovascular disease mostly in the same body part where the cancer was found. However, it was found that this side effect of radiotherapy does not surface for many years after the treatment. As per www.medcompare.com, the study revealed that the radiotherapy processed arteries of the patients developed chronic inflammation.

This inflammation expression of the gene was found to be present even after many years of radiotherapy. This discovery aims to reveal the reason why survivors of cancer often fall prey to cardiovascular diseases. Speaking about the revelation Dr. Martin Halle, a researcher at the Karolinska Institutet said “Hopefully, these findings will one day help medicine to mitigate the side effects by administering radiotherapy in combination with an anti-inflammatory treatment.”

Celebrities who have had heart surgery include Star JonesMichael LohanBurt Reynolds,Bill Clinton and Robin Williams.

Images: http://commons.wikimedia.org/wiki/File:Human_heart_with_coronary_arteries.png; Author: Patrick J. Lynch, http://commons.wikimedia.org/wiki/File:Muscular_artery.jpg