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Browsing by Author "Simmons, Kimber"
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Item Proinsulin:C-peptide ratio trajectories over time in relatives at increased risk of progression to type 1 diabetes(Elsevier, 2021-02-19) Triolo, Taylor M.; Pyle, Laura; Seligova, Sona; Yu, Liping; Simmons, Kimber; Gottlieb, Peter; Evans-Molina, Carmella; Steck, Andrea K.; Medicine, School of MedicineObjective: Biomarkers are needed to characterize heterogeneity within populations at risk for type 1 diabetes. The ratio of proinsulin to C-peptide (PI:C ratio), has been proposed as a biomarker of beta cell dysfunction and is associated with progression to type 1 diabetes. However, relationships between PI:C ratios and autoantibody type and number have not been examined. We sought to characterize PI:C ratios in multiple islet autoantibody positive, single autoantibody positive and autoantibody negative relatives of individuals with type 1 diabetes. Methods: We measured PI:C ratios and autoantibodies with both electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA and ECL-IA2A) and radiobinding (RBA) assays (mIAA, GADA, IA2A and ZnT8A) in 98 relatives of individuals with type 1 diabetes followed in the TrialNet Pathway to Prevention Study at the Barbara Davis Center for a mean of 7.4 ± 4.1 years. Of these subjects, eight progressed to T1D, 31 were multiple autoantibody (Ab) positive, 37 were single Ab positive and 22 were Ab negative (by RBA). Results: In cross-sectional analyses, there were no significant differences in PI:C ratios between type 1 diabetes and/or multiple Ab positive subjects (4.16 ± 4.06) compared to single Ab positive subjects (4.08 ± 4.34) and negative Ab subjects (3.72 ± 3.78) (p = 0.92) overall or after adjusting for age, sex and BMI. Higher PI:C ratios were associated with mIAA titers (p = 0.03) and showed an association with ECL-IA2A titers (p = 0.09), but not with ECL-IAA, GADA, ECL-GADA, IA2A nor ZnT8A titers. In mixed-effects longitudinal models, the trajectories of PI:C ratio over time were significantly different between the Ab negative and multiple Ab positive/type 1 diabetes groups, after adjusting for sex, age, and BMI (p = 0.04). Conclusions: PI:C ratio trajectories increase over time in subjects who have multiple Ab or develop type 1 diabetes and may be a helpful biomarker to further characterize and stratify risk of progression to type 1 diabetes over time.Item Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children(Elsevier, 2017-04) Ballesteros, Luisa F. Gonzalez; Ma, Nina S.; Gordon, Rebecca J.; Ward, Leanne; Backeljauw, Philippe; Wasserman, Halley; Weber, David R.; DiMeglio, Linda A.; Gagne, Julie; Stein, Robert; Cody, Declan; Simmons, Kimber; Zimakis, Paul; Topor, Lisa Swartz; Agrawal, Sungeeta; Calabria, Andrew; Tebben, Peter; Faircloth, Ruth; Imel, Erik A.; Casey, Linda; Carpenter, Thomas O.; Department of Pediatrics, School of MedicineObjective Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. Methods A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. Results Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. Conclusion The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.