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(Journal of Leukocyte Biology. 2001;70:395-404.)
© 2001 by Society for Leukocyte Biology

Agonist-dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia

Linda M. McManus^*,, Rebecca C. Bloodworth^*, Thomas J. Prihoda^*,, Janet L. Blodgett and R. Neal Pinckard^*,

Departments of
^* Pathology,
Periodontics,
Psychiatry, and
Medicine, The University of Texas Health Science Center and
^|| South Texas Veterans Administration Hospital, San Antonio, Texas

Correspondence: Linda M. McManus, Department of Pathology—MSC 7750, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail: mcmanus{at}uthscsa.edu

Inexplicable controversies with regard to possible functional defects of neutrophilic polymorphonuclear leukocytes (PMNs) in diabetes persist. The purpose of the present study was to elucidate the relative effectiveness of several PMN agonists in stimulating lysosomal-enzyme secretion and leukotriene (LT) B₄ production by PMNs isolated from diabetic subjects. Formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) induced significantly less lysosomal-enzyme secretion and LTB₄ production in diabetic-subject PMNs than in normal-subject PMNs. It is surprising that PMNs from these same diabetic subjects responded normally after stimulation with A23187, serum-opsonized zymosan, or phorbol myristate acetate. The in vitro responsiveness of PMNs stimulated with fMLP or PAF was inversely correlated with indices of in vivo glycemic control (fasting plasma glucose and glycated-hemoglobin levels). In combination, these results indicate that hyperglycemia is associated with sustained decreases in PMN function but only in response to agonists that initiate stimulus-response coupling via G-protein-coupled receptors. This agonist-selective reduction in PMN responsiveness may contribute to the compromised host defense associated with sustained hyperglycemia in diabetes.

Key Words: fMLP • GPCR • inflammation • LTB4 • PAF

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