The proposed epidemiologic research is based on our prior 28-year achievements in the development of unique populations and our stored serum and lymphocyte libraries. These resources will be used to search for environmental triggers that initiate beta cell destruction or precipitate clinical diabetes. We will use cutting edge T lymphocyte technology in order to identify presumably viral precipitators of autoimmunity and factors that may accelerate the prediabetes process to clinical disease. We will seek to differentiate those with high-risk HLA alleles who progress rapidly to total destruction of insulin producing beta cells, from those who have an indolent autoimmune course or present with clinical diabetes without the usual multiple autoantibodies. The hypotheses to be tested are: 1) a typical T-cell V? bias is associated with enteroviral infection and with the autoimmune progression of prediabetes. 2) T-cell autoimmunity is precipitated by environmental triggers and precedes the appearance of autoantibodies. Increasing numbers of T-cell responses and autoantibodies are markers of progressive prediabetes. 3) Insulin resistance and / or obesity are diabetes accelerators in subjects with slowly progressive autoimmunity. 4) There are less T- and B-cell antigen spreading and more insulin resistance in obese and slowly progressive compared to rapidly progressing first degree relatives, with progression defined as antigen spreading and clinical diabetes.. Data derived from these research strategies, initiated 4 years ago, will give data regarding the environmental pathogenesis of T1D and identify the initial autoimmune abnormalities and insight into the reasons for variations of rates of progression to multiple antibody positivity in high-risk first-degree T1D relatives. These will assist in the design of intervention strategies in future studies. This research will also form the basis for other potential substudies of the T lymphocyte characteristics that are different in very young and older T1D children, allow further investigation of new genetic markers associated with these T cell responses and new autoantibody markers .
OF THE PROJECT Human and animal research has demonstrated that the development of autoantibodies directed against the islet cells that make insulin is a prelude of clinically overt type 1 diabetes mellitus, but is a relatively late event in the destruction of these islet cells. This destruction is mediated by the white cells of the blood (T-cells) and we have shown that these T-cells can be measured in human blood. It is likely that the appearance of these white cells will mark the environmental trigger which initiates of the destructive process. Our research is directed at finding out whether this trigger could be viral infection and whether the epidemic of obesity might initiate or accelerate islet cell destruction in some individuals.
|Haidet, Jaime; Cifarelli, Vincenza; Trucco, Massimo et al. (2012) C-peptide reduces pro-inflammatory cytokine secretion in LPS-stimulated U937 monocytes in condition of hyperglycemia. Inflamm Res 61:27-35|
|Bonner, Samantha M; Pietropaolo, Susan L; Fan, Yong et al. (2012) Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. J Biol Chem 287:17882-93|
|Helgeson, Vicki S; Honcharuk, Erin; Becker, Dorothy et al. (2011) A focus on blood glucose monitoring: relation to glycemic control and determinants of frequency. Pediatr Diabetes 12:25-30|
|Cifarelli, V; Geng, X; Styche, A et al. (2011) C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells. Diabetologia 54:2702-12|
|Morran, Michael P; Casu, Anna; Arena, Vincent C et al. (2010) Humoral autoimmunity against the extracellular domain of the neuroendocrine autoantigen IA-2 heightens the risk of type 1 diabetes. Endocrinology 151:2528-37|
|Luppi, P; Geng, X; Cifarelli, V et al. (2009) C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes. Diabetologia 52:2218-28|
|Ma, Xiaosu; Becker, Dorothy; Arena, Vincent C et al. (2009) The effect of age on insulin sensitivity and insulin secretion in first-degree relatives of type 1 diabetic patients: a population analysis. J Clin Endocrinol Metab 94:2446-51|
|Banwell, Brenda; Bar-Or, Amit; Cheung, Roy et al. (2008) Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes. Ann Neurol 63:98-111|
|Tsui, Hubert; Chan, Yin; Tang, Lan et al. (2008) Targeting of pancreatic glia in type 1 diabetes. Diabetes 57:918-28|
|Libman, Ingrid M; Sun, Kang; Foley, Thomas P et al. (2008) Thyroid autoimmunity in children with features of both type 1 and type 2 diabetes. Pediatr Diabetes 9:266-71|
Showing the most recent 10 out of 79 publications