The Role of Heparin Cofactor II in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice

Aim: Accelerated thrombin action is associated with insulin resistance. It is known that upon activation by binding to dermatan sulfate proteoglycans, heparin cofactor II (HCII) inactivates thrombin in tissues. Because HCII may be involved in glucose metabolism, we investigated the relationship between plasma HCII activity and insulin resistance. Methods and Results: In a clinical study, statistical analysis was performed to examine the relationships between plasma HCII activity, glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and homeostasis model assessment-insulin resistance (HOMA-IR) in elderly Japanese individuals with lifestyle-related diseases. Multiple regression analysis showed significant inverse relationships between plasma HCII activity and HbA1c (p = 0.014), FPG (p = 0.007), and HOMA-IR (p = 0.041) in elderly Japanese subjects. In an animal study, HCII(+/+) mice and HCII(+/−) mice were fed with a normal diet or high-fat diet (HFD) until 25 weeks of age. HFD-fed HCII(+/−) mice exhibited larger adipocyte size, higher FPG level, hyperinsulinemia, compared to HFD-fed HCII(+/+) mice. In addition, HFD-fed HCII(+/−) mice exhibited augmented expression of monocyte chemoattractant protein-1 and tumor necrosis factor, and impaired phosphorylation of the serine/threonine kinase Akt and AMP-activated protein kinase in adipose tissue compared to HFD-fed HCII(+/+) mice. The expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase was also enhanced in the hepatic tissues of HFD-fed HCII(+/−) mice. Conclusions: The present studies provide evidence to support the idea that HCII plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HCII production may serve as novel therapeutic tools for the treatment of type 2 diabetes.