Study of Association between Serum Hepsin Level and Lymphocyte-to-C-reactive Protein Ratio in Patients with Diabetes


HPN, TMPRSS1, hepsin, TTSP, diabetes, serine protease, Lymphocyte-to-C-reactive Protein Ratio, pro-HGF, obesity

How to Cite

Uçucu, S., Karabıyık, T., Ayan, D., & Ünal, S. (2022). Study of Association between Serum Hepsin Level and Lymphocyte-to-C-reactive Protein Ratio in Patients with Diabetes. Iranian Red Crescent Medical Journal, 24(3).


Background: Hepsin is known as a cell-surface serine protease expressed predominantly in the liver. Hepsin-deficient mice show resistance to high-fat diet-induced obesity, hyperlipidemia, and hyperglycemia. Up to the present, the physiological function of hepsin has not been fully determined. Hepsin may play significant and specific roles in diabetes.

Objectives: This study aimed to evaluate the relationship between hepsin protein concentrations in serum and type 2 diabetes mellitus (T2DM) and elucidate possible associations with disease activity andinflammatory and metabolic parameters. To the best of our knowledge, this is the first study evaluating the relationship between hepsin, lymphocyte-to-C-reactive protein ratio (LCR), and type 2 diabetes in humans in the existingliterature.

Methods: This case-control study included 60 patients (30 males and 30 females) diagnosed with type 2 diabetes, according to American Diabetes Association's criteria, and 30 healthy controls (14 males and 16 females) with similar demographic characteristics. Several laboratory parameters were assessed including fasting glucose, total cholesterol, insulin, hemoglobin A1c, gamma-glutamyl transferase, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, C-reactive protein, atherogenic index of plasma, LCR, monocyte-to-neutrophil ratio,neutrophil-to-lymphocyte ratio, and serum hepsin levels.

Results: The type 2 diabetes group had significantly higher LCR than controls (P<0.016). Correlation analysis in the patient group showed a statistically significant relationship between hepsin and LCR (rho=0.296,P=0.02). Hepsin was negatively correlated with CRP in the patient group (rho=-0.333, P=0.01). Correlation analysis in the patient group showed a statistically significant relationship between hepsin and cholesterol (rho= 0.29,P= 0.02). Age was positively correlated with hepsin in the patient group
(rho= 0.267, P=0.04). There was no statistically significant difference in serum hepsin levels between the diabetes group and the control group (P=0.157). 

Conclusion: To the best of our knowledge, this is the first study assessing the hepsin levels in patients with T2DM. Our results indicated that increased levels of hepsin could be associated with the inflammatory processes. Similar results were not found for diabetes. However, it is recommended that similar studies should be conducted in larger patient populations.


  1. Beard J, Eddington S, Bowman N, et al. Circulating hepsin as a novel serum biomarker in prostate cancer patients. American Assoc Cancer Research; 2020.
  2. Li S, Peng J, Wang H, et al. Hepsin enhances liver metabolism and inhibits adipocyte browning in mice. Proc Natl Acad Sci U S A. 2020;117(22):12359-67. doi: 10.1073/pnas.1918445117.
  3. Shin WJ, Seong BL. Type II transmembrane serine  proteases as potential target for anti-influenza drug discovery. Expert Opin Drug Discov. 2017;12(11):1139-52. doi: 10.1080/17460441.2017.1372417. [PMID: 28870104]
  4. Hooper JD, Clements JA, Quigley JP, Antalis TM. Type II transmembrane serine proteases insights into an emerging class of cell surface proteolytic enzymes. J Biol Chem. 2001;276(2):857-60. doi: 10.1074/jbc.R000020200. [PMID: 11060317]
  5. Wu, Q. and J. Peng, Hepsin, in Handbook of Proteolytic Enzymes. Elsevier; 2013.
  6. Pelkonen M, Luostari K, Tengström M, Ahonen H, Berdel B, Katahja V, et al. Low expression levels of hepsin and TMPRSS3 are associated with poor breast cancer survival. BMC Cancer. 2015;15:431. doi: 10.1186/s12885-015-1440-5. [PMID: 26014348].
  7. Bugge TH, Antalis TM, Wu Q. Type II transmembrane serine proteases. J Biol Chem. 2009;284(35):23177-81. doi: 10.1074/jbc.R109.021006. [PMID: 19487698]
  8. Kirchhofer D, Peek M, Lipari MT, Billeci K, Fan B, Moran P. Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2. FEBS Lett. 2005;579(9):1945-50. doi: 10.1016/j.febslet.2005.01.085. [PMID: 15792801]
  9. Qiu D, Owen K, Gray K, Bass R, Ellis V. Roles and regulation of membrane-associated serine proteases. Biochem Soc Trans. 2007;35(3):583-7. doi: 10.1042/BST0350583. [PMID: 17511657].
  10. Fafalios A, Ma J, Tan X, Stoops J, Luo J, Defrances MC, et al. A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nat Med. 2011;17(12):1577-84. doi:10.1038/nm.2531. [PMID: 22081023]
  11. Franco FM, Jones DE, Harris PK, Han Z, Wildman SA, Jarvis CM, et al. Structure-based discovery of small molecule hepsin and HGFA protease inhibitors: Evaluation of potency and selectivity derived from distinct binding pockets. Bioorg Med Chem. 2015;23(10):2328-43. doi: 10.1016/j.bmc.2015.03.072. [PMID: 25882520]
  12. Wu Q. Gene targeting in hemostasis. Hepsin. Front Biosci. 2001;6:D192-200. doi: 10.2741/a604. [PMID: 11171558]
  13. Okugawa Y, Toiyama Y, Yamamoto A,Shigemori T, Ide S, Kitajima T,et al. Lymphocyte-C-reactive Protein Ratio as Promising New Marker for Predicting Surgical and Oncological Outcomes in Colorectal Cancer. Ann Surg. 2020;272(2):342-351. doi: 10.1097/SLA.0000000000003239.[PMID:32675548]
  14. Aljakna A, Choi S, Savage H,  Blair RH, Gu T, Svenson KL,et al. Pla2g12b and Hpn are genes identified by mouse ENU mutagenesis that affect HDL cholesterol. PLoS One. 2012;7(8):e43139. doi: 10.1371/journal.pone.0043139. [PMID: 22912808]
  15. Wu Q, Yu D, Post J, Halks-Miller M, Sadler JE, Morser J. Generation and characterization of mice deficient in hepsin, a hepatic transmembrane serine protease. J Clin Invest. 1998;101(2):321-6. doi: 10.1172/JCI1617. [PMID: 9435303]
  16. Okumura Y, Kido H. Physiological roles of the type II transmembrane serine protease. Seikagaku. 2006;78(12): 1155-9. [PMID: 17243636.]
  17. Yu IS, Chen HJ, Lee YS, Huang PH, Lin SR, Tsai TW,et al. Mice deficient in hepsin, a serine protease, exhibit normal embryogenesis and unchanged hepatocyte regeneration ability. Thromb Haemost. 2000;84(5):865-70. doi: 10.1055/s-0037-1614129.[PMID: 11127869]
  18. Somoza JR, Ho JD, Luong C, Ghate M, Sprengeler PA, Mortara K,  et al. The structure of the extracellular region of human  hepsin reveals a serine protease domain and a novel scavenger receptor cysteine-rich (SRCR) domain. Structure. 2003;11(9):1123-31. doi: 10.1016/s0969-2126(03)00148-5. [PMID: 12962630]
  19. Torres-Rosado A, O'Shea KS, Tsuji A, Chou SH, Kurachi K. Hepsin, a putative cell-surface serine protease, is required for mammalian cell growth. Proc Natl Acad Sci U S A. 1993;90(15):7181-5. doi: 10.1073/pnas.90.15.7181.. [PMID: 8346233]
  20. Calle MC, Fernandez ML. Inflammation and type 2 diabetes. Diabetes Metab. 2012;38(3):183-91. doi: 10.1016/j.diabet. 2011.11.006. [PMID: 22252015]