MACROPHAGE FUNCTION IN ALLOXAN-DIABETIC MICE - EXPRESSION OF ADHESIONMOLECULES, GENERATION OF MONOKINES AND OXYGEN AND NO RADICALS

The increased incidence of bacterial and mycotic infections in poorly controlled diabetic patients or animals is frequently attributed to im paired activities of professional phagocytes (granulocytes, macrophage s) in hypoinsulinaemic milieu. We measured production of monokines (IL -6 and tumour necrosis factor-alpha (TNF-alpha)), active NO and reacti ve oxygen intermediates (ROIs), as well as expression of several cell surface adhesion molecules (Mac-l, -2 and -3, intercellular adhesion m olecule-1 (ICAM-1) and Fc gamma RII), by thioglycollate medium-induced peritoneal macrophages of normoglycaemic and alloxan diabetic CBA/J m ice (blood glucose level in the range 300 or 500 mg/dl). Macrophages o f animals with moderate diabetes (300 mg/dl) produced significantly mo re IL-6 and TNF-alpha and ROIs than cells of control mice and showed a n increased expression of all cell surface molecules, except Mac-3. NO /NO2 production was not affected. Administration of insulin restored e nhanced values to normal levels, except for the production of ROIs whi ch remained unusually high. We conclude that two separate mechanisms i nfluence macrophage physiology in diabetes-lack of saturation of insul in receptors on macrophages and an indirect effect due to formation of advanced glycosylation endproducts (AGE) on their surfaces. The latte r is possibly responsible for increased generation of ROIs, since it c annot be down-regulated by prolonged insulin treatment. How the increa sed activity of macrophages of moderately diabetic mice (enhanced prod uction of proinflammatory monokines and oxygen radicals as well as exp ression of molecules) is related to their ability to kill bacteria is now under investigation.