Inflammation, the process triggering the cascade of reactions commonly associated with fighting off infectious diseases, also appears to be closely involved with the risk between cardiovascular disease and obesity. Inflammation is known to involve four components: platelet activation, macrophage attraction, monocyte adhesion and smooth muscle migration.
When Ora Shovman spoke of the effect of statin drugs on the inflammatory reaction by their inhibition of nuclear factor kappa B (NF-kB), this is what he was referring to. This is basic clinical pathology, taught to all members of the health care community.
It has helped to define the good that statins do in cardiovascular disease risk reduction. It isn't the reduction of cholesterol that is giving the benefit, it is the direct suppression of inflammation.
A study at the Joslin Diabetes Center gives insight on just how anti-inflammatory mechanisms work.
Reading like a classic thriller, three elements are combined.
1. Our oldest anti-inflammatory drug, salsalate, a close relative of aspirin, long known to possess the mysterious side effect of blood sugar reduction.
2. Macrophages hidden in fat cells able to trigger both innocent clean-up reactions or dire thrombogenic responses.
3. The infusion of free fatty acids directly into the blood stream mimicking the release of stored body fat.
Steven Shoelson, MD discovered that salsalate inhibits NF-kB, that he calls a master switch in inflammation regulation. Preliminary studies found short-term use of salsalate, added to regular diabetes medication, helped patients with poorly controlled Type 2 diabetes lower their blood sugar to far more acceptable levels.
In the quest now to prove it, a major study is under way testing whether this anti-inflammatory drug - an old, cheap cousin of aspirin - can fight the Type 2 diabetes associated with obesity. Generic salsalate is used today primarily for arthritis.
Dr. Shoelson is a principal investigator at the Joslin Diabetes Center where his primary focus has been the role of inflammation in diabetes. He reports that epidemiologists have found that many patients with type 2 diabetes and cardiovascular disease have elevated levels of inflammatory markers in their bloodstream, supporting his special interest in inflammation regulation.
He has identified NF-kB to be the target of this salsalate effect and found that obesity is a very powerful activator of this effect. Another player in this study is Dr. Preeti Kishore of Albert Einstein College of Medicine. Dr. Kishore has studied the effect of infusing free fatty acids directly into the blood of obese but otherwise healthy individuals.
This study mimicked the release of fatty acid by fat cells and revealed the surprising release of highly thrombogenic proteins - another indication of the direct effect of excess weight on cardiovascular risk.
While NF-kB is well known as a master regulator of innate immunity and inflammation, its functions in fat and the liver with respect to metabolic diseases had not been investigated previously, says Dr Shoelson.
It appears to be at this point where obesity tilts the scales precipitously, converting the relatively mild, early insulin resistance of common metabolic syndrome to serious cardiovascular disease. It is at this point that the metabolic syndrome becomes a medically serious inflammatory response.
Most of those in medicine have never been satisfied with weight control therapies. Most have been content to pass off such patients to the various weight-loss groups, but here is research that dramatically illustrates the importance of obesity.
It is now far more than trying to get into last year's bathing suit. This effect of obesity to trigger a potentially catastrophic inflammatory response forces doctors to take another hard look at obesity control. We need much more effective control measures.
Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor