Abstract
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-α, 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.
Highlights
Hsin General Hospital, Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming www.nature.com/scientificreports worldwide prevalence of type 2 diabetes
The study results suggest that circulating serine protease activity is significantly elevated and associated with HBA1c, homeostasis model assessment-insulin resistance index (HOMA-IR), tumor necrosis factor-α (TNF-α), and adiponectin levels in patients with type 2 diabetes
Animal experiments in LDLR−/− mice confirmed these findings that administration of high-fat diet (HFD) produced progressive hyperglycemia and insulin resistance associated with upregulation of serine protease activity in plasma and visceral adipose (VAD) tissue
Summary
Elevation of plasma protease activity was shown to be associated with diet-induced obesity and insulin resistance or chronic inflammation[3,4,5,6,7,8,9]. The recent evidence showed that the soluble insulin-receptor ectodomain is elevated in the plasma of patients with diabetes[10], and the serine protease granzyme B is an inflammatory marker related to insulin receptor cleavage in human obesity and type 2 diabetes mellitus[11]. We investigated the postulated mechanisms that elevated plasma serine protease activities which may cause excessive proteolytic cleavage of insulin receptor-α followed by insulin resistance and related abnormal metabolic parameters in this mouse model. We explored the possible therapeutic effects of 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF), a selective serine protease inhibitor
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