Browsing by Subject "Type 1 Diabetes (T1D)"

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    Analysis of serum Hsp90 as a potential biomarker of β cell autoimmunity in type 1 diabetes
    (PLOS, 2019-01-10) Ocaña, Gail J.; Sims, Emily K.; Watkins, Renecia A.; Ragg, Susanne; Mather, Kieren J.; Oram, Richard A.; Mirmira, Raghavendra G.; DiMeglio, Linda A.; Blum, Janice S.; Evans-Molina, Carmella; Microbiology and Immunology, School of Medicine
    Heat shock protein 90 (Hsp90) is a protein chaperone that is upregulated and released from pancreatic β cells under pro-inflammatory conditions. We hypothesized that serum Hsp90 may have utility as a biomarker of type 1 diabetes risk and exhibit elevations before the onset of clinically significant hyperglycemia. To this end, total levels of the alpha cytoplasmic isoform of Hsp90 were assayed in autoantibody-positive progressors to type 1 diabetes using banked serum samples from the TrialNet Pathway to Prevention Cohort that had been collected 12 months prior to diabetes onset, with comparison to age, sex, and BMI-category matched autoantibody-positive nonprogressors and healthy controls. Hsp90 levels were higher in autoantibody-positive progressors and nonprogressors ≤ 18 years of age compared to matched healthy controls. However, Hsp90 levels were not different between progressors and nonprogressors in any age group. Hsp90 was positively correlated with age in control subjects, but this correlation was absent in autoantibody positive individuals. In aggregate these data indicate that elevated Hsp90 levels are present in youth with β cell autoimmunity, but are not able to distinguish youth or adult type 1 diabetes progressors from nonprogressors in samples collected 12 months prior to diabetes development.
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    eIF5A inhibition influences T cell dynamics in the pancreatic microenvironment of the humanized mouse model of Type 1 Diabetes
    (Springer Nature, 2019-02-07) Imam, Shahnawaz; Prathibha, R.; Dar, Pervaiz; Almotah, Khalil; Al-Khudhair, Ahmed; Hasan, Syed Abdul-Moiz; Salim, Nancy; Jilani, Talha Naser; Mirmira, Raghavendra G.; Jaume, Juan Carlos; Pediatrics, School of Medicine
    We have developed a transgenic mouse model of Type 1 Diabetes (T1D) in which human GAD65 is expressed in pancreatic β-cells, and human MHC-II is expressed on antigen presenting cells. Induced GAD65 antigen presentation activates T-cells, which initiates the downstream events leading to diabetes. In our humanized mice, we have shown downregulation of eukaryotic translation initiation factor 5 A (elF5A), expressed only in actively dividing mammalian cells. In-vivo inhibition of elF5A hypusination by deoxyhypusine synthase (DHS) inhibitor "GC7" was studied; DHS inhibitor alters the pathophysiology in our mouse model by catalyzing the crucial hypusination and the rate-limiting step of elF5A activation. In our mouse model, we have shown that inhibition of eIF5A resets the pro-inflammatory bias in the pancreatic microenvironment. There was: (a) reduction of Th1/Th17 response, (b) an increase in Treg numbers, (c) debase in IL17 and IL21 cytokines levels in serum, (d) lowering of anti-GAD65 antibodies, and (e) ablation of the ER stress that improved functionality of the β-cells, but minimal effect on the cytotoxic CD8 T-cell (CTL) mediated response. Conclusively, immune modulation, in the case of T1D, may help to manipulate inflammatory responses, decreasing disease severity, and may help manage T1D in early stages of disease. Our study also demonstrates that without manipulating the CTLs mediated response extensively, it is difficult to treat T1D.
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    Nighttime is the worst time: Parental fear of hypoglycemia in young children with type 1 diabetes
    (Wiley, 2018-02) Van Name, Michelle A.; Hilliard, Marisa E.; Boyle, Claire T.; Miller, Kellee M.; DeSalvo, Daniel J.; Anderson, Barbara J.; Laffel, Lori M.; Woerner, Stephanie E.; DiMeglio, Linda A.; Tamborlane, William V.; Pediatrics, School of Medicine
    BACKGROUND: Fear of hypoglycemia is common in parents of young children with type 1 diabetes (T1D), but little is known about the specific fears that parents most often experience. Hypoglycemia fear has been associated with poorer glycemic control in older children, though not yet studied in a large cohort of very young children. MATERIALS AND METHODS: Parents of 549 children <7 years (mean 5.2 ± 1.2 years [19% <3 years]) with a mean diabetes duration of 2.4 ± 1.0 years (range 1-6 years) and mean HbA1c 8.2% ± 1.1% (66 ± 12 mmol/mol) registered in the T1D Exchange completed the worry scale of the Hypoglycemia Fear Survey modified for parents (HFS-P). RESULTS: Mean parental fear of hypoglycemia worry score was 36.1 ± 23.1 (possible range 0-100), with most frequent worries related to the child having a low while asleep and the child not recognizing a low. The mean worry score was not associated with the child's age, glycemic control, or recent severe hypoglycemic event. Parental worries about lows while sleeping were significantly higher in pump users than non-users (61% vs. 45%; P < .001), and tended to be higher in CGM users than non-users (62% vs 51%; P = .02). CONCLUSIONS: The greatest worries of parents of young children with T1D were related to hypoglycemia during sleep and other times/circumstances during which it would be difficult to detect hypoglycemia. Using advanced diabetes technologies may be an effort to temper fears about hypoglycemia during sleep, though the directionality of this relationship is undetermined. Additional studies can clarify this association and leverage use of diabetes technologies to improve glycemic control.