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

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. Metabolic syndrome is a global public health issue of increasing magnitude. Obesity, insulin resistance, proinflammatory and prothrombotic states, atherogenic dyslipidemia, and higher blood pressure are risk factors for metabolic syndrome 1. Among these factors, obesity-induced insulin resistance is a major contributor to the

Cleavage of the vaspin N-terminus releases cell-penetrating peptides that affect early stages of adipogenesis and inhibit lipolysis in mature adipocytes

“…Thus, the generation of functional proteolytic peptides may present a second mechanism by which vaspinprotease interactions modulate obesity-induced inflammatory processes in adipose tissue in addition to the known inhibition of pro-inflammatory proteases [15,55]. We have previously found, that vaspin expression is induced in brown adipose tissue after thermogenic activation [56].…”

“…Vaspin expression in human adipose tissue is induced in obesity, and serum levels of vaspin are increased in obesity and type-2 diabetes [54]. This may be a direct response to increased proteolytic activity especially from serine proteases in serum observed in type-2 diabetic patients and also in adipose tissue of insulin resistant obese mice [55]. As a consequence of higher vaspin expression and increased protease activity in obesity, generation of vaspin-derived CPPs is likely to be increased as well.…”

<p>ZG02 Improved Hepatic Glucose Metabolism and Insulin Sensitivity via Activation of AMPK/Sirt1 Signaling Pathways in a High-fat Diet/Streptozotocin-induced Type 2 Diabetes Model</p>

“…28 HOMA-IR can be calculated with the following formula: HOMA-IR index=fasting glucose (mmol/L)×fasting insulin (mU/L)/22.5. 29,30 Western Blotting…”

Prevention and Management of Type 2 Diabetes and Metabolic Syndrome in the Time of COVID-19: Should We Add a Cup of Coffee?

“…As described earlier, the key components in SARSCoV-2 viral entry are ACE2 receptor for cell entrance and the serine protease TMPRSS2 for the proteolytic cleavage of viral spike (S) protein ( 44 ). Recently, it was shown that T2D patients had increased plasma total protease and serine protease activities ( 45 ). Interestingly, plasma serine protease activity was positively associated with levels of hemoglobin A1c (HbA1c), body mass index (BMI) and homeostasis model assessment-insulin resistance (HOMA-IR) index, thus, supporting the potential role of serine protease in development of T2D and offering novel drug targets for T2D management ( 45 ).…”

“…Recently, it was shown that T2D patients had increased plasma total protease and serine protease activities ( 45 ). Interestingly, plasma serine protease activity was positively associated with levels of hemoglobin A1c (HbA1c), body mass index (BMI) and homeostasis model assessment-insulin resistance (HOMA-IR) index, thus, supporting the potential role of serine protease in development of T2D and offering novel drug targets for T2D management ( 45 ). Furthermore, it was proposed that the already available recombinant ACE2 may be employed for treating COVID-19 ( 46 ).…”