Role of Vitamin D in the Prevention and Treatment of Diseases Associated With Insulin Resistance

Study Overview
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Brief Summary
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Prospective, randomized and placebo-controlled 6-month trial of vitamin D supplementation in 130 Caucasian and vitamin D-deficient men and women aged 25 years and over. Participants will have abdominal obesity and at least one factor associated with insulin resistance. Participants will be randomized by sex, BMI and age. The primary aim is to compare the effect of daily vitamin D3 (cholecalciferol, 5000 IU) vs. placebo for 6 mo on insulin sensitivity (M-value by the gold standard method, the euglycemic hyperinsulinemic clamp). Secondary aims are to evaluate the effects of vitamin D3 vs. placebo on other indices of glucose metabolism, the lipid profile, blood pressure and anthropometric measurements. Questionnaires on physical activity and sunlight exposure, and a food frequency questionnaire will be administered at 0 and 6 mo to adjust for confounding factors. At 0 and 6 mo, changes in serum 25(OH)D will be correlated with changes in blood markers associated with insulin sensitivity [hs-CRP, inflammatory cytokines (IL-6 and TNF-alpha), adiponectin, leptin, total and undercarboxylated osteocalcin]. This research project intends to test 2 major hypotheses: (1) that vitamin D deficiency plays a causal role in the pathogenesis of insulin resistance in humans; and (2) that vitamin D increases insulin sensitivity.

Detailed Description
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Part 1: Prospective, randomized and placebo-controlled 6-month trial of vitamin D supplementation in 130 Caucasian and vitamin D-deficient [serum 25(OH)D ≤55 nM] men and women aged 25 years and over with a BMI ≤40 kg/m2. Participants will have abdominal obesity (increased waist circumference of at least 102 cm for men and 88 cm for women) and at least one factor associated with insulin resistance, namely: (1) serum triglyceride levels of at least 1.7 mmol/L or treated dyslipidemia; (2) prediabetes or untreated type 2 diabetes (HbA1c >=5.6% or fasting glucose >=5.6 mmol/L or glucose 2h post OGTT >=7.8 mmol/L); (3) first degree relative with type 2 diabetes; (4) history of gestational diabetes. Participants will be randomized according to sex, BMI (<30 kg/m2 vs. 30 kg/m2 and over) and age (< or >=50 years old). The primary aim is to compare the effect of daily vitamin D3 (cholecalciferol, 5000 IU) vs. placebo for 6 mo on insulin sensitivity (M-value by the gold standard method, the euglycemic hyperinsulinemic clamp). Secondary aims are to evaluate the effects of vitamin D3 vs. placebo on other indices of glucose metabolism (fasting glucose, 2-h plasma glucose post OGTT, HbA1c, insulin sensitivity index (HOMA-IS using fasting glucose and insulin), insulin secretion index (HOMA-B using fasting glucose and C-peptide), insulinogenic index [(C-peptide at 30 min post OGTT - C-peptide at 0 min)/(glucose at 30 min post OGTT - glucose at 0 min)] and disposition index (insulinogenic index x M-value)), the lipid profile, blood pressure and anthropometric measurements (weight, waist and hip circumference, bioimpedance analysis). Questionnaires on physical activity and sunlight exposure, and a food frequency questionnaire will be administered at 0 and 6 mo to adjust for confounding factors. At 0 and 6 mo, biochemical markers associated with insulin sensitivity will be measured (point 2). Part 2: Mechanistic studies comparing, before and after vitamin D3 supplementation, changes in serum 25(OH)D with changes in blood markers associated with insulin sensitivity [hs-CRP, inflammatory cytokines (IL-6 and TNF-alpha), adiponectin, leptin, total and undercarboxylated osteocalcin].

Official Title
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Role of Vitamin D in the Prevention and Treatment of Diseases Associated With Insulin Resistance

Conditions
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Vitamin D-deficient, Insulin-resistant

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian men and women ≥25 yrs vitamin D deficiency [serum 25(OH)D concentration ≤55 nM] Abdominal obesity (waist circumference >=102 cm for men and >=88 cm for women) AND at least one factor associated with insulin resistance: (1) fasting serum triglycerides >=1.7 mmol/L or treated dyslipidemia; (2) prediabetes or untreated type 2 diabetes (HbA1c >=5.6% or fasting glucose >=5.6 mmol/L or 2h glucose post OGTT >=7.8 mmol/L); (3) first degree relative with type 2 diabetes; (4) history of gestational diabetes. Exclusion Criteria: Type 2 diabetes under drug therapy HbA1c >7% BMI >40 kg/m2 pregnancy or breast-feeding; medication influencing vitamin D or glucose metabolism in the last 3 mo regular consumption of supplements containing >400 IU/d of vitamin D3 over the last 2 mo; renal insufficiency (creatinine clearance <60 ml/min); cirrhosis, intestinal malabsorption (bypass surgery, celiac disease, etc); osteoporosis; history of nephrolithiasis; hypercalcemia (>2.6 mM); hypercalciuria (>0.6 fasting urine Ca/creatinine ratio); >5% change in weight in the last 3 mo; diseases affecting glucose metabolism (e.g. hyperthyroidism); pacemaker (for bioimpedance only); inability to provide informed consent and complete questionnaires due to physical or mental problems.

Ages Eligible for Study
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Minimum Age: 25 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D supplementation<br>5000 IU of vitamin D3 for 6 months | Dietary Supplement: Vitamin D<br> <br> |
| Placebo Comparator: Placebo<br>Placebo pill for 6 months | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in peripheral insulin sensitivity assessed by the euglycemic-hyperinsulinemic clamp between placebo and vitamin D groups | M-value | 0 and 6 months | 
| Change in peripheral insulin sensitivity assessed by the euglycemic-hyperinsulinemic clamp between placebo and vitamin D groups | M/I ratio | 0 and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin sensitivity indice assessed by fasting- and oral glucose tolerance test between placebo and vitamin D groups | HOMA2%S | 0 and 6 months | 
| Change in insulin sensitivity indice assessed by fasting- and oral glucose tolerance test between placebo and vitamin D groups | Matsuda index | 0 and 6 months | 
| Change in insulin secretion indice between placebo and vitamin D groups | area under the curve for C-peptide | 0 and 6 months | 
| Change in insulin secretion indice between placebo and vitamin D groups | HOMA2-B | 0 and 6 months | 
| Change in insulin secretion indice between placebo and vitamin D groups | insulinogenic index | 0 and 6 months | 
| Change in B-cell function between placebo and vitamin D groups | Disposition index | 0 and 6 months | 
| Change in metabolic markers between placebo and vitamin D groups | HbA1c | 0 and 6 months | 
| Change in metabolic markers between placebo and vitamin D groups | Fasting glucose | 0 and 6 months | 
| Change in metabolic markers between placebo and vitamin D groups | 2h glucose post-OGTT | 0 and 6 months | 
| Change in anthropometry between placebo and vitamin D groups | Weight | 0 and 6 months | 
| Change in anthropometry between placebo and vitamin D groups | BMI | 0 and 6 months | 
| Change in anthropometry between placebo and vitamin D groups | waist circumference | 0 and 6 months | 
| Change in anthropometry between placebo and vitamin D groups | hip circumference | 0 and 6 months | 
| Change in anthropometry between placebo and vitamin D groups | fat mass by bioimpedance analysis | 0 and 6 months | 
| Change in blood pressure between placebo and vitamin D groups | Systolic and diastolic blood pressure | 0 and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D supplementation, Insulin resistance