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Objective: Acute glycemic variability contributes to diabetic complications potentially through induction of inflammation. Our objective was to determine whether acute hyperglycemia affects urinary secretion of inflammatory cytokines/chemokines in humans with uncomplicated type 1 diabetes.Research Design and Methods: Blood pressure, renal hemodynamics (inulin and paraaminohippurate clearances), and urine samples were obtained after 6 h of clamped euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l) on two consecutive days in subjects with type 1 diabetes (n = 25). Forty-two urinary cytokines/chemokines were measured using a Luminex platform.Results: Clamped hyperglycemia produced an expected increase in glomerular filtration rate (131 ± 4 to 148 ± 8 ml/min/1.73 m²). Clamped hyperglycemia was associated with significant increases in urinary eotaxin, fibroblast growth factor-2, granulocyte-macrophage colony-stimulating factor, interferon-α 2, interleukin-2 and -12, monocyte chemoattractant protein-3, macrophage-derived chemokine, macrophage inflammatory protein-1α, platelet-derived growth factor, tumor necrosis factor-α, and CD40 ligand (P < 0.05).Conclusions: Acute hyperglycemia results in increased urinary excretion of inflammatory cytokines/chemokines in humans with uncomplicated type 1 diabetes, and this may contribute to kidney injury. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity (PA) is an important determinant of skeletal health. In young adults with type 1 diabetes (T1D) fracture risk is increased, yet few studies have examined the PA and bone health relationship. Therefore, this pilot cross-sectional study characterized PA levels and their association with bone parameters measured by high resolution peripheral quantitative computed tomography (HR-pQCT) in young adults with T1D., Methods: HR-pQCT (Xtreme CTII) was used to measure bone outcomes at the distal tibia and radius, and accelerometery (ActiGraph GT3X) recorded daily minutes of light and moderate-vigorous physical activity (MVPA). Quadratic regression analyses were conducted with a p -value ≤ 0.05 considered significant., Results: PA data from 19 young adults (23.1 ± 1.9 years) with T1D was analyzed. Over half (63 %) of participants completed ≥150 min of MVPA per week, however, most measured activity time per day (57 %) was spent in sedentary pursuits. Significant non-linear associations were found between the duration of MVPA and several trabecular bone parameters at the tibia., Conclusions: In young adults with T1D, MVPA may have site specific (tibia) and compartment specific (trabecular) non-linear associations with bone. Further studies should confirm these findings, which may help inform evidence-based exercise recommendations to optimize bone health in young adults with T1D., Competing Interests: The authors (Sarah L West, Michelle Furman, Rahim Moineddin, and Etienne Sochett) have no conflicts of interest, or competing interest to declare., (© 2024 The Authors. Published by Elsevier Inc.)

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n  = 6; crossover, n  = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z -score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks., Competing Interests: L.M.W. has been a consultant to Ultragenyx and Kyowa Kirin and participated in clinical trials with Ultragenyx Pharmaceutical Inc., with funds to Dr Ward’s institution. W.H. served as an investigator in clinical trials with, and as a consultant for, Ultragenyx Pharmaceutical Inc. and serves as a clinical investigator in clinical trials with, and has received research funding from, Kyowa Kirin. F.H.G. has been a consultant to, and participated in clinical trials with, Ultragenyx Pharmaceutical Inc. and Kyowa Kirin. A.A.P. has been a consultant to, and served as an investigator in clinical trials with, Ultragenyx Pharmaceutical Inc. M.P.W. has lectured for Ultragenyx Pharmaceutical Inc. C.F.M. is a consultant for Kyowa Kirin and has received research funding from Kyowa Kirin. O.N. has received speakers’ honoraria from Kyowa Kirin, Abbott, and BioMarin, consulting fees from Kyowa Kirin and BioMarin, and research support from Kyowa Kirin. J.H.S. has received institutional research funding from and personal honoraria for participation in an advisory board from Ultragenyx Pharmaceutical Inc. R.P. has no conflicts to disclose. N.N. has been a consultant to, and participated in clinical trials with, Kyowa Kirin. H.I.C. has been a consultant to, and participated in clinical trials with, Ultragenyx Pharmaceutical Inc. H.T. has received research funding from Kyowa Kirin co. Ltd. P.P. has been an employee of Lumos Pharma Inc. and owns stock in Lumos Pharma Inc. and Ascendis Pharma. G.S.G. has been a consultant for Ultragenyx Pharmaceutical Inc. A.C. and J.L.M. are employees of and own stock in Ultragenyx Pharmaceutical Inc. E.A.I. has been a consultant to, and participated in clinical trials with, Ultragenyx Pharmaceutical Inc. E.S., K.M., A.B., and F.P. report no conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Context: In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional therapy with active vitamin D and phosphate., Objective: We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy., Methods: Conventional therapy dose groups were defined as higher-dose phosphate [greater than 40 mg/kg] (HPi), lower-dose phosphate [40 mg/kg or less] (LPi), higher-dose alfacalcidol [greater than 60 ng/kg] or calcitriol [greater than 30 ng/kg] (HD), and lower-dose alfacalcidol [60 ng/kg or less] or calcitriol [30 ng/kg or less] (LD)., Results: At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses., Conclusion: Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum ALP more than continuing either higher or lower doses of phosphate or active vitamin D., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Idiopathic Infantile Hypercalcemia (IIH) is characterized by hypercalcemia and hypercalciuria owing to PTH-independent increases in circulating concentrations of 1,25(OH)2D. At least 3 forms of IHH can be distinguished genetically and mechanistically: infantile hypercalcemia-1 (Hypercalcemia, Infantile, 1; HCINF1) due to CYP24A1 mutations results in decreased inactivation of 1,25(OH)2D; HCINF2 due to SLC34A1 mutations results in excessive 1,25(OH)2D production; and HCINF3 in which a variety of gene variants of uncertain significance (VUS) have been identified and where the mechanism for increased 1,25 (OH)2D is unclear. Conventional management with dietary calcium and vitamin D restriction has only limited success. Induction of the P450 enzyme CYP3A4 by rifampin can provide an alternate pathway for inactivation of 1,25(OH)2D that is useful in HCINF1 and may be effective in other forms of IIH. We sought to assess the efficacy of rifampin to decrease levels of serum 1,25(OH)2D and calcium, and urinary calcium concentrations in subjects with HCINF3, and to compare the response to a control subject with HCINF1. Four subjects with HCINF3 and the control subject with HCINF1 completed the study using rifampin 5 mg/kg/day and 10 mg/kg/day each for 2 months separated by a 2-month washout period. Patients had age-appropriate intake of dietary calcium plus 200 IU vitamin D/day. Primary outcome was efficacy of rifampin to lower serum concentrations of 1,25(OH)2D. The secondary outcomes included the reduction of serum calcium, urinary calcium excretion (as random urine calcium: creatinine (ca:cr) ratio) and serum 1,25(OH)2D/PTH ratio. Rifampin was well tolerated and induced CYP3A4 at both doses in all subjects. The control subject with HCINF1 showed significant response to both rifampin doses with decreases in the serum concentration of 1,25(OH)2D and the 1,25(OH)2D/PTH ratio while the serum and urine ca:cr levels were unchanged. The four patients with HCINF3 showed reductions in 1,25(OH)2D and urinary ca:cr after 10 mg/kg/d, but hypercalcemia did not improve and there were variable responses in 1,25(OH)2D/PTH ratios. These results support further longer-term studies to clarify the usefulness of rifampin as a medical therapy for IIH., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)