Role of the B2 receptor of bradykinin in insulin sensitivity

Abstract

The biological actions of bradykinin (BK) are attributed to its B2 type receptor (B2R), whereas the B1R is constitutively absent, inducible by inflammation and toxins. Previous studies in B2R gene knockout mice showed that the B1R is overexpressed, is further upregulated by hypertensive maneuvers, and assumes some of the hemodynamic functions of the B2R. The current experiments were designed to further clarify the metabolic function of the B2R and to explore whether the upregulated B1R can also assume the metabolic function of the missing B2R. One group of B2R-/- mice (n=9) and one of B2R+/+ controls (n=8) were treated for 3 days with captopril (which produced a similar blood pressure-lowering response in both groups) and studied with the hyperinsulinemic euglycemic clamp. The knockout mice had fasting and steady-state blood glucose levels similar to those of the wild-type mice but a had tendency to higher fasting insulin levels (at 27.8±5.2 versus 18±2.9 mU/L, respectively). However, they had significantly higher steady-state insulin levels (749±127.2 versus 429.1±31.5 mU/L, P<0.05) and a significantly lower glucose uptake rate (31±2.4 versus 41±2.3 mg/kg per minute, P<0.05) and insulin sensitivity index (4.6±0.9 versus 10±0.7 P<0.001). Analysis of B1R and B2R gene expression by reverse transcription-polymerase chain reaction in cardiac muscle, skeletal muscle, and adipose tissues revealed significantly higher B1R mRNA level in the knockouts versus wild-type (P<0.05) at baseline and a further significant upregulation in mRNA by 1.8- to 3.2-fold (P<0.05) after insulin infusion. We conclude that absence of B2R confers a state of insulin resistance because it results in impaired insulin-dependent glucose transport; this is probably a direct B2R effect because, unlike the hemodynamic autacoid-mediated effects, it cannot be assumed by the upregulated B1R.