Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist

Aims: Inhibition of transient receptor potential vanilloid 1 (TRPV1) suppresses Calcitonin gene-related peptide (CGRP) secretion in pancreatic nerve fiber cells, thereby stimulating Insulin secretion. We examined the effects of repeat administration of the TRPV1 antagonist N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamidte monohydrochloride (BCTC) to ob/ob mice, a model of type 2 diabetes with Insulin resistance, on whole body glucose and lipid metabolism.

Main methods: We measured blood parameters, including levels of glucose, Insulin, and triglycerides, and performed the oral glucose tolerance test (OGTT) after repeat administration of BCTC to ob/ob mice twice a day for four weeks.

Key findings: We found that BCTC treatment reduced fasting glucose, triglyceride, and Insulin levels in the whole body. The effects were comparable to that of pioglitazone, a major insulin-sensitizing agent. Further, we found that administration of BCTC significantly increased plasma Insulin secretion in the OGTT, which differed from the effect of pioglitazone treatment.

Significance: Our study is the first to show the anti-diabetic pharmacological effects of the TRPV1 signal inhibitor BCTC. These findings suggest that TRPV1 antagonists may represent a new class of drugs effective in treating type 2 diabetes mellitus because of their dual effects as Insulin sensitizers and secretagogues.