An Inflammatory Story in Type 2 Diabetes
Drs. Steven Shoelson and Jongsoon Lee are broadening their studies of how the anti-inflammatory drug salsalate achieves its positive results.
For most scientists, discoveries in the lab do not translate directly into medical uses. But for the Joslin researchers investigating inflammation as a troublemaker in type 2 diabetes, the road to the clinic has run smoothly so far. Unexpected plot twists are popping up, however, in their search for the drug’s elusive underlying molecular mechanisms.
Ten years ago, Steven Shoelson, M.D., Ph.D., and his co-authors reported that salicylates, a family of anti-inflammatory agents that includes aspirin, could boost insulin sensitivity, lower blood glucose levels and even reduce blood lipids in rodents. The drug seemed to work by blocking a specific lowgrade inflammatory pathway activated by weight gain and obesity. The paper provided a plausible way that obesity promoted insulin resistance—and suggested a way to intervene.
The findings set the stage for tests in people of a stomach-sparing formulation called salsalate, an inexpensive generic drug widely prescribed for rheumatoid arthritis joint pain. The multi-center clinical trial was co-headed by Dr. Shoelson and Allison Goldfine, M.D.
Positive results from the first stage of this trial were reported in 2010. There are also two large ongoing trials of salsalate—one to further confirm treatment of type 2 diabetes and another for cardiovascular disease, specifically to alter plaque built up in blood vessels and to prevent heart attacks. Results of the diabetes trial are expected in late 2011. Those for the heart disease trial will follow by several years.
That gives the salicylate family the strange honor of being among the oldest and newest experimental remedies for type 2 diabetes and for one of its major complications, since scattered reports of its usefulness date back to 1876.
“The clinical path has been unusually straightforward,” Dr. Shoelson says. “The surprise is its efficacy. But trying to figure out exactly how it works has been a challenge.”
Drawing out details for the fat attack
The original inflammation hypothesis was launched nearly 20 years ago by an observation from a neighboring lab at Dana-Farber Cancer Institute that fat tissue in obese mice releases an inflammatory substance. This bumps up insulin resistance in the liver and muscle and cuts back insulin secretion from the pancreas—all big steps on the road to type 2 diabetes.
The connection was strengthened by epidemiological studies showing other inflammatory substances in the blood of people with insulin resistance or type 2 diabetes. Then came the paper by Dr. Shoelson and his colleagues identifying a pro-inflammatory molecular target that prompted and sustained a vicious cycle of fat-induced insulin resistance. Suddenly, white fat took on a new and nastier identity, morphing from an unsightly storage depot to a dispenser of disease-promoting proteins.
The plot thickened when other scientists discovered immune cells known as macrophages lurking amid fat cells in obese animals and people, and identified them as the source of several of the pro-inflammatory substances previously attributed solely to fat. In the last few years, scientists have found almost every type of immune cell tucked among over-nourished fat cells and contributing to the potent mix. Macrophages remain the centerpiece in the type 2 diabetes story.
Fat-friendly inflammatory macrophages do increase with obesity, but Dr. Shoelson and collaborator Jongsoon Lee, Ph.D., believe the biology is much more complex and systemic. “We are working on how different immune cells are involved in the induction of inflammation by obesity and eventually how they regulate insulin resistance in obesity,” Dr. Lee says.
Teaming up with the lab of Harvard Medical School’s Diane Mathis, Ph.D., the Joslin colleagues discovered that abdominal fat in lean rodents held T regulatory cells (“Tregs,” known as the guardians of the immune system) with a distinctive molecular signature. Further study showed that in obese rodents and people, these lean-fat–specific Treg cells dwindled while destructive macrophages piled in. But in obese mice, salsalate seems to prevent this switch.
The immunological framework holds promise for revealing how obesity correlates not just with type 2 diabetes but with Alzheimer’s disease, asthma and certain cancers. “Obesity seems to affect the immune system everywhere,” Dr. Shoelson says.
However, as Dr. Shoelson and his colleagues probe the molecular and cellular diorama of salicylate activity in mice and people, unexpected anomalies have cropped up: Their recent comprehensive evaluation showed that inflammatory pathways don’t account for all of the salicylate effects.
The scientists knew that plants make salicylate in response to bacteria, fungi, extreme temperatures, drought and other stresses. Could salicylate also activate a stress response in people?
To find answers, Drs. Shoelson and Lee are teaming up with Joslin’s T. Keith Blackwell, Ph.D., who works in C. elegans, a tiny worm that serves as a fundamental biological discovery tool. In early work in both worm and mammalian cells, Dr. Blackwell says, “we see that salicylate acts on a stress defense mechanism that may be critical for its anti-inflammatory function and effects on insulin resistance.”
“Salicylate is doing something important and quite wonderful,” Shoelson sums up. “It reduces levels of chronic inflammation, and thus suppresses the collateral damage caused by that inflammation. And at the same time salicyate protects against a variety of cellular stresses.”
“For us to make the next leap, we need to figure out how the inflammation and stress response pathways are interrelated and regulated,” he says. “The clues are there, we just need to be a bit smarter.”
In these fat tissues from lean and obese mice, green indicates lipids and red shows immune system cells known as macrophages.
Greater inflammation in obese mice (right) is illustrated by the way in which fat cells are selectively surrounded by macrophages. Images: Hyuek Jong Lee, Ph.D.