Inhibition of Thrombin Action Ameliorates Insulin Resistance in Type 2 Diabetic db/db Mice

Abstract

The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. It also reduced adipocyte size and macrophage infiltration into adipose tissue. The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation.

Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes KKAy mice

“…The concentrations of plasma glucose and insulin were measured, and homeostasis model assessment-insulin resistance was determined as previously described (30).…”

“…After defatting, the samples were cut into 10-m-thick sections and stained with hematoxylin-eosin. Adipocyte size was determined by the average of five different sections in each sample (30).…”

Inflammation, obesity, and thrombosis

“…54,96 Furthermore, thrombin increases the release of inflammatory cytokines and growth factors from adipocytes and inhibits insulin-stimulated Akt activation. 97,98 In genetically obese (db/db) mice, treatment with a selective thrombin inhibitor ameliorates insulin resistance and ATM infiltration. 98 In mice fed a diet deficient in methionine and choline, a model of hepatic steatosis, TF-dependent thrombin generation and PAR1 signaling drive macrophage and neutrophil accumulation as well as hepatic inflammation.…”

“…97,98 In genetically obese (db/db) mice, treatment with a selective thrombin inhibitor ameliorates insulin resistance and ATM infiltration. 98 In mice fed a diet deficient in methionine and choline, a model of hepatic steatosis, TF-dependent thrombin generation and PAR1 signaling drive macrophage and neutrophil accumulation as well as hepatic inflammation. 99 Similarly, PAR1 deficiency decreases inflammation and steatosis in mice fed a Western diet.…”

Tissue factor pathways linking obesity and inflammation

“…Genetically caused obesity due to leptin receptor mutation in db/db mice increases adipose tissue inflammation and insulin resistance that are improved by treatment with a selective thrombin inhibitor (40). In steatohepatitis induced by a diet deficient in methionine and choline or Western diet-induced hepatic steatosis, TF-dependent thrombin generation and PAR1 signaling drive macrophage and neutrophil accumulation and hepatic inflammation (41;42).…”