Inflammatory Markers Sign of Impending Type 2 Diabetes
Elevated CRP, IL-6 Predict Onset of Disease Down the Road
By Aman Shah, MD
WebMD Medical News
Reviewed by Michael W. Smith, MD
July 17, 2001 -- Researchers have identified inflammatory markers that are associated with a significantly increased risk of developing type 2 diabetes -- markers that have already been linked to heart disease. A study in the July 18 issue of JAMA shows that elevations in both C-reactive protein and interleukin-6 are highly predictive of being diagnosed with diabetes within the next several years. Now the questions are: Should we begin testing for them? And what do we do if they are high?
"The underlying etiology of diabetes remains very complicated," senior author Paul M. Ridker, MD, PhD, tells WebMD. "This paper is suggesting that low-grade abnormalities [in CRP and IL-6] seem to contribute rather substantially to the risk for developing disease."
The Harvard researchers analyzed data from 27,628 women in the Women's Health Study who did not have diabetes, cardiovascular disease, or cancer at baseline. Over a 4-year period, 188 women were diagnosed with diabetes and compared with 362 matched controls.
Women with diabetes were much more likely to have elevated CRP and IL-6 levels at baseline than the controls. Women in the highest quartile of IL-6 and CRP levels were 7.5 times and 15.7 times more likely to develop type 2 diabetes, respectively, compared with women in the lowest quartile of IL-6 and CRP levels.
Even after adjusting for obesity, smoking, exercise, hormone replacement therapy, and alcohol use, says Ridker, women with elevated IL-6 and CRP levels were much more likely to develop diabetes over the follow-up period than were women with the lowest levels of the inflammatory markers.
Ridker, who has published extensively on the use of CRP as a predictor for heart disease and who recommends testing CRP for heart disease risk, says it's too soon to support similar testing to gauge the risk for diabetes.
Last month, Ridker published research that suggests statins can also lower the levels of CRP in the blood.
So could statins be used to prevent diabetes? It's too soon to say for sure, but Ridker points out that there was a report earlier this year that one of the statins, pravastatin (Pravachol), was associated with a 30% decrease in the incidence of diabetes in a large study in Scotland.
Om Ganda, MD, of the Joslin Diabetes Center and Harvard Medical School in Boston, tells WebMD that Ridker's new study is "one of a number of recent studies that have indicated that low-grade chronic inflammation might underlie type 2 diabetes." But Ganda says that there are still several unanswered questions.
"There is a very small number of diabetic cases in this study -- just 188 women," says Ganda. He says it is difficult to make assumptions based on so few cases.
Moreover, even if one accepts that inflammation may be the driving factor behind diabetes, what is the best way to treat it? Ganda says that while the study from Scotland suggested that statins may prevent diabetes, another study suggested that ACE inhibitors may have a similar benefit. "Or what about aspirin, since it also reduces inflammation?" he adds.
Zachary Bloomgarden, MD, tells WebMD that the new study is interesting but not convincing. He points out that Ridker is measuring very low levels of the markers -- so low that the elevations reported don't suggest "clinical inflammation," meaning that there would be none of the usual physical signs of inflammation, such as swelling.
So what Ridker is seeing may be another aspect of these markers, says Bloomgarden, associate clinical professor at Mt. Sinai School of Medicine, New York. He says, for example, that CRP is also produced by fat tissue, especially abdominal fat. CRP produced by fat can affect organs "such as the pancreas leading to a state of insulin resistance." So it may be that the significance of CRP to diabetes is not as a marker for inflammation but rather as a "mediator" of the disease process.
"What we are looking at may be a co-marker or indicator, not a cause and effect," agrees Ganda. "The next step is that we should continue studies like this one and we would look for real proof of the hypothesis that some anti-inflammatory management strategy can reduce the incidence of type 2 diabetes."