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Bradykinin Augments Insulin-Stimulated Glucose Transport in Rat Adipocytes via Endothelial Nitric Oxide Synthase–Mediated Inhibition of Jun NH₂-Terminal Kinase

¹ Department of Medicine and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
² Banting and Best Diabetes Centre, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada

Address correspondence and reprint requests to Dr. I. George Fantus, Mount Sinai Hospital, 600 University Ave., Lebovic Building, Suite 5-028, Toronto, ON, Canada M5G 1X6. E-mail: fantus{at}mshri.on.ca

Abbreviations: 2DG, 2-deoxyglucose; ACEI, ACE inhibitor; AngII, angiotensin II; ARB, angiotensin receptor blocker; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal–regulated kinase; GFP, green fluorescent protein; iNOS, inducible nitric oxide synthase; IRS-1, insulin receptor substrate-1; JNK, Jun NH₂-terminal kinase; KKP, kallikrein-kinin pathway; LDM, low-density microsome; L-NAME, N-nitro-L-arginine methyl ester hydrochloride; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; NOS, nitric oxide synthase; nNOS, neuronal nitric oxide synthase; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; PTIO, 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazol-1-oxyl-3-oxide potassium salt; RAS, renin-angiotensin system; SNP, sodium nitroprusside; TNF, tumor necrosis factor

An increase in bradykinin has been suggested to contribute to the enhanced insulin sensitivity observed in the presence of ACE inhibitors. To investigate a potential direct, nonvascular effect on an insulin target tissue, the effect of bradykinin on glucose uptake and insulin signaling was studied in primary rat adipocytes. Whereas basal glucose uptake was not altered, bradykinin augmented insulin-stimulated glucose uptake twofold, which was blocked by HOE-140, a bradykinin B₂ receptor antagonist. The bradykinin effect on glucose uptake was nitric oxide (NO) dependent, mimicked by NO donors and absent in adipocytes from endothelial NO synthase^–/– mice. Investigation of insulin signaling revealed that bradykinin enhanced insulin receptor substrate-1 (IRS-1) Tyr phosphorylation, Akt/protein kinase B phosphorylation, and GLUT4 translocation. In contrast, insulin-stimulated extracellular signal–regulated kinase1/2 and Jun NH₂-terminal kinase (JNK) activation were decreased in the presence of bradykinin, accompanied by decreased IRS-1 Ser³⁰⁷ phosphorylation. Furthermore, bradykinin did not enhance insulin action in the presence of the JNK inhibitor, SP-600125, or in adipocytes from JNK1^–/– mice. These data indicate that bradykinin enhances insulin sensitivity in adipocytes via an NO-dependent pathway that acts by modulating the feedback inhibition of insulin signaling at the level of IRS-1.

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