Case Report: Insulin hypersensitivity in youth with type 1 diabetes.

Objective: Immediate type I, type III, and delayed type IV hypersensitivity reactions to insulin are rare, but potentially serious complications of exogenous insulin administration required for the treatment of type 1 diabetes (T1D). Methods: We present four cases of insulin hypersensitivity reactions occurring in youth with T1D and a literature review of this topic. Results: Insulin hypersensitivity reactions included types I, III, and IV with presentations ranging from localized urticaria, erythematous nodules, and eczematous plaques to anaphylaxis with respiratory distress. Reactions occurred in youth with newly diagnosed T1D and in those with long-standing T1D who were using both injection and insulin pump therapy. Multidisciplinary care involving pediatric endocrinology and allergy/immunology utilizing trials of many adjunct therapies yielded minimal improvement. Despite the use of various treatments, including antihistamines, topical therapies, immunosuppressant medications, desensitization trials, and intravenous immune globulin, cutaneous reactions, elevated hemoglobin A1c levels, and negative effects on quality of life remain persistent challenges. One patient became one of the youngest pancreas transplant recipients in the world at age 12 years due to uncontrollable symptoms and intolerable adverse effects of attempted therapies. Conclusion: Although rare, insulin hypersensitivity reactions negatively affect glycemic control and quality of life. These cases demonstrate the varying severity and presentation of insulin hypersensitivity reactions along with the limited success of various treatment approaches. Given the life-sustaining nature of insulin therapy, further studies are needed to better understand the underlying pathophysiology of insulin hypersensitivity and to develop targeted treatment approaches.

Pleiotropic defects in TCR signaling in a Vav-1-null Jurkat T-cell line.

The Rac/Rho-specific guanine nucleotide exchange factor, Vav-1, is a key component of the T-cell antigen receptor (TCR)-linked signaling machinery. Here we have used somatic cell gene-targeting technology to generate a Vav-1-deficient Jurkat T-cell line. The J.Vav1 cell line exhibits dramatic defects in TCR-dependent interleukin (IL)-2 promoter activation, accompanied by significant reductions in the activities of the NFAT(IL-2), NFkappaB, AP-1 and REAP transcription factors that bind to the IL-2 promoter region. In contrast, loss of Vav-1 had variable effects on early TCR-stimulated signaling events. J.Vav1 cells display a selective defect in sustained Ca(2+) signaling during TCR stimulation, and complementation of this abnormality by exogenously introduced Vav-1 is dependent on the Vav-1 calponin homology domain. While JNK activation was severely impaired, the stimulation of Ras, ERK and protein kinase C-theta activities, as well as the mobilization of lipid rafts, appeared normal in the J.Vav1 cells. Finally, evidence is presented to suggest that the alternative Vav family members, Vav-2 and Vav-3, are activated during TCR ligation, and partially compensate for the loss of Vav-1 in Jurkat T cells.