Diabetes enhancement and increased islet antigen expression following neonatal injections of glucose and arginine in non-obese diabetic mice

Modulation of β-cell antigens at birth may affect the course of type I diabetes. Since the functional state of β cells modulates antigen 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 first 6 days of life with G-A or saline. To determine whether these injections influenced β cell functional maturation, isolated islets were characterized according to insulin response to glucose or arginine. Modulation 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) mRNA were evaluated by polymerase chain reaction (PCR), hybridization with a 32P-labeled probe, and densitometry of the autoradiographic bands. Female NOD mice treated with G-A displayed diabetes earlier and with a higher incidence (P < .01) than control mice, whereas the diabetes incidence was not statistically modified in G-A-treated male NOD mice. Insulitis was more severe (P < .03) in 2-month-old G-A-treated female NOD mice than in control mice, but was not statistically modified in male NOD mice. In both sexes, ICA antigens and GAD 67 mRNA were higher 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 cytofluorometry, as well as splenocyte proliferations in the presence of concanavalin or rat insulinoma cells or during syngeneic mixed-lymphocyte reaction, were not modified after G-A treatment. We conclude that neonatal injections of G-A enhance diabetes in female NOD mice. Even though hypotheses as to the direct effects on the immune system or deleterious effects of glucose and arginine on the β cells cannot be excluded, the mechanisms behind the clinical effect could be related to accelerated maturation of β cells and overexpression of islet antigens during 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 male NOD mice whose resistance to disease could not be overcome simply by peripheral modulation of β-cell antigens.