Correction of Vitamin D Levels and Its Effect on Insulin Resistance and Weight Gain in Obese Youth

Study Overview
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Brief Summary
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Vitamin D deficiency is extremely common in obese youth. In our obese population followed in the Endocrinology clinic at Children's Medical Center Dallas, vitamin D levels were inversely correlated with a measure of insulin resistance. We propose to show that correction of vitamin D levels in obese children and adolescents improves their insulin sensitivity. Obese youth presenting to the Center for Obesity and its Consequences on Health (COACH) clinic will be randomized to receive either the most recent Institute of Medicine (IOM) recommendations of minimum D3 dose of 600 IU/day (1), or receive higher doses of D3 such that the blood levels of vitamin D will be brought to a target level in either the low part or high part of the normal range. The goal is to determine if correction of vitamin D deficiency will improve insulin sensitivity in this group. Secondary goals include determining whether correction of vitamin D deficiency in obese adolescents and children results in less weight gain, and determining the amount of D3 required to correct vitamin D levels in this population. Our specific hypotheses are as follows: Hypothesis #1 Obese youth treated with Vitamin D3 who achieve low-normal 25-hydroxyvitamin D3 (OHD) levels (30-50 ng/mL) or high-normal 25-OHD levels (60-80 ng/mL) will have improved insulin resistance, as measured by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), compared to those individuals with deficient 25-OHD levels (< 30 ng/mL). Hypothesis #2 Subjects with a higher BMI will have higher Vitamin D dose requirements than current IOM recommendations of 600 IU/day and will take a longer period of time to reach target 25-OHD levels. Hypothesis #3 Subjects with normal 25-OHD levels will demonstrate less weight gain compared to subjects on the control arm.

Detailed Description
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Concise Summary of Project: The proposed study is a prospective, unblinded dose-ranging trial to examine in obese youth 1) the effect of correcting Vitamin D (Vit D) deficiency on insulin resistance, 2) the effect of correcting Vit D deficiency on weight gain, and 3) the amount of Vit D3 required to achieve Vit D sufficiency in obese adolescents. Subjects will be recruited from obese children and adolescents aged 6 to 17 years presenting to the COACH clinic, a referral clinic for obese children at Children's Medical Center of Dallas. Approximately 1300 new patients are seen in the COACH clinic each year. Ethnicity will be self-assigned as African-American, Caucasian, Hispanic, or Other. The ethnic makeup of the COACH clinic over the last 20 months was as follows: African-American 25%, Caucasian 19.5%, Hispanic 52%, and Other 3.5%. As per standard practice in the COACH clinic, a height (cm), weight (kg), and blood pressure will be obtained, and body mass index (kg/m2) calculated for each patient. Fasting total cholesterol, LDL, HDL, triglyceride, 25-OHD, Hemoglobin A1c (A1c), and fasting insulin will be obtained, and an Oral Glucose Tolerance Test (OGTT) performed. The baseline estimate of insulin sensitivity is calculated from the fasting insulin and glucose values, and reported as the HOMA-IR. After Informed Consent has been obtained, participants will be randomized to either the Control group (5000 IU/wk), the Low-normal 25-OHD group (target 25-OHD 30-50 ng/mL), or the High-normal 25-OHD group (target 25-OHD 60-80 ng/mL). A 25-OHD < 25 ng/mL will be confirmed. These groups will be matched for age (6-12 years versus 13-17 years) and ethnicity (Caucasian versus African-American verus Hispanic). Approximately 60 patients will be recruited for each group. Subject participation will continue until Vit D sufficiency has been documented for 4 consecutive months, at which point the fasting insulin and glucose values will be repeated for calculation of HOMA-IR and assessment of insulin sensitivity, and amount of weight gain will be measured.

Official Title
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Normalization of Vitamin D Levels and Its Effect on Glucose Homeostasis in Obese Youth

Conditions
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Obesity, Insulin Resistance, Vitamin D Deficiency

Intervention / Treatment
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* Drug: Vitamin D3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 6-17 years BMI > 95% for age serum 25-OH D level < or + to 25 ng/mL Exclusion Criteria: BMI < 95% for age serum 25-OH D level > 25 ng/mL current Vitamin D supplementation > 400 IU/day anti-convulsant therapy, anti-hypertensive therapy, lipid lowering medication any medications that affect glucose metabolism (e.g., metformin, insulin) daily glucocorticoid therapy diabetes any disorders of bone or calcium metabolism hepatic or renal disease any malabsorptive disorder baseline serum Calcium > 11 ng/dL (> 2 SD above the mean) any genetic disorder that predisposes to obesity (e.g., Prader Willi hypothalamic obesity

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Group<br>Standard vitamin D3 dose as per IOM (Institute of Medicine) recommendations; actual dose will be 5000 IU per week, which is just slightly higher than the IOM recommendation of 600 IU per day. Length of time proposed to be 4 months at 5000 IU D3 per week. End of study measures at 4 months to be HOMA-IR, BMI Z score, 25-OHD level. | Drug: Vitamin D3<br>* Vitamin D3, liquid formulation, 5000 IU/mL.<br>* Other names: calcidiol;|
| Experimental: Low-Normal Group<br>Initial D3 dose will be 30,000 IU per week; at 6 week intervals serum D3 levels will be checked, and dose adjustments made to reach target 25-OHD level of between 30-50 ng/mL (inclusive). Once within target, D3 dose will be continued for 4 months, and end of study measurements done (HOMA-IR, BMI Z score, 25-OHD level). | Drug: Vitamin D3<br>* Vitamin D3, liquid formulation, 5000 IU/mL.<br>* Other names: calcidiol;|
| Experimental: High-Normal Group<br>Initial D3 dose will be 60,000 IU/week; at 6 week intervals 25-OHD levels will be done, and dose adjustments made to achieve target level of 40-60 ng/mL (inclusive). Once within target range, D3 dose will be continued for 4 months, and end of study measures obtained (HOMA-IR, BMI Z score, 25-OHD level). | Drug: Vitamin D3<br>* Vitamin D3, liquid formulation, 5000 IU/mL.<br>* Other names: calcidiol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HOMA-IR | Change in HOMA-IR from initial visit to end-of-study visit; i.e., the value at the later time point minus the value at the earlier time point. HOMA-IR= Fasting insulin (mIU/ml) x Fasting glucose (mg/dl) / 405. | 4-12 mo after randomization (4 months after target 25-hydroxyvitamin D level is reached). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Normalization of Vit D Level Versus BMI Z Score | The time required to reach a normal Vitamin D level (> 30) versus BMI Z score at each vitamin D3 dose; OR vitamin D level at 6 weeks versus BMI Z score at each starting vitamin D3 dose. | 1 to 12 months | 
| Change in BMI Z-score | The change in BMI z-score from baseline to end-of-study visit; i.e., the value at the later time point minus the value at the earlier time point. The BMI Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of a reference population (i.e., healthy, age and sex-matched children). Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population. | 4-12 mo after randomization (4 months after target 25-hydroxyvitamin D level is reached). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Insulin Resistance, Vitamin D Deficiency, Children, Adolescents