Role of the B ₂ Receptor of Bradykinin in Insulin Sensitivity

Abstract

Abstract-The biological actions of bradykinin (BK) are attributed to its B 2 type receptor (B 2 R), whereas the B 1 R is constitutively absent, inducible by inflammation and toxins. Previous studies in B 2 R gene knockout mice showed that the B 1 R is overexpressed, is further upregulated by hypertensive maneuvers, and assumes some of the hemodynamic functions of the B 2 R. The current experiments were designed to further clarify the metabolic function of the B 2 R and to explore whether the upregulated B 1 R can also assume the metabolic function of the missing B 2 R. One group of B 2 RϪ/Ϫ mice (nϭ9) and one of B 2 Rϩ/ϩ controls (nϭ8) 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 27.8Ϯ5.2 versus 18Ϯ2.9 mU/L, respectively). However, they had significantly higher steady-state insulin levels (749Ϯ127. radykinin mediates a variety of biological effects such as vasodilation, vascular permeability, inflammation, pain, and edema. 1 It is also known to play an important role in glucose metabolism. 2,3 Indeed, it was shown in vitro and in vivo that administration of bradykinin increases the glucose uptake in cultured adipocytes 4 as well as in long-term rat experiments 5 and in skeletal muscle of human forearm. 6 ACE inhibitors were shown to improve glucose utilization, 7 an action that is attributed to bradykinin. 8,9 In keeping with these data, kininogen-deficient rats were found to be resistant to insulin. 10 The effects of bradykinin are mediated by the B 1 -or B 2 -type receptor (B 1 R or B 2 R). It has been accepted that almost all of the physiologically significant effects of bradykinin, including the metabolic ones, are exerted by activation of the B 2 R. Indeed, inhibition of the B 2 R by various antagonists was shown to reverse the amelioration of insulindependent glucose transport by ACE inhibitors, 11,12 whereas blockade of downstream mediators, such as prostaglandins and NO, had no effect on insulin sensitivity. 12 Several studies have shown that the B 2 R is expressed in tissues dependent on insulin for glucose uptake, such as skeletal muscle and adipocytes. 4,13,14 On the contrary, the B 1 R is not expressed under normal conditions; it has long been known that its expression is induced by toxins or inflammatory mediators and it contributes to endotoxic shock, 15 but it has not been associated with metabolic functions.In a recent series of studies, investigators have used genetically engineered mice with deleted B 2 R 16 to further explore the physiological actions of bradykinin. Using these mice, we observed that the B 1 R is highly expressed in B 2 R knockout mice and appears to take over some of the hemodynamic properties of the B 2 R. 17 The present experiments were designed to further explore the metabolic function of t...

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

“…The first finding is that BRKO mice are insulin resistant, which is in agreement with a previous report that B2R-null mice are insulin-resistant (51). Thus the KKS may play an important role in insulin sensitivity in mice.…”

General aspects of muscle glucose uptake

“…Studies have shown that bradykinin influences glucose metabolism through both insulindependent and insulin-independent pathways (Motoshima et al 2000). It has been shown that the administration of bradykinin increases glucose uptake in cultured adipocytes and skeletal muscles of the forearm in humans (Duka et al 2001). In addition, bradykinin reduces hyperinsulinemia, decreases the concentration of plasma free fatty acids, improves glucose tolerance, increases insulin action in target tissues (Henriksen et al 1998) and enhances glucose transport through exercise (insulin-independent pathway) (Kishi et al 1998).…”

Bradykinin inhibits hepatic gluconeogenesis in obese mice

“…Duka et al 5 showed that the lean B2KO mice have significantly higher steady-state insulin levels, significantly lower glucose uptake rates and insulin sensitivity indexes, but did not analyze hepatic gluconeogenesis. We challenged these lean mice with the pyruvate tolerance test (Supplementary Figure S1) and we also carried out hepatic mRNA expression analysis of some gluconeogenesis factors (FoxO1, G6Pase, PEPCK and PGC-1; Supplementary Figure S2).…”

“…The kallikrein-kinin system (KKS) modulates pain, vasodilatation, vascular permeability, inflammation and edema and has been linked to insulin resistance. [4][5][6][7] Bradykinin (BK), the agonist of the constitutively expressed BK B2 receptor (BKB2R), has been reported to increase glucose uptake in skeletal muscle and adipose tissue. 8 At the same time, the kinin B1 receptor and its agonist, the des-arg 9 -kinin, have been shown to control leptin sensitivity 7 and insulin secretion.…”