Nearly 21 million Americans suffer from type 2 diabetes, and every year 800,000 more are diagnosed. Considering the growing numbers, scientists are trying to fit together the disease’s disparate puzzle pieces. People who acquire it are typically obese, suffer from chronic inflammation and are resistant to insulin, the hormone that removes sugar from the blood and stores it as energy. For years no one has known exactly how the three characteristics are related, if at all. But a handful of recent studies suggest that they are inextricably linked through the actions of specific inflammatory immune cells and a master genetic switch—and the hope is that an understanding of the relations could open the door to new therapeutic opportunities.
Several decades ago scientists noticed that people with type 2 diabetes have overly active immune responses, leaving their bodies rife with inflammatory chemicals. In the early 1990s researchers at Harvard University pinpointed one major immune player as TNF-alpha, a chemical secreted by immune cells; such compounds are generally referred to as cytokines. They found high levels of the cytokine in the fat tissue of rats with type 2 diabetes, and when they bred obese rats that could not make the cytokine, diabetes did not develop in the animals. Researchers have since shown that TNF-alpha—and, more generally, inflammation—activates and increases the expression of several proteins that suppress insulin-signaling pathways, making the human body less responsive to insulin and increasing the risk for insulin resistance.
So what causes the inflammation? Although type 2 diabetes can develop in patients of normal weight, most scientists agree that “obesity is the driving force,” says Jerrold Olefsky, an endocrinologist at the University of California, San Diego. After fat cells have expanded as a result of weight gain, they sometimes do not get enough oxygen from the blood and start to die, he explains. The cellular death recruits immune cells to the scene.
Insulin resistance causes inflammation, too. In a study published in the August online version of Diabetes, H. Henry Dong and his colleagues at the University of Pittsburgh showed that a protein called FOXO1 serves as a master switch that turns on the expression of another key inflammatory cytokine, interleukin 1-beta, which also interferes with insulin signaling. Normally insulin keeps FOXO1 in check; it “rapidly inhibits FOXO1” by moving it out of the nucleus so it can be targeted for degradation, Dong says. But when a person becomes insulin-resistant and pancreatic cells no longer produce enough insulin to overcome the resistance, activity of FOXO1 increases.
Dong’s results suggest that inflammation and insulin resistance reinforce each other via a positive feedback loop. And indeed, the two often come together: for instance, rheumatoid arthritis, an inflammatory disease, heightens the risk of insulin resistance developing, Dong states.
The findings could lead to the development of new therapeutics. Dong says that “we are trying to create an antagonist, a molecule, to inhibit FOXO1 activity” enough to end diabetes but not so much as to impair FOXO1’s other roles in the body, which include aiding muscle cell growth.
Other scientists are targeting the immune cells that release cytokines. In 2003 researchers at Columbia University and at Millennium Pharmaceuticals discovered hoards of macrophages, immune cells whose primary role is to engulf pathogens, in the fat stores of people with type 2 diabetes. Olefsky and his colleagues later genetically engineered mice that could not produce these macrophages and showed that “the animals were protected from obesity-induced insulin resistance,” even if they were fat, he says. “That throws out the idea that if you could find a less noxious way in humans of inhibiting that macrophage inflammatory program, you could have a therapeutic.” The key would be to ensure that such a drug did not interfere with essential immune system activity, Olefsky notes.
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8 Comments
Add CommentI read this article with a vested interest as a diabetic. I've developed a complication -- frozen shoulder -- which is described in internet articles as much more frequent among diabetics and thought to be some sort of auto-immune disease, in and of itself.
Reply | Report Abuse | Link to thisFor some time now I have considered insulin resistance, diabetes, depression (serotonin and other neurotransmitter resistance) and some kinds of infertility as different manifestations of cell membrane resistance, where the membranes don't let in nutrients. Often the membranes are "stiff" from a high Omega 6/ Omega 3 ratio and low mineral intake interferes with enzymes involved with cellular transport. So nutrients and their ferries, like the inflammatory insulin, stay in the blood, circulating and irritating the tissues. Diets high in sugar or other carbohydrates and allergenic foods increase the inflammatory conditions.
Reply | Report Abuse | Link to thisif you have a computer you could help find a cure
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If you *don't* have a computer--what are you doing here?
Reply | Report Abuse | Link to thisI'm jus' sayin'
Having reviewed articles in both medicine and nutrition, I found hyperglyucemia is inflammatory and pro-inflammatory, in addition to prothrombotic, hypertensive, and pro-glycation. Hyperglycemia is directly related to excessive consumption of carbohydrates. At first, beta cells were able to produce enough insulin to return the postprandial hyperglycemia to normal BG level, while they were attacked by the inflammation from hyperglycemia. They lose the cells more daily if excessive carbohydrate consumption continues. Eventually, the mass of beta cells is reduced to 40-60% of its original size and can no longer produce enough insulin for reducing the BG level to normal, thus diabetes mellitus is diagnosed.
Reply | Report Abuse | Link to thisYes, indeed, inflammation, a result of hyperglycemia from over-consumption of carbohydrates is the most important cause for the development of diseases including diabetes mellitus.
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Does this in any way relate to the type of inflammation that copper spirales for contraception supposedly induce as well?
Reply | Report Abuse | Link to thisDiabetes and Obesity is a direct result of food chemicals. The drug makers make 50 billions$$$ yearly of this disease! The FDA allows the drug makers chemicals in the food to do this and this has been scientifically proven.
Reply | Report Abuse | Link to thisDiabetes drugs are criminal and destroy the heart muscle and still bring in 40 billion a year to the drug makers without a cure
A filmmaker has been reversing diabetes in now 10 countries worldwide WITHOUT medications and the drug companies do not promote this
just google SPIRIT HAPPY DIET
If you would like a diabetes program that addresses insulin resistance AND inflammation, then, get the Death to Diabetes book. It was written by an engineer/biochemist who almost died from a diabetes coma.
Reply | Report Abuse | Link to thisMy wife was able to get off the insulin, lisinopril, and other drugs after 4 months on this program:
http://www.deathtodiabetes.com/
Here is the author on YouTube:
http://www.youtube.com/watch?v=_ECUOu2rFto
p.s. You don't have too buy his book -- his program is spelled out on his website.