Plasma Heparin Cofactor II Activities are Inversely Associated With Aberrant Glucose Metabolism in Humans and Mice

Background: Heparin cofactor II (HCII), a serine protease inhibitor, inactivates thrombin action. We previously showed that HCII is an antiatherogenic factor in humans and mice. In addition, we previously demonstrated that thrombin inactivation ameliorates insulin resistance in type 2 diabetic db/db mice. Therefore, we hypothesized that HCII is associated with glucose metabolism. Methods and Results: Plasma HCII activity and surrogate markers of glucose metabolism, including HbA1c, fasting plasma glucose (FPG) and homeostasis model assessment ratio (HOMA-R), were determined in elderly Japanese individuals (81 males and 69 females, mean age of 63.6 ± 10.7 years). Relationships between HCII and those surrogate markers were statistically evaluated after adjustment of age and sex. In addition, HCII+/- mice were fed normal or high-fat diet chow and analysed at the age of 25 weeks. There were significant inverse relationships between HCII and HbA1c value (r=0.246, p≤0.005), between HCII and FPG (r=0.203, p≤0.05) and between HCII and HOMA-R (r=0.167, p≤0.05). Moreover, HCII+/- mice fed a high-fat diet showed higher FPG (149.6 ± 11.2 vs 193.3 ± 8.2 mg/dl, p≤0.01) and HOMA-R (58.5 ± 8.1 vs 113.5 ± 27.7, p≤0.05) than those in HCII+/+ mice fed a high-fat diet. Gene expression levels of MCP-1, F4/80 and TNF-alpha were prominently increased in adipose tissue of HCII+/- mice compared to those in HCII+/+ mice. Conclusions: The present study demonstrated that heparin cofactor II is a novel regulating factor for glucose metabolism. Therefore, HCII may be a therapeutic target for diabetes as well as atherosclerotic diseases.