Insulin Resistance Also Mediated by White Blood Cells

The discovery also provides a potential new treatment target.

Using live mouse models as well as cultured liver and fat cells, a study team based at the University of California, San Diego, School of Medicine (La Jolla, CA, USA) discovered that an enzyme secreted by neutrophils called neutrophil elastase (NE) impairs insulin signaling and boosts resistance. Conversely, deletion of NE in obese mice fed a high-fat diet improved insulin sensitivity. “These results are largely unexpected. Although several immune cells have been established in the etiology of insulin resistance, the role of neutrophils in this process has remained unclear until now,” said Da Young Oh, co-author and assistant project scientist in the laboratory of study leader Jerrold M. Olefsky, MD and professor of medicine.

Chronic low-grade inflammation is an important cause of systemic insulin resistance. Neutrophils are the first immune cells to respond to tissue inflammation and can promote chronic inflammation by helping to recruit additional white blood cells - macrophages. Oh noted that neutrophils were considered to be “transient infiltrates” incapable of sustaining chronic, low-grade inflammation. “Our studies now suggest neutrophils possess powerful immune modulatory effects,” Oh said. Specifically, neutrophils use NE to activate a signaling pathway that triggers macrophages to secrete proinflammatory cytokines. NE degrades IRS1, a key protein in the insulin-signaling pathway in both liver and fat cells. The scientists noted that although NE has been shown to degrade this protein in lung cancer cells, the effect on insulin target tissues such as liver and adipose is striking.

The insulin-mediating role of neutrophils makes them a new target for developing treatments of insulin resistance in particular and diabetes in general. “One could, in theory, take an NE activity inhibitory approach to reverse or improve insulin resistance,” Oh said, noting that NE inhibiting drugs are already used for treatment of emphysema in Japan and are being tested in the United States for both emphysema and type 1 diabetes.

The findings have been reported in the August 5, 2012, advance online edition of the journal Nature Medicine.

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University of California, San Diego, School of Medicine