Some Further Inflammatory Remarks

To an endocrinologist, there is nothing quite as exciting as the discovery of a new hormone. If the title of this month’s Viewpoint suggests an analysis of Harvard President Larry Summers’ comments on women in science, I apologize. I'm going to sidestep that one, and I swear it has nothing to do with the fact that Summers is my boss (please keep the checks coming, Larry). No, I'm talking about the connection between inflammation and diabetes, a link that may already be on the minds of regular readers of this column.

Over the last three to four years of diabetes research, there has been a huge shift in our thinking about type 2 diabetes. Rather than considering insulin resistance to be the result of simple hormonal abnormalities, we now recognize that this condition can be largely attributed to unchecked inflammation in critical insulin target tissues like liver, muscle, and fat. It has been known for a while that adding inflammatory proteins to animals can cause diabetes, but this was thought to be something of a specialty phenomenon, without much relevance to the garden-variety cases of insulin resistance that we see every day in the clinic. Today, a Medline search for keywords "Inflammation" and "Type 2 diabetes" yields more than 560 references, the vast majority of which were written in the past four years.

Now, two new papers have come out that expand our understanding of inflammation and insulin resistance, and suggest some potential new therapies. In the first paper, a group from the Joslin Diabetes Center activated a single critical protein (called NF-kB) that turns on a variety of inflammatory genes in the liver, using some tricks of genetic engineering. This action was sufficient to cause significant insulin resistance in the liver, as well as in distant tissues like muscle. The group also showed that feeding mice a high fat diet causes activation of NF-kB in the liver, and that blocking NF-kB could prevent the onset of insulin resistance even after a high fat diet. The major take home message from this paper, and from previous work from this lab, is that one of the ways that obesity can cause insulin resistance is by starting an inflammatory reaction in the liver that can spread to other organs. This suggests, and the authors have proven, that anti-inflammatory drugs (including high-dose aspirin) can be used to treat diabetes.

In the second paper, a group from San Diego used genetic engineering to remove a key inflammatory enzyme from the liver of mice. As in the Joslin paper, this action prevented the mice from becoming insulin resistant in the liver tissue itself. By now, that should be no surprise. What was more amazing, though, was that the authors made a second group of mice that lacked the inflammatory enzyme only in certain white blood cells. These cells, including macrophages, are known to release inflammatory proteins, but are not typically thought of as part of the system that regulates the response to insulin. Yet the mice with reduced inflammatory power only in white blood cells were almost completely protected from insulin resistance and diabetes!
What does it all mean? Well, first of all it means we need to broaden our thinking about which cells in the body participate in causing diabetes. Specifically, we really need to include macrophages and possibly other blood cells when we investigate this disease and devise new therapies. And it opens the door for a variety of new approaches to diabetes treatment based solely on anti-inflammatory action. This concept has been fully embraced by academic and industrial labs around the world, and it’s a good bet that the next generation of anti-diabetic drugs will emerge from this new way of thinking about an old disease.

Reference:
Dongsheng Cai, Minsheng Yuan, Daniel F Frantz, Peter A Melendez, Lone Hansen, Jongsoon Lee and Steven E Shoelson. Local and systemic insulin resistance resulting from hepatic activation of IKK-ß and NF-kB. Nature Medicine 2005. 11, 183–190
Melek C Arkan, Andrea L Hevener, Florian R Greten, Shin Maeda, Zhi-Wei Li, Jeffrey M Long, Anthony Wynshaw-Boris, Giuseppe Poli, Jerrold Olefsky and Michael Karin. IKK-ß links inflammation to obesity-induced insulin resistance. Nature Medicine 2005. 11, 191–198.

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