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Bradykinin enhances GLUT4 translocation through the increase of insulin receptor tyrosine kinase in primary adipocytes: evidence that bradykinin stimulates the insulin signalling pathway

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Summary

It has been suggested that bradykinin stimulates glucose uptake in experiments in vivo and in cultured cells. However, its mechanism has not yet been fully elucidated. In this study, the effects of bradykinin on the insulin signalling pathway were evaluated in isolated dog adipocytes. The bradykinin receptor binding study revealed that dog adipocytes possessed significant numbers of bradykinin receptors (Kd=83 pmol/l, binding sites = 1.7×104 site/cell). Reverse transcription-polymerase chain reaction amplification showed the mRNA specific for bradykinin B2 receptor in the adipocytes. Bradykinin alone did not increase 2-deoxyglucose uptake in adipocytes; however, in the presence of insulin (10−7 mol/l) it significantly increased 2-deoxyglucose uptake in a dose-dependent manner. Bradykinin also enhanced insulin stimulated GLUT4 translocation from the intracellular fraction to the cell membrane, and insulin induced phosphorylation of the insulin receptor Β subunit and insulin receptor substrate-1 (IRS-1) without affecting the binding affinities or numbers of cell surface insulin receptors in dog adipocytes. The time-course of insulin stimulated phosphorylation of the insulin receptor Β subunit revealed that phosphorylation reached significantly higher levels at 10 min, and stayed at the higher levels until 120 min in the presence of bradykinin, suggesting that bradykinin delayed the dephosphorylation of the insulin receptor. It is concluded that bradykinin could potentiate insulin induced glucose uptake through GLUT4 translocation. This effect could be explained by the potency of bradykinin to upregulate the insulin receptor tyrosine kinase activity which stimulates phosphorylation of IRS-1, followed by GLUT4 translocation.

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Abbreviations

NIDDM:

non-insulin-dependent diabetes mellitus

IRS-1:

insulin receptor substrate-1

PI3′-kinase:

phosphatidylinositol 3′-kinase

GLUT4:

glucose transporter type 4

HEPES:

N-(2-hydroxyethyl)-piperazine-N′-2-ethane sulphonic acid

PMSF:

phenylmethyl sulphonyl fluoride

BSA:

bovine serum albumin

PBS:

phosphate buffered saline

HBSS:

Hanks' balanced salt solution

LDM:

low density microsome

RT-PCR:

reverse transcriptase-polymerase chain reaction

PL(C, A):

phospholipase (C, A)

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Authors and Affiliations

  1. Department of Metabolic Medicine, Kumamoto University School of Medicine, 1-1-1, Honjo, 860, Kumamoto, Japan

    S. Isami, H. Kishikawa, E. Araki, M. Uehara, K. Kaneko, T. Shirotani, M. Todaka, S. Ura, S. Motoyoshi, K. Matsumoto, N. Miyamura & M. Shichiri

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  1. S. Isami
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  2. H. Kishikawa
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  3. E. Araki
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Isami, S., Kishikawa, H., Araki, E. et al. Bradykinin enhances GLUT4 translocation through the increase of insulin receptor tyrosine kinase in primary adipocytes: evidence that bradykinin stimulates the insulin signalling pathway. Diabetologia 39, 412–420 (1996). https://doi.org/10.1007/BF00400672

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  • DOI: https://doi.org/10.1007/BF00400672

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