White Blood Cells, Fat, and Diabetes: How Neutrophils Mediate Insulin Resistance

The consultative hematologist is occasionally asked to assess a minimally elevated white blood cell (WBC) count. After a careful history, physical, and a review of the blood film and other laboratory studies, the hematologist concludes that this elevation is not due to underlying marrow pathology but rather reflects ongoing, low-grade inflammation. Innocent enough? Maybe not. An elevated WBC count is a risk factor for atherosclerotic disease. Several prospective studies have shown an independent association between an above- normal WBC and coronary disease or mortality. Elevated WBC is associated with other risk factors, such as smoking and fasting glucose or insulin levels, and inversely related to physical activity, plasma HDL concentration, and family income.¹  Inflammation underlies the pathophysiology of non-alcoholic steatohepatitis, which is associated with the metabolic syndrome of obesity, diabetes, hyperlipidemia, and cardiovascular disease.²  The WBC count is elevated in obese patients and in patients with impaired glucose tolerance.³  Although most studies have focused on the role of the WBCs in atherosclerotic vascular injury, the experiments of Talukdar and colleagues in the laboratory of Jerrold Olefsky at the University of California, San Diego, suggest a novel mechanism by which WBCs contribute to cardiovascular disease by participating in inflammation-induced disorders of metabolism. They show that, as a consequence of elastase secreted by WBCs, chronic inflammation induces insulin resistance in mice fed a high-fat diet.

Feeding mice a high-fat diet induced obesity and caused a 20- fold increase in infiltrating neutrophils in adipose tissue that was associated with a marked increase in neutrophil elastase release. Notably, mice treated with a neutrophil elastase inhibitor showed improved glucose tolerance, while treatment with recombinant elastase led to markedly greater glucose intolerance. Additional experiments by Talukdar and colleagues indicated that the proinflammatory effects are mediated, at least in part, by direct activation of Toll-like receptor 4 by neutrophil elastase. When compared with wild-type littermates, neutrophil elastase-knockout mice fed a high-fat diet gained less weight, had fewer infiltrating neutrophils, and had better glucose tolerance and greater insulin sensitivity. mRNA levels of liver lipogenic and cholesterol synthesis genes were also lower in the knockout mice.