Effect of High-Dose Vitamin D Repletion on Glycemic Control in African-American Males with Prediabetes and Hypovitaminosis D

doi:10.4158/EP14548.OR

Endocrine Practice

Volume 21, Issue 6, June 2015, Pages 604-612

https://doi.org/10.4158/EP14548.OR Get rights and content

ABSTRACT

Objective: This double-blind, randomized, controlled trial evaluated whether 12 months of high-dose vitamin D2 supplementation improved insulin sensitivity and secretion and glycemic status.

Methods: African-American males (AAM) with prediabetes (glycosylated hemoglobin [A1C] 5.7-6.4%), hypovitaminosis D (25-hydroxyvitamin D [25OHD] 5-29 ng/mL), and prevalent medical problems were supplemented with vitamin D3 (400 IU/day) and then randomized to weekly placebo or vitamin D2 (50,000 IU). The primary outcome was the change in oral glucose insulin sensitivity (OGIS, from an oral glucose tolerance test [OGTT]) after 12 months of treatment. Secondary outcomes included other glycemic indices, A1C, and incident diabetes.

Results: Baseline characteristics were similar in vitamin D-supplemented (n = 87) and placebo (n = 86) subjects completing the trial with average concentrations 14.4 ng/mL, 362 mL × min^-1 × m^-2, and 6.1% for 25OHD, OGIS and A1C, respectively. After 12 months, the vitamin D-supplemented group had a change in serum 25OHD +35 versus +6 ng/mL for placebo, P<.001; OGIS +7.8 versus -16.0 mL × min^-1 × m^-2 for placebo, P = .026; and A1C -0.01 versus +0.01% for placebo, P = .66. Ten percent of subjects in both groups progressed to diabetes. A posthoc analysis of participants with baseline impaired fasting glucose (IFG) showed that more subjects in the vitamin D subgroup (31.6%) than placebo (8.3%) returned to normal glucose tolerance, but the difference did not reach significance (P = .13).

Conclusion: The trial does not provide evidence that 12 months of high-dose D2 repletion improves clinically relevant glycemic outcomes in subjects with prediabetes and hypovitaminosis D (NCT01375660).

Abbreviations: AAM = African-American males A1C = glycosylated hemoglobin BMI = body mass index D2 = ergocalciferol D3 = cholecalciferol IFG = impaired fasting glucose IGT = impaired glucose tolerance JBVAMC = Jesse Brown VA Medical Center OGIS = oral glucose insulin sensitivity index OGTT = oral glucose tolerance test 25OHD = 25-hydroxyvitamin D VHA = Veterans Health Administration

Section snippets

INTRODUCTION

Vitamin D deficiency contributes to health disparities and disease burden in African-American males (AAM), but controversy remains on whether repletion improves outcomes. African Americans are at increased risk for type 2 diabetes mellitus (T2DM) and hypovitaminosis D. The prevalence rates of diabetes and vitamin D deficiency in African Americans are 18% and 30%, respectively, compared to 8.3% and 8.1%, respectively, in the general U.S. population (1,2). AAM are ordinarily underrepresented in

Study Design and Subjects

This was a double-blind, randomized, placebocontrolled trial “D vitamin Intervention in Veteran Administration (DIVA).” The primary objective was to determine whether a high dose of vitamin D supplementation (designed to raise 25-hydroxyvitamin D [25OHD] into normal range) would improve oral glucose insulin sensitivity (OGIS) in AAM with dysglycemia and hypovitaminosis D. The eligible participants were randomized to placebo or vitamin D (1:1 ratio) with stratification according to age (35-65 or

RESULTS

The data on screening, randomization, attrition, and completion rates are summarized in Figure 1. The baseline characteristics were similar in the placebo and vitamin D groups (Table 1). Likewise, baseline characteristics were similar between 173 and 32 subjects who completed and discontinued the study, respectively (data not shown). Compliance was similar in both groups (77% and 76% in placebo and vitamin D groups, respectively, P = .736). Disease burden was relatively high; the average

DISCUSSION

The results of the present study show that high-dose vitamin D2 supplementation for a year does not improve A1C or prevent diabetes in subjects with prediabetes. These results are in line with previously reviewed (10) and recently published trials, as well as a meta-analysis (11,26,27). Two of the published trials administered highdose vitamin D3 (=20,000 IU/week) for 1 year in subjects with prediabetes (26,27). These studies demonstrated no effect of vitamin D3 supplementation on insulin

CONCLUSION

In conclusion, the trial does not provide evidence that 12-month high-dose D2 repletion improves clinically relevant glycemic outcomes in AAM subjects with prediabetes and hypovitaminosis D. Further trials powered for diabetes prevention are warranted, and it is necessary to identify populations that can benefit from vitamin D supplementation.

DISCLOSURE

The authors have no multiplicity of interest to disclose.

ACKNOWLEDGMENT

This work was supported by a Merit Review grant from the Department of Veterans Affairs and in part by a National Institutes of Health grant for the University of Illinois at Chicago Center for Clinical and Translational Science.

The authors thank Brian Glovack, PharmD and Michael Pacini, PharmD for maintaining drug inventory and dose adjustments; Bharathi Reddivari for recruiting and following subjects; and Hajwa Kim for help with statistical analysis. The authors also thank Hiba Mohiuddin,

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This meta-analysis indicates that the supplementation of vitamin D2 significantly increases the serum concentrations of total vitamin D, 25(OH)D2, and 1,25(OH)D, but decreases 25(OH)D3 concentrations. Careful consideration of patient characteristics, dosage, and treatment duration is recommended for vitamin D2 supplementation.
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Diabetes is a metabolic illness that increases protein glycosylation in hyperglycemic conditions, which can have an impact on almost every organ system in the body. The role of vitamin D in the etiology of diabetes under RAGE (receptor for advanced glycation end products) stress has recently received some attention on a global scale. Vitamin D's other skeletal benefits have generated a great deal of research. Vitamin D's function in the development of type 1 and type 2 diabetes is supported by the discovery of 1,25 (OH)2D3 and 1-Alpha-Hydroylase expression in immune cells, pancreatic beta cells, and several other organs besides the bone system. A lower HBA1c level, metabolic syndrome, and diabetes mellitus all seems to be associated with vitamin D insufficiency. Most of the cross-sectional and prospective observational studies that were used to gather human evidence revealed an inverse relationship between vitamin D level and the prevalence or incidence of elevated HBA1c in type 2 diabetes. Several trials have reported on the impact of vitamin D supplementation for glycemia or incidence of type 2 diabetes, with varying degrees of success. The current paper examines the available data for a relationship between vitamin D supplementation and HBA1c level in diabetes and discusses the biological plausibility of such a relationship.
Combined vitamin D and magnesium supplementation does not influence markers of bone turnover or glycemic control: A randomized controlled clinical trial
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High-dose vitamin D supplementation can increase total osteocalcin concentrations that may reduce insulin resistance in individuals at risk for prediabetes or diabetes mellitus. Magnesium is a cofactor in vitamin D metabolism and activation. The purpose of this study was to determine the combined effect of vitamin D and magnesium supplementation on total osteocalcin concentrations, glycemic indices, and other bone turnover markers after a 12-week intervention in individuals who were overweight and obese, but otherwise healthy. We hypothesized that combined supplementation would improve serum total osteocalcin concentrations and glycemic indices more than vitamin D supplementation alone or a placebo. A total of 78 women and men completed this intervention in 3 groups: a vitamin D and magnesium group (1000 IU vitamin D₃ and 360 mg magnesium glycinate), a vitamin D group (1000 IU vitamin D₃), and a placebo group. Despite a significant increase in serum 25-hydroxyvitamin D concentrations in the vitamin D and magnesium group compared with the placebo group (difference = 5.63; CI, –10.0 to –1.21; P = .001) post-intervention, there were no differences in serum concentrations of total osteocalcin, glucose, insulin, and adiponectin or the homeostatic model assessment of insulin resistance (HOMA-IR) among groups (P > .05 for all). Additionally, total osteocalcin (β = –0.310, P = .081), bone-specific alkaline phosphatase (β = 0.004, P = .986), and C-terminal cross-linked telopeptide (β = 0.426, P = .057), were not significant predictors of HOMA-IR after the intervention. Combined supplementation was not associated with short-term improvements in glycemic indices or bone turnover markers in participants who were overweight and obese in our study. This trial was registered at clinicaltrials.gov (NCT03134417).
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Increasing evidence from animal and human studies point to an important role of vitamin D in modifying risk of type 2 diabetes. Vitamin D has both direct (through activation of the vitamin D receptor) and indirect (via regulation of calcium homeostasis) effects on various mechanisms related to the pathophysiology of type 2 diabetes, including pancreatic beta-cell dysfunction, impaired insulin action, and systemic inflammation. Longitudinal observational studies report highly consistent results showing inverse associations between measured blood 25(OH)D concentration and risk of developing type 2 diabetes. The results from mostly underpowered trials and post hoc analyses of large trials that used small doses of vitamin D do not support a role of vitamin D for treatment of established type 2 diabetes or prevention of diabetes among those with normal glucose tolerance; however, in people with prediabetes, vitamin D reduces risk of progression from prediabetes to diabetes and promotes regression to normal glucose regulation. For optimal risk reduction, blood 25(OH) levels higher than those recommended by the National Academy of Medicine are needed.
Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice
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Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance.
We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue.
To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks.
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In recent years, clinical trials increasingly have given large doses of vitamin D supplements to investigate possible health benefits beyond bone at high 25-hydroxyvitamin D levels. However, there are few publications on the safety of high-dose vitamin D given long term. The study objective was to investigate the cumulative relative risk (RR) of total adverse events, kidney stones, hypercalcemia and hypercalciuria from ≥2800 IU/d vitamin D₂ or D₃ supplementation, followed for one year or more in randomized controlled trials (RCTs). A systematic review was conducted in Medline Ovid, EMBASE and Cochrane in March 2018 to update results of studies published since a previous review in October 2015. RCTs were included if they gave vitamin D₂ or D₃ at ≥2800 IU/d for at least one year and reported on total adverse events or at least one calcium-related adverse event. There were a total of 32 studies that met the inclusion criteria. Of these, only 15 studies (3150 participants) reported one or more event of the outcomes of interest. Long-term high-dose vitamin D supplementation did not increase total adverse events compared to placebo in 1731 participants from 10 studies (RR = 1.05; 95% CI = 0.88, 1.24; p = 0.61), nor kidney stones in 1336 participants from 5 studies (RR = 1.26; 95% CI = 0.35, 4.58; p = 0.72). However, there was a trend for vitamin D to increase risk of hypercalcemia in 2598 participants from 10 studies (RR = 1.93; 95% CI = 1.00, 3.73; p = 0.05); while its effect on hypercalciuria in only 276 participants from 3 studies was inconclusive (RR = 1.93; 95% CI = 0.83, 4.46; p = 0.12). In conclusion, one year or longer supplementation with a large daily, weekly or monthly dose of vitamin D₂ /D₃ did not significantly increase a risk of total adverse events or kidney stones, although there was a trend towards increased hypercalcemia, and possibly for hypercalciuria.

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Original ArticlesEffect of High-Dose Vitamin D Repletion on Glycemic Control in African-American Males with Prediabetes and Hypovitaminosis D

ABSTRACT

Section snippets

INTRODUCTION

Study Design and Subjects

RESULTS

DISCUSSION

CONCLUSION

DISCLOSURE

ACKNOWLEDGMENT

J Natl Med Assoc

Mayo Clin Proc

Endocr Pract

J Chronic Dis

Diabetes Res Clin Pract

Metabolism

Adv Nutr

Metabolism

Lancet Diabetes Endocrinol

Am J Clin Nutr

Second National Report of Biochemical Indicators of Diet and Nutrition in the U.S. Population 2012

Evaluation of a brief questionnaire for assessing barriers to research participation

Ethn Dis

Executive summary: standards of medical care in diabetes--2014

Diabetes Care

Pharmacological and surgical intervention for the prevention of diabetes

Nestle Nutr Workshop Ser Clin Perform Programme

The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis

J Clin Endocrinol Metab

Effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: a systematic review and metaanalysis

J Clin Endocrinol Metab

Dietary Reference Intakes for Calcium and Vitamin D

Standards of medical care in diabetes 2012

Diabetes Care

Original Articles
Effect of High-Dose Vitamin D Repletion on Glycemic Control in African-American Males with Prediabetes and Hypovitaminosis D