Can Vitamin D Supplementation Prevent Type 2 Diabetes?

Study Overview
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Brief Summary
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The aim of this study is to determine whether vitamin D supplementation in overweight/obese individuals with vitamin D deficiency can improve insulin secretion and/or insulin resistance by decreasing subclinical inflammation. Results of the present study may help to identify new strategies to prevent type 2 diabetes in high-risk groups (i.e. overweight and obese individuals, and individuals with a strong family history of diabetes). Hypothesis: That increasing plasma 25(OH)D concentrations in healthy individuals at risk for type 2 diabetes with low vitamin D levels through vitamin D supplementation, will improve insulin sensitivity and also insulin secretion by reducing the underlying sub-clinical chronic inflammation. Aims: To establish whether 16-week vitamin D supplementation given to healthy individuals with low vitamin D levels will: improve insulin sensitivity (in vivo and tissue) and/or insulin secretory function determine whether this relationship is mediated by a reduced chronic inflammation

Detailed Description
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Numerous studies documented that low vitamin D levels are a serious health risk. Despite the sunny climate in Australia, low vitamin D status is becoming increasingly prevalent and people with vitamin deficiency represent more than 30% of the healthy Australian population. Although sun exposure can maintain good vitamin D levels, often sun exposure is limited as people work long hours indoors, and use sunscreen or protective clothing to reduce skin cancer risk when outdoors. Moreover, it is difficult to obtain sufficient vitamin D from food alone; few foods are naturally rich in vitamin D and in Australia, few foods are fortified. While the importance of vitamin D for bone mineralization is well known, it is less clear how vitamin D protects against type 2 diabetes and cardiovascular disease. Every day in Australia around 275 adults develop diabetes and its prevalence continues to rise. We are therefore arguing for a well-designed intervention trial to define the preventive potential and physiological mechanisms of the effects of vitamin D supplementation. In addition, we plan to explore the mechanisms underlying the relationship between vitamin D deficiency and the risk for type 2 diabetes, via its influence on chronic inflammation. Our clinical trial will focus on healthy adults with low vitamin D status and will examine the effects on insulin sensitivity and secretion measured by 'gold standard' methodology when vitamin D is restored to optimum levels. It is in particularly important to determine whether vitamin D affects both or only one of these defects because there is evidence from observational studies that there is a relationship between vitamin D levels and both insulin sensitivity and secretion. The proposed intervention study will potentially supply important evidence on how restoring vitamin D levels may protect against type 2 diabetes. Such findings could have direct relevance for novel approaches to diabetes prevention.

Official Title
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Can Vitamin D Supplementation Prevent Type 2 Diabetes by Improving Insulin Sensitivity and Secretion in Overweight Humans?

Conditions
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Type 2 Diabetes Mellitus

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 or <60 years, 25(OH)D < 50 nmol/L Weight change < 5 kg in last 12 months BMI >25kg/m2 but weight <159kg due to DEXA scan restrictions Non-diabetic, no allergy, non-smoker, no high alcohol use No current intake of medications including vitamin supplements No kidney, cardiovascular, haematological, respiratory, gastrointestinal, endocrine or central nervous system disease, as well as no psychiatric disorders, no active cancer within the last five years; no presence of acute inflammation (by history, physical or laboratory examination) Not menopausal, pregnanct or lactating Exclusion Criteria: Age <18 or > 60 years 25(OH)D > 50 nmol/L Weight change > 5 kg in last 12 months Diabetes (diagnosed or oral glucose tolerance test (OGTT), hypercalcaemia, allergy Current smoking habit, high alcohol use Current intake of medications including vitamin supplements Kidney, cardiovascular, haematological, respiratory, gastrointestinal, endocrine or central nervous system disease, as well as psychiatric disorder, active cancer within the last five years; presence of acute inflammation (by history, physical or laboratory examination) Menopause, pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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 |
| --- | --- |
| Experimental: Vitamin D Group<br>Each participant will be given an initial stat dose of 2500 μg (100,000 IU) of Ostelin (Reckitt Benckiser). Thereafter, participants will take 100 μg/day (4,000 IU, 4 tablets) Ostelin daily for a period of 16 weeks. | Dietary Supplement: Vitamin D<br> <br> * Other names: Ostellin;|
| Placebo Comparator: Placebo group<br>Each participant will be given an equivalent number of placebo tablets | Dietary Supplement: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial Insulin Sensitivity Measure using Euglycaemic glucose clamp | The clamp will be used to measure insulin sensitivity. The clamp is initiated by an intravenous bolus injection of insulin (9milliUnit/kg). Insulin is then constantly infused at a rate of 40 milliUnit.m-2.min-1 for 120 min into an arm vein, whilst glucose is variably infused to maintain euglycaemia. Plasma glucose values will be monitored every 5 minutes during the clamp and the variable infusion rate of glucose is adjusted to maintain blood glucose at a constant value of 5mmol/L. | Week 1 | 
| Follow up Insulin Sensitivity Measure using Euglycaemic glucose clamp | The clamp will be used to measure insulin sensitivity. The clamp is initiated by an intravenous bolus injection of insulin (9milliUnit/kg). Insulin is then constantly infused at a rate of 40 milliUnit.m-2.min-1 for 120 min into an arm vein, whilst glucose is variably infused to maintain euglycaemia. Plasma glucose values will be monitored every 5 minutes during the clamp and the variable infusion rate of glucose is adjusted to maintain blood glucose at a constant value of 5mmol/L. | Week 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial measurement of inflammatory markers | Plasma inflammatory markers (interleukin 1β, 6, 8 and 10, TNFα, macrophage migration inhibitory factor, monocyte chemotactic protein-1) will be measured by quantitative sandwich enzyme immunoassays (R & D Systems Inc, USA) (interassay Coefficients of Variation: 7.2%, 10.2%, 5.8%, respectively). Plasma C- reactive protein (hsCRP) via a high sensitivity assay (BN-II nephelometer; Dade Behring Diagnostics, NSW). | Week 1 | 
| Follow Up Measurement of inflammatory markers | Plasma inflammatory markers (interleukin 1β, 6, 8 and 10, TNFα, macrophage migration inhibitory factor, monocyte chemotactic protein-1) will be measured by quantitative sandwich enzyme immunoassays (R & D Systems Inc, USA) (interassay Coefficients of Variation: 7.2%, 10.2%, 5.8%, respectively). Plasma C- reactive protein (hsCRP) via a high sensitivity assay (BN-II nephelometer; Dade Behring Diagnostics, NSW). | Week 17 | 
| Initial Measure of Adiposity (DEXA) | body composition by dual energy x-ray absorptiometry (DEXA), which is a non-invasive assessment of soft tissue composition by region with a precision of 4-5%; central adiposity assessed in duplicate using a constant-tension tape for taking waist, and hip circumference. Bioimpedance measurement will be also collected for validation purposes. | Week 1 | 
| Follow Up Measure of Adiposity (DEXA) | body composition by dual energy x-ray absorptiometry (DEXA), which is a non-invasive assessment of soft tissue composition by region with a precision of 4-5%; central adiposity assessed in duplicate using a constant-tension tape for taking waist, and hip circumference. Bioimpedance measurement will be also collected for validation purposes. | Week 17 | 
| Initial Oral Glucose Tolerance Test - OGTT | After a 10-12 h overnight fast, participants will ingest 75g of glucose over 2 mins. Blood samples will be drawn at 0, 30, 60, 90 and 120 min for plasma glucose and insulin concentrations. We will evaluate the area under the curve. | Week 1 | 
| Follow Up Oral Glucose Tolerance Test -OGTT | After a 10-12 h overnight fast, participants will ingest 75g of glucose over 2 mins. Blood samples will be drawn at 0, 30, 60, 90 and 120 min for plasma glucose and insulin concentrations. We will evaluate the area under the curve. | Week 17 | 
| Initial Acute Insulin Secretory Response - Intravenous Glucose Tolerance Test | This will be measured in response to 25g intravenous glucose and calculated as the average incremental plasma insulin level from the third to the fifth minute after the glucose bolus. | Week 1 | 
| Follow up Acute Insulin Secretory Response- Intravenous Glucose Tolerance Test | This will be measured in response to 25g intravenous glucose and calculated as the average incremental plasma insulin level from the third to the fifth minute after the glucose bolus. | Week 17 |