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Innate Immune Signaling Drives Pathogenic Events Leading to Autoimmune DiabetesType 1 diabetes (T1D) is a chronic autoimmune disease characterized by the immune-mediated destruction of insulin-producing beta-cells of pancreatic islets, culminating in critical insulin deficiency. Both genetic and environmental factors likely orchestrate an immune-mediated functional loss of beta cell mass, leading to the clinical manifestation of disease and lifelong dependence on insulin therapy. Additional evidence suggests the role of innate and adaptive immune mechanisms leading to inflammation in beta cells mediated by proinflammatory cytokines and chemokines, activation of beta-cell-reactive T cells,and failure of immune tolerance. Viral infections have been proposed as causal determinants or initiating triggers for T1D but remain unproven. Understanding the relationship between viral infections and the development of T1D is essential for T1D prevention. Importantly, virus-induced innate immune responses, particularly type I interferon (IFN-I, IFN-a/b), have been implicated in the initiation of islet autoimmunity and development of T1D. The goal of my thesis project is to investigate how the IFN-I signaling pathway affects the development of T1D using the LEW.1WR1 rat model of autoimmune diabetes. My hypothesis is that disrupting IFN-Isignaling via functional deficiency of the IFN-I interferon receptor (IFNAR) prevents or delays the development of virus-induced diabetes.For this purpose, I generated IFNAR subunit 1(IFNAR1)-deficient LEW.1WR1 rats using CRISPR-Cas9 genome editing and confirmed the functional disruption of IFNAR1. The absence of IFNAR1 results in a significant delay in onset and frequency of diabetes following poly I:C challenge and reduces the incidence of insulitis after poly I:C treatment. The frequency of diabetes induced by Kilham rat virus (KRV) is also reduced in IFNAR1-deficient LEW.1WR1 rats. Furthermore, I observe a decrease in CD8+T cells in spleens from KRV-infected IFNAR1-deficient rats relative to that in KRV-infected wild-type rats. While splenic regulatory T cells are depleted in WT rats during KRV-infection, no such decrease is observed in KRV-infected IFNAR1-deficient rats. A comprehensive bulk RNA-seq analysis reveals a decrease of interferon-stimulated genes and inflammatory gene expression in IFNAR1-deficient rats relative to wild-type rats following KRV challenge. Collectively, the results from these studies provided mechanistic insights into the essential role of virus-induced, IFN-I-initiated innate immune responses in the early phase of autoimmune diabetes pathogenesis.
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Hepatic dysfunction is associated with vitamin D deficiency and poor glycemic control in diabetes mellitusBackground/Aims: The effect of the rising prevalence of nonalcoholic fatty liver disease on the 25-hydroxylation of pre-vitamin D in the liver, and consequent glycemic control in children with diabetes mellitus is not known. Our aim was to determine whether mild hepatic dysfunction was associated with impaired 25-hydroxylation of pre-vitamin D, and if this vitamin D deficiency was associated with impaired glycemic control in children and adolescents with type 1 diabetes (TIDM) and type 2 diabetes (T2DM). Methods: We analyzed simultaneously measured HbA1c, ALT, AST, and 25OHD levels and clinical parameters in 121 children and adolescents with T1DM (n=81) and T2DM (n=40). The subjects, ages 11–21 years, all had diabetes of >6 months duration. Multivariate linear regression was used to analyze the associations, while comparisons between subgroups were made using two-tailed Student’s t-test. Results: Vitamin D deficiency (25OHD/mL (37.5 nmol/L) was more prevalent in T2DM patients (47.5%) compared to T1DM patients (18.5%). Subjects with T2DM had significantly elevated transaminases (AST 39.3±2.0 vs. 22.4±1.4, p Conclusions: The association of elevated ALT with vitamin D deficiency suggests that hepatic dysfunction could impair vitamin D metabolism and negatively impact glycemic control in youth with T2DM.
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Frequency and Predictors of Self-Reported Hypoglycemia in Insulin-Treated DiabetesAIMS: Hypoglycemia is a limiting factor for achieving stringent glycemic control in diabetes. This study analyzes the frequency and predictors of hypoglycemia in insulin-treated diabetes in an ambulatory setting. METHODS: A retrospective chart review was performed to study self-monitored blood glucose (SMBG) data for 3 months prior to a patient's HbA1c test. RESULTS: Hypoglycemia occurred more frequently in type 1 than in type 2 diabetes; however, 19% of type 2 diabetes patients did experience at least one episode of severe hypoglycemia. For type 1 diabetes, hypoglycemia had a positive association with glycemic variability and duration of diabetes and a negative association with HbA1c and lowest blood glucose (BG). For type 2 diabetes, a positive association was noted with glycemic variability and a negative association with age and lowest BG. CONCLUSIONS: Delineating factors predisposing to hypoglycemia in type 2 diabetes is difficult. Lower HbA1c is a potential predictor of hypoglycemia in type 1 but not in type 2 diabetes. Longer duration of diabetes for type 1 and younger age for type 2 are associated with more hypoglycemia. Glycemic variability portends increased risk for hypoglycemia and should be a focus of further research.
