Animal study shows over-the-counter medications lower weight and treat type 2 diabetes
Over-the-counter allergy medications turn obese, diabetic mice into healthy, normal-weight mice, researchers report.
The new research focuses on mast cells, immune system players critical to the inflammatory response involved in allergies.
The study appears along with three other independent studies in the July 26 online Nature Medicine that show a connection between type 2 diabetes and the immune system.
“Certainly the study is very exciting,” says George King of Harvard University’s Joslin Diabetes Center in Boston, who was not involved in the research. “It’s the first type to identify mast cells as having a potential role in developing obesity.”
Researchers from Harvard and their colleagues found that the inflammatory mast cells are as much as six times more abundant in the fat tissue of obese and diabetic humans and mice than in the fat tissue of normal-weight humans and mice.
Under certain conditions (such as when a person with allergies inhales pollen), these mast cells leak inflammation-inducing molecules “like a trash bag with holes in it,” says Guo-Ping Shi, a coauthor of the study on mast cells. Anti-inflammatory drugs, such as those used in anti-allergy eye drops and nasal sprays, reduce allergic symptoms by stabilizing the mast cells, effectively putting an extra trash bag around the leaky one so inflammatory molecules can’t be released. Shi says the team was curious about whether pre-existing medicines that stabilize mast cells might also alleviate the symptoms of diabetes.
For two months, obese, diabetic mice were given one of four regimens: one group continued to eat a high-fat diet; another group was switched to healthier chow; a third stayed on the high-fat diet and was given daily injections of either Zaditor or cromolyn, two common over-the-counter allergy medications that stabilize mast cells; and a fourth group ate healthy chow in addition to receiving the allergy medicine injections.
By the end of the study, the third group had lost about 12 percent of body weight, on average, even though continuing to eat a high-fat diet. Mice in the fourth group lost enough weight to put them back in the normal-weight range. Mice in both these groups had lower blood sugar levels, suggesting an alleviation in diabetes symptoms. In contrast, mice in the first group, which had no diet change, continued to gain weight and had relatively high blood sugar levels. And the second group, which switched diet but received no medications, had only a marginal decrease in body mass and showed some improvements in blood sugar levels.
The allergy injections were also given to normal mice on a high-fat diet, which can trigger diabetes and obesity. At the end of three months, the treated mice had not become obese or diabetic.
Many experimental treatments work well to prevent diabetes and obesity, comments inflammation researcher Giamila Fantuzzi of the University of Illinois at Chicago, “but not too many work in a therapeutic fashion” as this one does. However, she adds, it remains to be seen whether the approach will also work in people.
Another study published in Nature Medicine, carried out by an independent team of Harvard researchers led by Diane Mathis, shows that immune system cells called regulatory T cells, or “Tregs,” are also correlated with obesity and diabetes.
Regulatory T cells have a guardian role in the body, controlling allergic reactions, autoimmune responses, tumors and other cells that are out of control.
A study published in 2003 in the Journal of Clinical Investigation revealed huge populations of macrophages, white blood cells that consume dead tissue and microbes, in the fat tissue of obese mice. Obesity was somehow causing this chronic inflammatory response, Mathis says. But it seemed the checks and balances usually provided by the regulatory T cells were missing. “We wondered why there was no control of this inflammation,” she says.
Mathis and her colleagues found that where macrophages proliferated in fat tissue, regulatory T cells were gone, and vice versa. The fat tissue of normal-weight mice and humans was teeming with Tregs and light on macrophages. But the fat tissue of obese mice and humans showed high numbers of macrophages and very few Tregs.
Since the molecular mechanisms connecting Tregs and mast cells to obesity are not yet fully understood, the authors say the new studies supply more questions than answers. Shi’s group plans to test the allergy medications on a group of obese monkeys; Mathis’ team will investigate why the population of Tregs in fat tissue goes down as a person (or mouse) gains weight.
“We’re learning a lot, but the more we learn, the more we realize that we don’t know a lot,” says Steven Shoelson of Harvard’s Joslin Diabetes Center, a coauthor of the Treg study.
And researchers are learning fast. “There is not a single textbook out there in any medical area that even suggests that the immune system is involved in type 2 diabetes in any way,” Shoelson says. “This is kind of a paradigm-shifting concept that is being developed.”
“Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice.” Jian Liu, Adeline Divoux, Jiusong Sun, Jie Zhang, Karine Clément, Jonathan N Glickman, Galina K Sukhova, Paul J Wolters, Juan Du, Cem Z Gorgun, Alessandro Doria, Peter Libby, Richard S. Blumberg, Barbara B. Kahn, Gökhan S Hotamisligil, Guo-Ping Shi. Nature Medicine. Published online July 26, 2009. doi: 10.1038/nm.1994. Available at [Go to].
“Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.” Markus Feuerer, Laura Herrero, Daniela Cipoletta, Afia Naaz, Jamie Wong, Ali Nayer, Jongsoon Lee, Allison B Goldfine, Christophe Benoist, Steven Shoelson, Diane Mathis. Nature Medicine. Published online July 26, 2009. doi: 10.1038/nm.2002. Available at [Go to].
“CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity.” Satoshi Nishimura, Ichiro Manabe, Mika Nagasaki, Koji Eto, Hiroshi Yamashita, Mitsuru Ohsugi, Makoto Otsu, Kazuo Hara, Kohjiro Ueki, Seiryo Sugiura, Kotaro Yoshimura, Takashi Kadowaki, Ryozo Nagai. Nature Medicine. Published online July 26, 2009. doi: 10/1038/nm.1964.
“Normalization of obesity-associated insulin resistance through immunotherapy.” Shawn Winer, Yin Chan, Geoffrey Paltser, Dorothy Truong, Hubert Tsui, Jasmine Bahrami, Ruslan Dorfman, Yongqian Wang, Julian Zielenski, Fabrizio Mastronardi, Yuko Maezawa, Daniel J Drucker, Edgar Engleman, Daniel Winer, H.-Michael Dosch. Nature Medicine. Published online July 26, 2009. doi: 10/1038/nm.2001.