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Item Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions(Springer Verlag, 2018-10-17) Goldberg, Ronald B.; Bray, George A.; Marcovina, Santica M.; Mather, Kieren J.; Orchard, Trevor J.; Perreault, Leigh; Temprosa, Marinella; Medicine, School of MedicineWe compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. METHODS: The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. RESULTS: E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). CONCLUSIONS/INTERPRETATION: These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.Item Selectin Dependence of Allergic Skin Inflammation Is Diminished by Maternal Atopy(American Association of Immunologists, 2021-08-25) Khan, Ibrahim M.; Ulrich, Benjamin J.; Nelson, Andrew S.; Sehra, Sarita; Kansas, Geoffrey S.; Kaplan, Mark H.; Microbiology and Immunology, School of MedicineAllergic skin inflammation requires the influx of inflammatory cells into the skin. Extravasation of leukocytes into the skin requires interactions between endothelial selectins and their glycan ligands on the surface of leukocytes. Selectin-ligand formation requires the activity of several glycosyltransferases, including Fut7 In this report, we tested the importance of Fut7 for the development of allergic skin inflammation in the Stat6VT transgenic mouse model. We observed that Fut7 deficiency was protective but did not eliminate disease. Segregation of the data by gender of the parent that transmitted the Stat6VT transgene, but not by gender of the pups, which were analyzed for disease, revealed that the protective effects of Fut7 deficiency were significantly greater when dams were Stat6VT negative. In contrast, in mice from litters of Stat6VT+ dams, Fut7 deficiency resulted in only modest protection. These findings indicate that pups from atopic dams exhibit a greater propensity for allergic disease, similar to observations in humans, and that the effect of maternal atopy is due to enhanced selectin-independent mechanisms of leukocyte recruitment in their offspring. Together, these results demonstrate that Fut7 deficiency can be protective in a model of atopic dermatitis but that maternal atopy diminishes these protective effects, suggesting alternative pathways for leukocyte recruitment in the absence of Fut7 enzyme activity. These observations have implications for understanding how the environment in utero predisposes for the development of allergic disease.