Rationale and Design of the Vitamin D and Type 2 Diabetes (D2d) Study: A Diabetes Prevention Trial (original) (raw)
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Background: Despite Australia's sunny climate, low vitamin D levels are increasingly prevalent. Sun exposure is limited by long working hours, an increase in time spent indoors, and sun protection practices, and there is limited dietary vitamin D fortification. While the importance of vitamin D for bone mineralization is well known, its role as a protective agent against chronic diseases, such as type 2 diabetes and cardiovascular disease, is less understood. Observational and limited intervention studies suggest that vitamin D might improve insulin sensitivity and secretion, mainly via its anti-inflammatory properties, thereby decreasing the risk of development and progression of type 2 diabetes. The primary aim of this trial is to investigate whether improved plasma concentrations of 25-hydroxyvitamin D (25(OH)D), obtained through vitamin D supplementation, will increase insulin sensitivity and insulin secretion. A secondary aim is to determine whether these relationships are mediated by a reduction in underlying subclinical inflammation associated with obesity. Methods/Design: Fifty overweight but otherwise healthy nondiabetic adults between 18 and 60 years old, with low vitamin D levels (25(OH)D < 50 nmol/l), will be randomly assigned to intervention or placebo. At baseline, participants will undergo a medical review and anthropometric measurements, including dual X-ray absorptiometry, an intravenous glucose tolerance test, muscle and fat biopsies, a hyperinsulinemic euglycemic clamp, and questionnaires assessing diet, physical activity, sun exposure, back and knee pain, and depression. The intervention group will receive a first dose of 100,000 IU followed by 4,000 IU vitamin D (cholecalciferol) daily, while the placebo group will receive apparently identical capsules, both for a period of 16 weeks. All measurements will be repeated at follow-up, with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion for the intervention group compared with the placebo group. Secondary outcome measures will compare changes in anthropometry, cardiovascular risk factors, and inflammatory markers.
Effect of Vitamin D Supplementation on the Incidence of Diabetes Mellitus
The Journal of Clinical Endocrinology & Metabolism, 2020
Context The effect of vitamin D supplementation on the risk of type 2 diabetes mellitus (T2DM) remains controversial because most randomized controlled trials (RCTs) have been small or have reported low doses of vitamin D. Objective To conduct a meta-analysis of RCTs testing vitamin D supplementation in the prevention of T2DM. Data Sources Database search of PubMed/MEDLINE, EMBASE, and the Cochrane Library was performed by 2 reviewers from inception through September 15, 2019. Study Selection We included RCTs that reported the effect of vitamin D supplementation for at least 1 year on T2DM prevention. Data Extraction Two independent reviewers extracted the data. The risk ratios (RRs) and 95% confidence intervals (CIs) were reported. Primary outcome of the meta-analysis was the incidence of T2DM. Data Synthesis Nine RCTs were included (43 559 participants). The mean age (standard deviation) was 63.5 (6.7) years. The RR for vitamin D compared with placebo was 0.96 (95% CI, 0.90-1.03);...
European Journal of Clinical Nutrition, 2022
Background/Objectives Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D3 in the vitamin D and type 2 diabetes (D2d) study. Subjects/Methods In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D3 (the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations. Results A total of 8304 AEs occurred during 3 years of follow-up a...
BMJ open, 2016
Recent research suggests that vitamin D deficiency may cause both bone diseases and a range of non-skeletal diseases. However, most of these data come from observational studies, and clinical trial data on the effects of vitamin D supplementation on individuals with pre-diabetes are scarce and inconsistent. The aim of the Diabetes Prevention with active Vitamin D (DPVD) study is to assess the effect of eldecalcitol, active vitamin D analogue, on the incidence of type 2 diabetes among individuals with pre-diabetes. DPVD is an ongoing, prospective, multicentre, randomised, double-blind and placebo-controlled outcome study in individuals with impaired glucose tolerance. Participants, men and women aged ≥30 years, will be randomised to receive eldecalcitol or placebo. They will also be given a brief (5-10 min long) talk about appropriate calorie intake from diet and exercise at each 12-week visit. The primary end point is the cumulative incidence of type 2 diabetes. Secondary endpoint i...
The FASEB Journal, 2014
Background: Little or no research has determined the effect of vitamin D3 supplementation in conjunction with pharmacological and non-pharmacological approaches in the diabetes mellitus type 2 (DMT2) patients. The objective of this study was to determine the effect of vitamin D3 supplementation in a cohort of Saudi DMT2 population on diet, insulin and/or different oral hypoglycemic agents and compare them with a non-DMT2 control cohort. Methods: A total of 499 randomly selected Saudi subjects divided into 8 groups [Non-DMT2 Control = 151; Rosiglitazone alone = 49; Diet = 15; Insulin alone = 55; Insulin + Orals = 12; Metformin alone = 121; Oral agents combination = 37; Sulphonylurea alone = 59] were included in this 12-month interventional study. All DMT2 patients were given 2000 IU vitamin D3 daily, while the control group received none but were advised to increase sun exposure. Anthropometrics, glucose, lipid profile and 25-hydroxyvitamin D (25-OHVitD) were measured at baseline, 6 and 12 months. Results: Circulating 25-OHVitD concentrations improved in all patient groups. The metformin group showed the highest change in circulating vitamin D levels both at 6 months (62.6%) and 12 months (50.6%) as compared to baseline (p < 0.001). No significant changes were observed in the BMI and glucose in any of the DMT2 groups. In contrast, the insulin + oral agents group showed more significant improvements in the metabolic profile, which included triglycerides and total cholesterol, as well as systolic blood pressure and HDL-cholesterol in males. Also, significant decreases in triglycerides were observed in the rosiglitazone and insulin + oral hypoglycemic agent groups both at 6 and 12 months of supplementation (both p-values <0.001). Conclusion: While in all DMT2 groups circulating levels of 25-OHVitD increased after supplementation, in DMT2 patients on insulin in combination with other drugs benefitted the most in improving cardiovascular risk. Metformin improves 25-hydroxyvitamin D levels but did not seem to confer other added cardiometabolic benefits.
New insights on the role of vitamin D in type 2 diabetes mellitus: Review Article
Abstract: Background: Type 2 diabetes mellitus (T2DM) and vitamin D deficiency are both disorders of high prevalence in the world. Evidence supports an association between low vitamin D levels and risk for T2DM, and its complications. There remains insufficient evidence to suggest whether treatment of low vitamin D can prevent or improve T2DM. Aim: this review will focus on the current understanding of the role of vitamin D in the pathogenesis of T2DM, and questioning if vitamin D supplementation can improve the pancreatic function, thus providing a better glycemic control or slow down its complications. Conclusion and recommendation: deficient vitamin D levels increases the risk of developing T2DM. This finding highlights the need for conducting large-scale health screening to identify those at risk of DM using vitamin D blood level assessment. However, more studies are required to ascertain the effect of vitamin D supplementation in T2DM patients.
Cardiovascular Diabetology, 2013
Background: Little or no research has determined the effect of vitamin D3 supplementation in conjunction with pharmacological and non-pharmacological approaches in the diabetes mellitus type 2 (DMT2) patients. The objective of this study was to determine the effect of vitamin D3 supplementation in a cohort of Saudi DMT2 population on diet, insulin and/or different oral hypoglycemic agents and compare them with a non-DMT2 control cohort. Methods: A total of 499 randomly selected Saudi subjects divided into 8 groups [Non-DMT2 Control = 151; Rosiglitazone alone = 49; Diet = 15; Insulin alone = 55; Insulin + Orals = 12; Metformin alone = 121; Oral agents combination = 37; Sulphonylurea alone = 59] were included in this 12-month interventional study. All DMT2 patients were given 2000 IU vitamin D3 daily, while the control group received none but were advised to increase sun exposure. Anthropometrics, glucose, lipid profile and 25-hydroxyvitamin D (25-OHVitD) were measured at baseline, 6 and 12 months. Results: Circulating 25-OHVitD concentrations improved in all patient groups. The metformin group showed the highest change in circulating vitamin D levels both at 6 months (62.6%) and 12 months (50.6%) as compared to baseline (p < 0.001). No significant changes were observed in the BMI and glucose in any of the DMT2 groups. In contrast, the insulin + oral agents group showed more significant improvements in the metabolic profile, which included triglycerides and total cholesterol, as well as systolic blood pressure and HDL-cholesterol in males. Also, significant decreases in triglycerides were observed in the rosiglitazone and insulin + oral hypoglycemic agent groups both at 6 and 12 months of supplementation (both p-values <0.001). Conclusion: While in all DMT2 groups circulating levels of 25-OHVitD increased after supplementation, in DMT2 patients on insulin in combination with other drugs benefitted the most in improving cardiovascular risk. Metformin improves 25-hydroxyvitamin D levels but did not seem to confer other added cardiometabolic benefits.
2018
Vitamin D status is inversely associated with insulin resistance, β-cell dysfunction, and an increased risk for type 2 diabetes (T2D). Clinical trials examining the effect of vitamin D supplementation on various glycemic outcomes and incident T2D have been equivocal. The objectives of this thesis were to determine the effect of weekly vitamin D3 supplementation on oral glucose tolerance, indices of insulin resistance/sensitivity and β-cell function and inflammatory markers in individuals at an increased risk for T2D. We conducted a 24-week, double-blind, randomized, placebo-controlled trial to examine the effect of 28,000 IU of vitamin D3 once weekly on plasma glucose 2 hours after a 75g oral glucose tolerance test (2hPC glucose) and additional glucose-related outcome measures. Seventy-one participants with serum 25-hydroxyvitamin-D [25(OH)D] ≤65 nmol/L, impaired fasting glucose, and/or elevated glycated haemoglobin (HbA1c) were randomly assigned to receive 28,000 IU of vitamin D3 (vitD, n=35) or placebo (n=36) cheese once weekly. The primary outcome was the change in 2hPC glucose. Additional outcomes of interest included fasting glucose, fasting and postprandial insulin, insulin resistance/sensitivity and β-cell function, HbA1c, fasting lipids and inflammatory biomarkers. Participants underwent an oral glucose tolerance test at baseline and week-24. Mean±SD baseline 25(OH)D was 48.1±14.3 iii and 47.6±14.3 nmol/L in the vitD and placebo groups, respectively; vitamin D3 supplementation increased 25(OH)D to 98.7±36.8 nmol/L (p<0.0001). No effects on 2hPC glucose (0.04, vitD vs 0.03 mmol/L, placebo; p=0.55) or other glycemic-related measures including HbA1c (p=0.60) were observed. Subgroup analyses of individuals with 25(OH)D <50 nmol/L and prediabetes (n=14, vitD; n=14, placebo) did not alter these results. LDL-cholesterol was significantly reduced in the vitD group compared to placebo (−0.27 vs. 0.01 mmol/L; p=0.03) with no significant differences in LDL response to supplementation between males and females (−0.137 and −0.165; p=0.85). No effect on markers of inflammation including CRP (p=0.72), IL-6 (p=0.59), leptin (p=0.48) and TNFα (p=0.10), or anti-inflammatory adiponectin (p=0.95). Vitamin D supplementation did not improve oral glucose tolerance, glycemic markers or inflammation, but significantly reduced LDL-cholesterol. Future work should examine the effect of long-term vitamin D supplementation in individuals with 25(OH)D <50 nmol/L and who are at high-risk for T2D. iv ACKNOWLEDGEMENTS There are several people who have supported me throughout my PhD studies, and, therefore, have contributed greatly to my success. I am deeply grateful to the following people for their encouragement and support throughout my years at the University of Toronto. First and foremost, I would like to sincerely thank my supervisor, Dr. Thomas Wolever for providing me with the opportunity to pursue graduate studies at the University of Toronto and for allowing me to pursue an area of study that was out of his study purview (vitamin D) but that was an interest of mine since my undergraduate years. I thank you for allowing me to chart my own course throughout my PhD program, providing me with guidance and constructive feedback and for providing me with an immense amount of material and educational support. Thank you for teaching me how to properly run a clinical trial and for allowing me to coordinate and lead the EVIDENCE trial. I am also very grateful to my committee members, Dr. Anthony Hanley and Dr. Julia Knight for providing me with great insight, guidance and helpful feedback throughout my years as a doctoral student. I am also very appreciative to Dr. Reinhold Vieth who provided me with a lot of educational training related to vitamin D at the beginning of my studies and during conception of the EVIDENCE trial.