Secondary Prevention of Diabetes Type 1 with Oral Calcitriol and Analogs, the PRECAL Study

Abstract

Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3–6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1–4 mcg × 1–3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5–10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32–1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1–4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month–2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.

Refined protocol for newly onset identification in non-obese diabetic mice: an animal-friendly, cost-effective, and efficient alternative

“…Early onset period is crucial for diabetes treatment [ 7 ], but screening of NOD mice in the newly onset phase can be laborious and challenging. When BG levels before onset are not absolutely required for studies, conducting massive BG tests to identify near onset mice can be extremely inefficient.…”

“…However, unlike human cases, NOD mouse model exhibits strong sex bias with a higher incidence in female mice ranging from 60 to 90% and a lower incidence in male mice ranging from 20 to 50%, depending on the individual colony [ 3 , 4 ]. Given the importance of early intervention in autoimmune diseases, identifying mice near or newly diabetes onset is crucial for therapeutic treatments [ 5 – 7 ]. BG testing is the conventional standard for diagnosing diabetes, with a BG level exceeding the threshold (ranging from 200 to 400 mg/dl) in one or two consecutive tests to confirm the overt diabetes state [ 8 – 10 ].…”

Intense Testing and Use of Vitamin D Supplements Leads to Slow Improvement in Vitamin D Adequacy Rates: A Cross-Sectional Analysis of Real-World Data

“…Despite that explosive rise in VDT, the rise in VDS use is much slower and the rates of adequacy achieved are even much lower, mostly limited to those using high-dose supplements continuously. Recently, an interesting novel public health strategy has been proposed regarding vitamin D repletion and supplementation, using the upper tolerable doses—as defined by the Endocrine Society’s guidelines’ expert committee—for 6–8 weeks, followed by continuous maintenance doses all year long except sunny vacations, which are characterized as not requiring medical supervision at Endocrine Society’s vitamin D guidelines and are at the same time recognized as upper tolerable by the former Institute of Medicine (IOM) [ 36 , 37 ]. Our results are in complete accordance with such a strategy that seems able to assure vitamin D sufficiency in the optimal range of 40–60 ng/mL, minimizing costs for testing and medical supervision.…”