UC San Diego researchers have discovered an unexpected cause of insulin resistance , an obesity-causing metabolic disorder that can lead to type 2 diabetes. The culprit is a chemical made by neutrophils, the most common kind of white blood cell.
Moreover, drugs already on the market inhibit this chemical, and could be used as new obesity-fighting agents, said an expert on neutrophils who praised the findings.
The study was performed in mice and in mouse and human liver cells, said co-author Da Young Oh , of UCSD's Department of Medicine. Normal mice fed a high-fat diet developed fatty, inflamed liver tissue and became resistant to insulin. Resistance results in blood glucose rising to unhealthy levels, eventually helping to cause obesity, heart disease and other disorders.
Insulin resistance was blocked in mice fed the high-fat diet that were given a drug to inhibit the chemical, neutrophil elastase . It was also blocked in mice genetically engineered to lack the chemical. Their livers appeared normal, even on the high-fat diet.
Nearly 26 million Americans have diabetes, according to the Centers for Disease Control and Prevention in Atlanta. About 90 percent have type 2 diabetes. The rest have type 1 diabetes, caused by a lack of insulin.
The results are "exciting", said Klaus Ley , a professor at the La Jolla Institute for Allergy & Immunology, who was not involved in the research. Ley studies inflammation and a team he led recently published a paper on neutrophils.
"These findings could have therapeutic potential, because neutrophil elastase inhibitors are available and could be developed for use in obesity," Ley said. "Type 2 diabetes poses an enormous societal health problem and is associated with huge economic costs. Improving glucose tolerance by NE inhibitors could be beneficial for millions of Americans at risk for type 2 diabetes."
Glucose tolerance is the normal ability of the body to counteract glucose intake. The pancreas secretes insulin when blood glucose rises too high, causing it to be removed from the blood and stored in cells.
The neutrophil elastase inhibitors are used in Japan to treat emphysema, and are being tested in the U.S. for emphysema and for type 1 diabetes. It is much faster and easier to get approval for a new use of an existing drug than for an entirely new drug.
The research also sheds more light on the delicate balance the immune system must play, active enough to fight infections, but not so active as to attack the body itself. Inflammation is known to play a role in such big killers as cardiovascular disease, as well autoimmune disorders.
Neutrophil elastase plays an important part in the immune response to infection by destroying bacterial protein. It has been shown to cause inflammation in the lungs of smokers, in animal studies , leading to emphysema.
Other white blood cells are already known to cause inflammation and play a role in insulin resistance. However, neutrophils, the first responders to infection, weren't thought to stick around long enough to cause the long-term inflammation that causes insulin resistance, UCSD's Oh said.
"But our studies suggest a powerful immune modulatory effect of neutrophils through elastase," Oh said.
Since neutrophil elastase is a normally occurring chemical involved in fighting infection, inhibiting it presumably carries the risk of causing some undesirable side effect. But studies of its inhibitors for treating emphysema proves there is no serious side effect, Oh said.
The paper's other co-authors are Saswata Talukdar, Gautan Bandyopadhyay, Jianfeng Xu, Joanne McNelis, Min Lu, Pingping Li, Jachelle Ofrecio and Michael Lin, Department of Medicine, all of UCSD; and Dongmei Li, Qingyun Yan, Yimin Zhu and Martin B. Brenner, of Pfizer.