DIABETES ENHANCEMENT AND INCREASED ISLET ANTIGEN EXPRESSION FOLLOWINGNEONATAL INJECTIONS OF GLUCOSE AND ARGININE IN NONOBESE DIABETIC MICE

Modulation of beta-cell antigens at birth may affect the course of typ e I diabetes. Since the functional state of beta cells modulates antig en expression, we investigated whether neonatal injections of glucose and arginine (G-A) influence diabetes in non-obese diabetic (NOD) mice . Two groups of 90 mice (45 female, 45 male) were injected for the fir st 6 days of life with GA or saline. To determine whether these inject ions influenced beta cell functional maturation, isolated islets were characterized according to insulin response to glucose or arginine. Mo dulation of antigens for islet-cell autoantibodies (ICA antigens) was analyzed by indirect immunofluorescence using ICA-positive human sera. Variations of pancreatic glutamic acid decarboxylase 67-kD (GAD 67) m RNA were evaluated by polymerase chain reaction (PCR), hybridization w ith a P-32-labeled probe, and densitometry of the autoradiographic ban ds. Female NOD mice treated with G-A displayed diabetes earlier and wi th a higher incidence (P < .01) than control mice, whereas the diabete s incidence was not statistically modified in G-A-treated male NOD mic e. Insulitis was more severe (P < .03) in 2-month old G-A-treated fema le NOD mice than in control mice, but was not statistically modified i n male NOD mice. In both sexes, ICA antigens and GAD 67 mRNA were high er in G-A-treated mice than in control mice (P < .01). Islets isolated after neonatal G-A injections exhibited improved insulin sensitivity to both stimuli (P < .01). Splenocyte subsets analyzed by cytofluorome try, as well as splenocyte proliferations in the presence of concanava lin or rat insulinoma cells or during syngeneic mixed-lymphocyte react ion, were not modified after G-A treatment. We conclude that neonatal injections of G-A enhance diabetes in female NOD mice. Even though hyp otheses as to the direct effects on the immune system or deleterious e ffects of glucose and arginine on the beta cells cannot be excluded, t he mechanisms behind the clinical effect could be related to accelerat ed maturation of beta cells and overexpression of islet antigens durin g the completion of immune self-tolerance, or to amplification of the destructive process due to the existence of more targets for effector cells. The same treatment does not significantly affect diabetes in ma le NOD mice whose resistance to disease could not he overcome simply b y peripheral modulation of beta-cell antigens. Copyright (C) 1994 by W .B. Saunders Company