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

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].

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.