A Trial to Study the Effect of Long Term Vitamin D Supplementation on Insulin Sensitivity
Condition: Obesity; Insulin Resistance
MeSH terms: Insulin Resistance; Hypersensitivity
Study type: Interventional
Phase: Phase 4

Summary: 
      Type 2 diabetes is a major public health problem in India with an estimated a prevalence of
      approximately 4% and 12% in rural and urban areas respectively. Accumulating evidence
      suggests that serum cholecalciferol levels may be inversely related to the prevalence of
      diabetes, insulin resistance and metabolic syndrome. The trials available on the effect of
      Vitamin D supplementation on insulin/glucose metabolism have been conducted using small
      sample sizes in different subgroups document variable results (significant decrease in HbA1c
      concentration with insulin concentration in hemodialysis patients; insulin levels lower with
      oral Vitamin D in gestational diabetes; no effect of Vitamin D on serum insulin levels in
      post menopausal women). A double blind randomized controlled trial conducted at our institute
      using 3,60,000 IU of cholecalciferol over 6 weeks documented improvement in OGIS index of
      insulin sensitivity. We therefore, plan to study the long term effect of vitamin D
      supplementation on peripheral insulin sensitivity.
    

Detailed description: 
      Volunteers will be recruited from amongst the preventive health check subjects, neighboring
      offices, hospital employees and corporate associates of SBISR after obtaining a detailed
      informed consent. The study will include 300 subjects with the following selection criteria.

      INCLUSION CRITERIA

        1. 35 to 75 years of age

        2. Waist circumference (WC) ≥78 cm in men and ≥ 72 cm in women

      Recruited subjects will be randomized into two groups on the basis of random numbers
      generated by a computer after pre-stratification by gender (to allow equal representation of
      both sexes) and baseline Vitamin D levels. The baseline information will be recorded on
      standardized questionnaire include age, education, marital status, annual household income,
      family history, smoking and alcohol use. A complete physical examination will be done
      including height, weight, waist circumference and blood pressure. Weight will be recorded on
      a manual weighing scale (sensitivity 500 g), height using SECA stadiometer (sensitivity 0.1
      cm), waist circumference (WC) at the midpoint between the lower rib and iliac crest using a
      measuring tape (sensitivity 0.1 cm), and blood pressure using an OMRON electronic instrument
      (sensitivity 1 mmHg; accuracy 3 mmHg) validated in an earlier trial. Height, WC and weight
      will recorded with light clothing and without shoes. Three serial BP recordings from the
      right arm will be taken after 10 minutes of rest at 10 minute intervals in the sitting
      posture as per WHO recommendations. The mean of the three recordings will used for analysis.
      Daily sun exposure will be calculated by taking a detailed history of sun exposure separately
      during summers and winters and the type of clothing worn. Sun exposure will be calculated as
      hours of exposure per day x percentage of body surface area (BSA) exposed (calculated
      according to Wallace rule of nine). A detailed dietary assessment by the 24 hour recall
      method will be done at baseline to determine the dietary intake of calcium, phosphate and
      Vitamin D.

      Consenting subjects will be advised to fast from 8 pm of the previous night. 10 ml of blood
      will be drawn at baseline for the following tests between 9 am to 10 am on the next day.

        -  25 (OH) vitamin D levels

        -  Serum calcium and phosphorus

        -  Liver function tests including total proteins, SGOT, SGPT and alkaline phosphatase

        -  Serum creatinine levels The 3-hour Oral GTT will be done after a loading glucose dose of
           75 grams with blood sampling at 0, 120 and 180 minutes. The sampling arm will be warmed
           for 20 minutes prior to sampling to obtain arterialized venous samples. The blood
           samples will be immediately transported to the laboratory where plasma will be separated
           for all samples immediately. The samples will be labeled with a random numbers (to avoid
           revealing the time sequence of the samples to the laboratory) and stored at -70 C until
           assay.

      The subjects in the treatment group will be given cholecalciferol 120,000 IU monthly orally
      for one year (~ 4000 IU per day). This dose has been documented to be safe in an earlier
      review.The drug will be advised and provided to the subjects at enrollment. The control group
      will receive a placebo which will be identical in taste, color and texture. The subjects will
      be advised to continue their normal routine and lifestyle and to report immediately for any
      vomiting, headache, blurring of vision, abdominal pain, muscle cramps hematuria or hospital
      admission. For the purpose of the trial hypercalcemia would be defined as > 2.65 mmol/L,
      Urinary calcium: creatinine ratio and ultrasonography will be done if clinically indicated.
      Any volunteer developing any adverse effect would be treated as recommended and free of
      charge.. Compliance will be monitored by means of a home diary. A mid-term follow-up will be
      done at 6 months after recruitment. Instructions will be reinforced at the 6 month follow-up
      especially for subjects with poor compliance or other deviations. Final assessment will be
      done at 1 year (with margin of +10 days) after recruitment. Follow up assessment for any
      subject with a febrile illness will be postponed till 5 days after recovery from fever. A
      detailed dietary assessment by the 72 hour recall method will be done at baseline and at the
      two follow up visits to determine the dietary intake of calcium, ,phosphate and Vitamin D.
      All investigations done at baseline will be repeated at the two follow-up visits. The
      investigators and the laboratory will be blinded to the random allocation and the code will
      be broken only after the reports are available for all subjects.

      Outcome measures:

      The oral glucose sensitivity index as calculated by the Mari's formula as a measure of the
      post prandial insulin sensitivity will be evaluated as the primary outcome variable and the
      changes in the index will be compared between the supplemented and unsupplemented groups. The
      HOMA and QUICKI indices will be similarly analyzed as secondary outcomes indicating the
      fasting insulin sensitivity. The incidence of adverse effects will also be compared between
      the two groups as a secondary outcome.

      Biochemical Analysis The sample will be centrifuged at 3000 rpm and the serum/plasma would be
      stored at -70 C. Serum 25(OH) D will be measured by solvent extraction followed by
      radioimmunoassay (Diasorin, USA). Plasma Insulin will be measured by double antibody IRMA
      (IMMUNOTECH, France). PTH levels will also be estimated using the double antibody IRMA
      (IMMUNOTECH, France). 5% of the samples will be re-run for quality control.

      Sample size considerations It is estimated that a sample size of 98 subjects in each group
      will be required to detect a change in OGIS (Oral Glucose insulin sensitivity; primary
      outcome variable) of 10% with an alpha error of 0.05 and a power of 90% based on data
      available from the earlier trial conducted at the institute on the subject. To account for
      attrition over one year 150 subjects in each group will be recruited.

      Data Analysis Data entry and analysis will be done using Epi-Info 2002 and SPSS v13.0
      software. The values for plasma glucose and insulin at the specified times will be used to
      calculate the following indices OGIS calculated using the Mari's formula as described
      elsewhere will be the primary outcome variable.

      HOMA and QUICKI indices will be calculated from the fasting insulin and glucose samples.

      The student's't' test for paired values will be used to estimate the pre and post
      intervention differences in each group. The crude mean difference in two groups will be
      compared using the unpaired't' test. Non- compliant subjects and trial deviates will be
      analysed in the group allocated for the 'Intention to treat' analysis and will be excluded
      for the "per protocol analysis" for studying the differences between groups. The outcomes
      will be adjusted for known confounders including age, waist circumference, BMI, baseline
      insulin sensitivity, changes in Vitamin D and PTH levels. The subjects will be stratified by
      their baseline 25 (OH) D levels into deficient and non-deficient for analysis. Regression
      analysis will be used to study the relationship of baseline characteristics with the outcome
      variables.
    

Intervention name(s): Cholecalciferol; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Oral Cholecalciferol sachets 120,000 IU monthly for 1 year; 2 sachets monthly for an year
Other intervention name(s): Calcirol
Intervention MeSH terms: Cholecalciferol; Vitamin D
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Vitamin D; Insulin sensitivity; Centrally obese