Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance

被引：25

作者：

Kuo, Chin-Sung ^{[1
,2
]}

Chen, Jia-Shiong ^{[2
]}

Lin, Liang-Yu ^{[3
,4
]}

Schmid-Schonbein, Geert W. ^{[5
]}

Chien, Shu ^{[6
]}

Huang, Po-Hsun ^{[2
,7
,8
]}

Chen, Jaw-Wen ^{[8
,9
]}

Lin, Shing-Jong ^{[8
,10
,11
,12
]}

机构：

[1] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Dept Med, Div Endocrinol & Metab, Taipei, Taiwan

[2] Natl Yang Ming Univ, Inst Clin Med, Taipei, Taiwan

[3] Taipei Vet Gen Hosp, Dept Med, Div Endocrinol & Metab, Taipei, Taiwan

[4] Natl Yang Ming Univ, Taipei, Taiwan

[5] Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Inst Engn Med, Dept Bioengn, Nanoengn, La Jolla, CA 92093 USA

[7] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Dept Crit Care Med, Div Cardiol, Taipei, Taiwan

[8] Natl Yang Ming Univ, Cardiovasc Res Ctr, Taipei, Taiwan

[9] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Inst & Dept Pharmacol, Dept Med Res & Educ, Taipei, Taiwan

[10] Natl Yang Ming Univ, Healthcare & Serv Ctr, Taipei, Taiwan

[11] Natl Yang Ming Univ, Cheng Hsin Gen Hosp, Taipei Vet Gen Hosp, Inst Clin Med,Dept Med Res,Heart Ctr,Div Cardiol, Taipei, Taiwan

[12] Taipei Med Univ, Taipei Heart Inst, Taipei, Taiwan

来源：

SCIENTIFIC REPORTS | 2020年 / 10卷 / 01期

关键词：

CARDIOVASCULAR-DISEASE; INDUCED OBESITY; ALPHA(1)-ANTITRYPSIN; RECEPTOR; SENSITIVITY; DYSFUNCTION; GLUCOSE;

D O I：

10.1038/s41598-020-58361-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Recent evidence suggests that enhanced protease-mediated inflammation may promote insulin resistance and result in diabetes. This study tested the hypothesis that serine protease plays a pivotal role in type 2 diabetes, and inhibition of serine protease activity prevents hyperglycemia in diabetic animals by modulating insulin signaling pathway. We conducted a single-center, cross-sectional study with 30 healthy controls and 57 patients with type 2 diabetes to compare plasma protease activities and inflammation marker between groups. Correlations of plasma total and serine protease activities with variables were calculated. In an in-vivo study, LDLR-/- mice were divided into normal chow diet, high-fat diet (HFD), and HFD with selective serine protease inhibition groups to examine the differences of obesity, blood glucose level, insulin resistance and serine protease activity among groups. Compared with controls, diabetic patients had significantly increased plasma total protease, serine protease activities, and also elevated inflammatory cytokines. Plasma serine protease activity was positively correlated with body mass index, hemoglobin A1c, homeostasis model assessment-insulin resistance index (HOMA-IR), tumor necrosis factor-a, and negatively with adiponectin concentration. In the animal study, administration of HFD progressively increased body weight, fasting glucose level, HOMA-IR, and upregulated serine protease activity. Furthermore, in-vivo serine protease inhibition significantly suppressed systemic inflammation, reduced fasting glucose level, and improved insulin resistance, and these effects probably mediated by modulating insulin receptor and cytokine expression in visceral adipose tissue. Our findings support the serine protease may play an important role in type 2 diabetes and suggest a rationale for a therapeutic strategy targeting serine protease for clinical prevention of type 2 diabetes.

引用

页数：11

共 28 条

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