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Recognition of β-cell antigens by autoreactive T cells is a critical step in the initiation of autoimmune type1 diabetes. A complete protection from diabetes development in NOD mice harboring a point mutation in the insulin B-chain 9-23 epitope points to a dominant role of insulin in diabetogenesis. Generation of NOD mice lacking the chromogranin A protein (NOD.ChgA-/-) completely nullified the autoreactivity of the BDC2.5 T cell and conferred protection from diabetes onset. These results raised the issue concerning the dominant antigen that drives the autoimmune process. Here we revisited the NOD.ChgA-/- mice and found that their lack of diabetes development may not be solely explained by the absence of chromogranin A reactivity. NOD.ChgA-/- mice displayed reduced presentation of insulin peptides in the islets and periphery, which corresponded to impaired T-cell priming. Diabetes development in these mice was restored by antibody treatment targeting regulatory T cells or inhibiting transforming growth factor-β and programmed death-1 pathways. Therefore, the global deficiency of chromogranin A impairs recognition of the major diabetogenic antigen insulin, leading to broadly impaired autoimmune responses controlled by multiple regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Activation of the polyol pathway has been linked to the development of secondary diabetic complications. However, the underlying molecular mechanisms remain unclear. To probe the contribution of this pathway, we examined whether inhibition of aldose reductase, which catalyzes the first step of the pathway, affects hyperglycemia-induced activation of the inflammatory transcription factor nuclear factor (NF)-kappaB. Treatment of vascular smooth muscle cells with the aldose reductase inhibitors tolrestat and sorbinil prevented high-glucose-induced protein kinase C (PKC) activation, nuclear translocation of NF-kappaB, phosphorylation of IKK, and the increase in the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and aldose reductase. High-glucose-induced NF-kappaB activation was also prevented by the PKC inhibitors chelerythrine and calphostin C. Ablation of aldose reductase by small interference RNA (siRNA) prevented high-glucose-induced NF-kappaB and AP-1 activation but did not affect the activity of SP-1 or OCT-1. Stimulation with iso-osmotic mannitol activated NF-kappaB and increased the expression of aldose reductase but not ICAM-1 and VCAM-1. Treatment with aldose reductase inhibitors or aldose reductase siRNA did not affect mannitol-induced NF-kappaB or AP-1 activation. Administration of tolrestat (15 mg . kg(-1) . day(-1)) decreased the abundance of activated NF-kappaB in balloon-injured carotid arteries of diabetic rats. Collectively, these results suggest that inhibition of aldose reductase, which prevents PKC-dependent nonosmotic NF-kappaB activation, may be a useful approach for treating vascular inflammation caused by diabetes. [ABSTRACT FROM AUTHOR]

Increased glucose utilization by aldose reductase (AR) has been implicated in the development of diabetes complications. However, the mechanisms that regulate AR during diabetes remain unknown. Herein we report that several nitric oxide (NO) donors prevent ex vivo synthesis of sorbitol in erythrocytes obtained from diabetic or nondiabetic rats. Compared with erythrocytes of nondiabetic rats, the AR activity in the erythrocytes of diabetic rats was less sensitive to inhibition by NO donors or by AR inhibitors-sorbinil or tolrestat. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, enhanced AR activity and sorbitol accumulation in tissues of nondiabetic rats. Application of transdermal nitroglycerin patches or treatment with L-arginine did not inhibit AR activity or sorbitol accumulation in the tissues of nondiabetic animals. Treatment with L-NAME increased, whereas treatment with L-arginine or nitroglycerine patches decreased AR activity and sorbitol content in tissues of diabetic rats. These observations suggest that NO maintains AR in an inactive state and that this repression is relieved in diabetic tissues. Thus, increasing NO availability may be a useful strategy for inhibiting the polyol pathway and preventing the development of diabetes complications. [ABSTRACT FROM AUTHOR]