The Role of Heparin Cofactor Ⅱ in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice
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- Kurahashi Kiyoe
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Inoue Seika
- Department of Nutrition and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Yoshida Sumiko
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Ikeda Yasumasa
- Department of Pharmacology, Tokushima University Graduate School of Biomedical Sciences
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- Morimoto Kana
- Department of Community Medicine for Diabetes and Metabolic Disorders, Tokushima University Graduate School of Biomedical Sciences
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- Uemoto Ryoko
- Department of Community Medicine for Diabetes and Metabolic Disorders, Tokushima University Graduate School of Biomedical Sciences
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- Ishikawa Kazue
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Kondo Takeshi
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Yuasa Tomoyuki
- Department of Community Medicine for Diabetes and Metabolic Disorders, Tokushima University Graduate School of Biomedical Sciences
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- Endo Itsuro
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Miyake Masato
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University
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- Oyadomari Seiichi
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University
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- Matsumoto Toshio
- Fujii Memorial Institute of Medical Sciences, Tokushima University
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- Abe Masahiro
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Sakaue Hiroshi
- Department of Nutrition and Metabolism, Tokushima University Graduate School of Biomedical Sciences
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- Aihara Ken-ichi
- Department of Community Medicine for Diabetes and Metabolic Disorders, Tokushima University Graduate School of Biomedical Sciences
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Abstract
<p>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.</p><p>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.</p><p>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.</p>
Journal
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- Journal of Atherosclerosis and Thrombosis
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Journal of Atherosclerosis and Thrombosis 24 (12), 1215-1230, 2017
Japan Atherosclerosis Society