Effect of Vitamin D Supplementation on Glucose Tolerance in Subjects at Risk for Diabetes With Low Vitamin D.

Study Overview
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Brief Summary
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Type 2 diabetes (T2D) is an increasingly common and serious condition. Studies show that low vitamin D levels are associated with increased diabetes risk and that vitamin D may protect against diabetes by reducing chronic inflammation and improving insulin sensitivity and insulin secretion. However, no studies have been able to show that vitamin D actually reduces post-prandial blood glucose levels, the most clinically relevant marker of diabetes. Previously the investigators have shown that cheddar cheese and low-fat cheese can be fortified with high levels of vitamin D and that this cheese is at least as a effective as vitamin D supplements in raising blood vitamin D levels. The main purpose of this study is to see whether vitamin D enriched cheese can improve oral glucose tolerance (reduce blood glucose 2 hours after consuming a drink containing 75g sugar) in people who have low vitamin D levels and are at risk for developing T2D. Other aims are to determine the effect of vitamin D may on insulin sensitivity, insulin secretion, markers of inflammation, blood cholesterol levels, and safety markers such as urinary calcium excretion.

Detailed Description
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Type 2 diabetes (T2D) is an increasingly prevalent and serious condition whose risk appears to be increased by low serum vitamin D concentrations. Epidemiological studies show an association between increased diabetes risk and low serum vitamin D and studies suggest that vitamin D may protect against diabetes by reducing chronic inflammation and improving insulin sensitivity and insulin secretion. Although clinical studies show some of these effects, no studies have been able to show that vitamin D supplementation reduces post-prandial blood glucose, the most clinically relevant marker of diabetes and dysglycemia. Previously, the investigators showed that cheddar cheese and low-fat cheese can be fortified with high levels of vitamin D3 (28,000IU/ 30g portion) and that, in this form, it is at least as a effective as vitamin D3 supplements in raising serum vitamin D concentrations. Since post-prandial glucose is most sensitive to changes in insulin sensitivity the main purpose of this study is to determine the effect of vitamin D supplementation on oral glucose tolerance (ie. serum glucose 2h after 75g oral glucose) in individuals who are at risk for developing T2D. Secondary objective are to determine the effect of vitamin D supplementation on insulin sensitivity, insulin secretion, inflammatory markers, blood lipids and markers of safety including serum parathyroid hormone levels and urinary calcium excretion.

Official Title
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Effect of Vitamin D Supplementation on Oral Glucose Tolerance in Subjects Exhibiting Marginal Vitamin D Status and an Increased Risk of Developing Diabetes.

Conditions
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Type 2 Diabetes Mellitus, Vitamin D Deficiency

Intervention / Treatment
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* Dietary Supplement: Control
* Dietary Supplement: Vitamin D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male or non-pregnant, non-lactating females, aged 18-75 volunteered to participate by signing the consent form BMI <40kg/ m2 vitamin D insufficient, defined as: serum 25(OH) vitamin D3 (25(OH)D) concentration ≤65nmol/ L increased risk for diabetes, defined as: FINDRISC score >10 for Caucasians or >6 for non-Caucasians OR presence of metabolic syndrome dysglycemia, defined as:fasting serum glucose 5.6 to 6.9 mmol/L, inclusive OR HbA1c 0.054 to 0.064, inclusive systolic blood pressure ≤150/95 mmHg if not being treated for hypertension or ≤140/90 mmHg if on treatment for hypertension. taking no prescription drugs, or stable (for at least 6 weeks) dose of birth control pill, or drug(s) used to treat hypertension, hyperlipidemia, depression or other mental illness or hypothyroid. taking no supplements, or stable (for at least 6 weeks) dose of supplement(s). Exclusion Criteria: subjects not meeting all inclusion criteria history of renal failure or liver disease serum creatinine >1.8 times upper limit of normal (ULN) serum aspartate or alanine transaminase (AST,ALT) >3 times ULN current use of drug or drugs to treat diabetes or use of steroids or pancreatic enzymes within 6 weeks of randomization, change in dose of supplements or drug(s) used to treat hypertension, hyperlipidemia, depression or other mental illness or hypothyroid. use of antibiotics within 3 months. medical or surgical event requiring hospitalization within 3 months of randomization presence of any condition affecting nutrient absorption intolerance to cheese plan to travel outside Canada for more than 14 consecutive days during the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>30g normal cheddar cheese once per week | Dietary Supplement: Control<br>* Normal cheddar cheese<br>|
| Experimental: Vitamin D<br>30g cheddar cheese containing 28,000IU vitamin D once per week | Dietary Supplement: Vitamin D<br>* Vitamin D3 supplemented cheddar cheese<br>* Other names: Vitamin D3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma glucose concentration 2 hours after consuming 75g oral glucose (2 hour PC glucose, or 2hrPC glucose) | Change from baseline in plasma glucose concentration 2 hours after consuming 75g oral glucose. | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin resistance assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) | Change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR) which is G*I/22.5 where G is fasting plasma glucose (mmol/L) and I is fasting plasma insulin (uU/mL). | 24 weeks | 
| Change in Matsuda insulin sensitivity index | Change from baseline in Matsuda insulin sensitivity index which is (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]). | 24 weeks | 
| Change in insulin secretion assessed using the homeostasis model assessment of beta-cell function (HOMA-B) | Change from baseline in homeostasis model assessment of beta-cell function (HOMA-B) which is 20*I/(G-3.5) where I is fasting plasma insulin (uU/mL) and G is fasting plasma glucose (mmol/L). | 24 weeks | 
| Change in insulinogenic index | Change from baseline in insulinogenic index which is dI0-30/dG0-30, where dI0-30 is the change in plasma insulin between fasting and 30min and dG0-30 is the change in plasma glucose between fasting and 30min after 75g oral glucose. | 24 weeks | 
| Change in disposition index derived from HOMA-IR and HOMA-B | Change from baseline in disposition index which is HOMA-B/HOMA-IR, which have been defined above. | 24 weeks | 
| Change in disposition index based on oral glucose tolerance test (OGTT) | Change from baseline in ISSI-2 index which is AUCi/AUCg x Matsuda insulin sensitivity index, where AUCi and AUCg, respectively, are the total areas under the plasma insulin and glucose response curves after 75g oral glucose and Matsuda insulin sensitivity index has been defined above. | 24 weeks | 
| Change in fasting plasma glucose | Change from baseline in fasting plasma glucose | 24 weeks | 
| Change in glucose area under the curve | Change from baseline in incremental area under the glucose response curve after 75g oral glucose | 24 weeks | 
| Change in glycated hemoglobin | Change from baseline in glycated hemoglobin (HbA1c) | 24 weeks | 
| Correlation between changes in serum 25-hydroxy-vitamin D concentration (25(OH)D) and changes in 2 hour PC glucose | Correlation between change from baseline in serum 25-hydroxy-vitamin D concentration and change from baseline in plasma glucose 2 hours after 75g oral glucose. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized controlled clinical trial, Diabetes, Vitamin D, Oral glucose tolerance, Blood glucose, Insulin resistance