Effect of Vitamin D3 Supplementation on Insulin Resistance- The DIR Study

Study Overview
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Brief Summary
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Insulin resistance is a state where the body does not respond as it should to the insulin it produces. Individuals who are insulin resistant are at increased risk of both heart disease and type 2 diabetes; importantly, diabetes more than doubles the risk of heart disease, independent of other recognised risk factors. Interventions that prevent or reverse insulin resistance may help to attenuate risk of heart disease and diabetes. A number of randomised controlled trials provide proof of concept evidence regarding a beneficial effect of vitamin D on insulin resistance and other cardiovascular risk markers but experts have stated that further studies are required. Importantly, these studies should use appropriate endpoints, provide a high enough dose of vitamin D to optimise vitamin D status, and they should be conducted in clearly defined populations, The vitamin D trial we propose addresses these issues and aims to evaluate a potentially straightforward and low cost health care intervention for populations at highrisk of heart disease and diabetes. Specifically, this study would provide clinically relevant information on the metabolic effects of optimising vitamin D status in these high risk patients. This has clear economic and social implications given the current, and projected, burden of heart disease and diabetes. This study will investigate the effect of vitamin D3 supplementation on insulin resistance and cardiovascular risk factors in people at high risk of type 2 diabetes and cardiovascular disease using the gold standard euglycaemic hyperinsulinaemic clamp method.

Official Title
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Effect of Vitamin D3 Supplementation on Insulin Resistance and Cardiovascular Risk Factors in People at High Risk of Type 2 Diabetes and Cardiovascular Disease (The DIR Study)

Conditions
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Sub-optimal Vitamin D Status, Pre-diabetes, Insulin Resistance

Intervention / Treatment
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* Dietary Supplement: Vitamin D3 supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Impaired glucose tolerance (Fasting glucose <7.0 mmol/L (126mg/dl) and 2hr post-glucose load 7.8-11.0 mmol/L (140-199 mg/dl) or Impaired fasting glucose 5.6-6.9 mmol/L (100-125mg/dL) defined according to American Diabetes Association Sub-optimal vitamin D status (<50nmol/L) Exclusion Criteria: Diabetes mellitus Established cardiovascular disease Psychiatric problems Pregnant or lactating Medical conditions or dietary restrictions that would substantially limit ability to complete the study requirements Excessive alcohol consumption (>28 Units/week men or >21 Units/week women) Already taking vitamin D supplements > 10 µg/d Medical conditions or medications that could influence vitamin D metabolism History of kidney stones Hypercalcaemia Hyperparathyroidism Significant liver and renal disease (liver function tests >3x upper limit of normal and glomerular filtration rate <30ml/min)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vitamin D3 supplementation<br>Patients will take 3000IU (75 µg) Vitamin D3 supplementation per day for a period of 26 weeks. | Dietary Supplement: Vitamin D3 supplementation<br>* 3000IU (75µg) vitamin D3 will be given daily for a period of 26 weeks to the group who receive the active comparator. The efficacy of vitamin D3 supplementation on insulin resistance will be compared to the placebo group.<br>|
| Placebo Comparator: Placebo<br>Placebo group | Dietary Supplement: Vitamin D3 supplementation<br>* 3000IU (75µg) vitamin D3 will be given daily for a period of 26 weeks to the group who receive the active comparator. The efficacy of vitamin D3 supplementation on insulin resistance will be compared to the placebo group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Insulin Resistance | Insulin resistance will be measured using the gold standard euglycaemic-hyperinsulinaemic clamp method (note - it is anticipated that a total of 60 volunteers will complete the primary endpoint assessment). | Measured at baseline and after 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Vitamin D Status | Change in vitamin D status will be measured using the gold standard Ultra performance liquid chromatography followed by tandem mass spectrometry | Measured at baseline and after 6 months | 
| Change in Markers of Cardiovascular Risk | Measurements of seated and 24-hour ambulatory blood pressure, lipids, homeostasis model assessment (HOMA), HbA1c, and inflammatory and immune function markers including tumour necrosis factor-alpha and high sensitivity c-reactive protein | Measured at baseline and after 6 months | 
| Change in Carotid-femoral Pulse Wave Velocity (PWV) | Assessed by sequential tonometry with ECG gating using the SphygmoCor PWV System | Measured at baseline and after 6 months | 
| Change in Hand Grip Strength | Assessed using hand held dynamometer | Measured at baseline and after 6 months | 
| Health Status | SF-36 Questionnaire | Measured at baseline and after 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, Pre-diabetes, Insulin Resistance