Amino acids differentially regulate insulin receptor tyrosine kinase and phosphatidyl inositol-3-OH-kinase activities in human monocytes exposed to high glucose concentration

Abstract

<span style="mso-bidi-language:HI">Chronic hyperglycemia and insulin resistance are the common factors involved in the development of vascular complications in diabetes mellitus (DM) patients. Since insulin signaling pathway has been shown to be regulated by nutritional supplements, in the present study, we investigated the possible effects of free amino acids, such as lysine, arginine and alanine and their mixture in modulating the insulin receptor tyrosine kinase (IRTK) and phosphatidyl inositol-3-OH-kinase (PI3K) activities and on the changes in actin dynamics in monocytes (MC), exposed to high glucose

<span style="mso-bidi-language:HI">concentration (25 <span style="mso-bidi-font-family: Arial;mso-bidi-language:HI">m<i>M). </i><span style="mso-bidi-language: HI">IRTK and PI3K activities were markedly decreased in MC, incubated with 25 <span style="mso-bidi-font-family:Arial;mso-bidi-language:HI">m<i>M </i><span style="mso-bidi-language:HI">glucose. However, on treatment with amino acids, only lysine was effective in augmenting IRTK and PI3K activities in a dose-dependent

<span style="mso-bidi-language:HI">manner. Arginine had marginal effect in promoting these activities. Equimolar mixture of amino acids showed marginal effect of augmenting only IRTK activity. Alanine had no effect. The F-actin filaments showed grossly diminished

<span style="mso-bidi-language:HI">organization in the cells treated with 25 <span style="mso-bidi-font-family:Arial;mso-bidi-language:HI">m<i>M </i><span style="mso-bidi-language:HI">glucose alone, as assessed by specific binding to phalloidin-FITC, when compared with cells treated with 5 <span style="mso-bidi-font-family: Arial;mso-bidi-language:HI">m<i>M </i><span style="mso-bidi-language: HI">glucose. On the other hand, a significant improvement in the F-actin organization was observed in the cells co-incubated with 25 <span style="mso-bidi-font-family: Arial;mso-bidi-language:HI">m<i>M </i><span style="mso-bidi-language: HI">glucose and lysine. A possible molecular mechanism is the antiglycating effect of amino acids. The signal transduction starts with binding of ATP to lysine at position 1030 in the <span style="mso-bidi-font-family:Arial;mso-bidi-language: HI">β <span style="mso-bidi-language:HI">sub unit of the receptor. This lysine (1030) may be protected by the added lysine or to some extent arginine from glycation and loss of function. In summary, our findings suggest that the amino acids apart from their antiglycating property can also modulate/influence the activities of pivotal enzymes that are upstream in the insulin-mediated signal transduction pathway

<span style="mso-bidi-language:HI">and bring down glucose.

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