Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency – a double-blind, randomized, placebo-controlled trial

doi:10.1016/j.metabol.2014.06.008

Metabolism

Volume 63, Issue 9, September 2014, Pages 1115-1124

https://doi.org/10.1016/j.metabol.2014.06.008 Get rights and content

Abstract

Objectives

Vitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes.

Materials/methods

A double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280 μg daily for 2 weeks, 140 μg daily for 10 weeks) and 8 patients received identical placebo tablets for 12 weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples.

Results

Serum-25(OH) vitamin D and serum-1,25(OH)₂ vitamin D increased significantly after 12 weeks in the intervention group (p = 0.01, p = 0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p = 0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass.

Conclusions

Improvement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes.

Introduction

Vitamin D deficiency is a worldwide health problem and the finding that most organs and immune cells in the body have vitamin D receptors has provided new insights into the non-skeletal effects of vitamin D [1]. A relationship between lack of vitamin D and development of type 1 diabetes has been reported [2], [3], [4] and several observational studies suggest a role of vitamin D in the pathogenesis of type 2 diabetes. In the Nurse's Health Study low vitamin D intakes were associated with a higher risk of developing type 2 diabetes [5] and serum 25OHD concentrations were inversely related to the prevalence of diabetes in the Third National Health and Nutrition Examination Survey (1988–1994) [6] as well as to insulin resistance in a smaller cross sectional study [7]. In a 10-year prospective study an inverse association between baseline serum 25OHD and future glycemia and insulin resistance was found [8]. Despite supporting evidence from abundant observational studies the results of intervention studies with vitamin D on glucose metabolism and other components of the metabolic syndrome have been inconsistent [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. The available trials are conducted in different settings with differences in subject populations, length of intervention and forms of vitamin D supplementation. In addition, most studies have used indirect measures of insulin secretion and sensitivity (HOMA) and are unable to show relevant increase in serum 25OHD [19], [23]. Most studies regarding the potential effects of vitamin D on glucose metabolism have examined normal subjects or subjects with impaired glucose tolerance (IGT). Whether vitamin D has an impact on metabolic control and complications in patients with established diabetes has not been well addressed. It is however an area of great importance as many individuals with diabetes are vitamin D insufficient [6], [23].

Also only limited and conflicting data exist concerning the relationship between vitamin D status and systemic inflammation in type 2 diabetes [5], [12], [24].

This study was designed to investigate the effects of improved vitamin D status on insulin sensitivity, insulin secretion, and on inflammatory markers in vitamin D insufficient patients with type 2 diabetes. As vitamin D status has been associated with plasma lipid concentrations, blood pressure [19], [22], [25], and bone mineral density (BMD) [26] these variables were also measured.

Section snippets

Methods

The study design was a randomized, placebo-controlled, double-blind trial. Danish participants aged ≥ 18 years with a diagnosis of type 2 diabetes mellitus were recruited from a primary care and a secondary care diabetes clinic. Exclusion criteria were as follows: Serum 25OHD level ≥ 50 nmol/L; serum urea > 12 mmol/L; serum total calcium > 2.52 mmol/L, a history of coronary infarction, sarcoidosis, malabsorption, primary hyperparathyroidism or malignancy. Women, who were pregnant, lactating or not

Results

One hundred and ninety-two patients with type 2 diabetes were recruited and screened for vitamin D insufficiency (25OHD ≤ 50 nmol/L). Thirty-two subjects qualified for participation and of those 16 accepted to be enrolled in the intervention trial. One patient in the vitamin D group was excluded shortly after inclusion due to renal insufficiency. It was not possible to include another subject as the intervention period was restricted to December, January, February, and March. Baseline

Discussion

Our findings indicate that increasing serum 25OHD levels from around 31 to 104 nmol/L over a 12 week period does not improve insulin sensitivity, glycemic control, inflammatory parameters, or blood pressure in patients with established type 2 diabetes. There are however indications that vitamin D supplementation might have an effect on insulin secretion as we found a significant increase in incremental AUC of insulin and a trend toward an increase in c-peptide in the vitamin D supplemented group

Author contributions

U. K. collected, analyzed and interpreted data and wrote the manuscript. L.M. designed the study, interpreted data and wrote the manuscript. C.J. analyzed and interpreted data and wrote the manuscript. N.M. designed the study and wrote the manuscript. B.C. collected and analyzed data. L. R. interpreted data and wrote the manuscript L.W. interpreted data and wrote the manuscript. L.O. designed the study, collected and interpreted data and wrote the manuscript.

Funding

The study was supported by funding from the FOOD Study Group/Ministry of Food, Agriculture and Fisheries and Ministry of Family and Consumer Affairs, Denmark, “Fonden af 17-12-1981”, “Den Sundhedsvidenskabelige Forskningsfond, Region Midtjylland” and “Hospitalsenheden Silkeborg Forskningspulje”.

Disclosures

The authors have no conflict of interests.

Acknowledgments

We owe great thanks to Marijke Vocks for performing the DXA scans and the ambulatory blood pressure monitoring. Medical laboratory technicians A Mengel and L Buus are thanked for excellent technical assistance and we are grateful to H Kampmann for her effort in recruiting the patients.

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The role of vitamin D in type 2 diabetes
2023, Feldman and Pike's Vitamin D: Volume Two: Disease and Therapeutics
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.
The short-term effect of high dose vitamin D3 supplementation in improving Hypovitaminosis in patients with type 2 diabetes - A randomized clinical trial
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Type 2 diabetes (T2D) is an epidemic public health concern with considerable morbidity and mortality. Previous research has shown the association between T2D and vitamin D deficiency. This vitamin significantly affects insulin function, which plays a critical role in T2D development.
A prospective double-blinded randomized controlled trial was conducted to test the hypothesis that vitamin D3 (VD3) supplementation can correct VD deficiency without the risk of hypervitaminosis.
The participants of this study included 62 patients with T2D and hypovitaminosis D3. Of these patients, 30 received cholecalciferol (50,000 IU weekly for 8 weeks), and 32 received identical placebo tablets for 8 weeks. Before and after the intervention, patients were subjected to VD3 level assessment through fasting blood samples.
After 8 weeks of intervention, the mean changes in serum VD3 levels in the VD3 group were significant compared to the placebo group (i.e., 21.9 ± 10 vs. 1.2 ± 7 ng/ml, P < 0.001). Also, comparing serum D3 levels of the endpoint with the baseline revealed statistically significant changes in the VD3 group (40 ± 10 vs. 18.1 ± 6 ng/ml, P < 0.001) but no significant change in the placebo group (18.9 ± 7 vs. 20.1 ± 7, P = 0.37).
The results showed that administering a weekly dose of VD3 supplement could improve serum levels above 30 ng/ml in patients with T2D and compensate for vitamin deficiency without the risk of hypervitaminosis, which occurs at the levels above 100 ng/ml of 25(OH)D. However, further large-scale studies are needed to determine if these findings are applicable.
The effects of vitamin D supplementation on inflammatory biomarkers in patients with abnormal glucose homeostasis: A systematic review and meta-analysis of randomized controlled trials
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Citation Excerpt :
General characteristics of these articles are summarized in Supplementary Table 4. All trials were randomized controlled parallel trials which were conducted in the USA [17,28,49,58], Finland [54], Denmark [39], Korea [45], Norway [50], Israel [31], UAE [46], Italy [30], Iran [15,27,32,34,35,37,38,40,42,43,47,48,52,53,56,57,59,60], Singapore [33], UK [16,36], Malaysia [61], India [51], Ireland [41], News Zealand [55], Saudi Arabia [29] and Lebanon [14]. These studies were published between 2010 and 2020.
on the level of inflammatory cytokines following vitamin D supplementation among individuals with abnormal glucose homeostasis (AGH) are controversial. Therefore, the present study was conducted on AGH patients to assess the impact of vitamin D on inflammatory cytokines such as CRP, TNF-α and IL-6. A systematic search up to September 2020 was performed through PubMed and Scopus databases. All clinical studies which evaluated the effect of oral vitamin D supplementation on inflammation in patients with AGH were included. The random-effects model was applied to obtain pooled results. For dose-response analysis, we used a fractional polynomial model. Overall, 38 studies, with 46 effect sizes, were included in this study. Combining effect sizes, we found that vitamin D considerably decrease serum concentrations of CRP (weight mean difference (WMD): − 0.67 mg/l; 95%CI: − 0.92, − 0.43; P < 0.001), IL-6 (WMD: −1.93 pg/mL; 95%CI: −2.80, −1.07; P < 0.001) and TNF-α (WMD: −0.81 pg/mL; 95%CI: −1.59, −0.03; P = 0.04). In the dose-response analysis, we failed to find any correlation between dosage of supplements and inflammatory biomarkers concentrations. Summarizing earlier studies, we demonstrated that circulating concentrations of inflammatory cytokines such as CRP, TNF-α, and IL-6 might be decreased following vitamin D supplementation among individuals with AGH.
Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice
2020, Molecular Metabolism
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.
25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance.
These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.
The effects of vitamin D and curcuminoids supplementation on anthropometric measurements and blood pressure in type 2 diabetic patients with coexisting hypovitaminosis D: A double-blind, placebo-controlled randomized clinical trial
2020, Clinical Nutrition ESPEN
Curcuminoids and vitamin D have been shown to improve blood pressure and body weight in diabetic animals; however, consistent findings in type 2 diabetes mellitus (T2DM) patients are limited. This study was performed to evaluate the effects of curcuminoids and vitamin D, simultaneously or singly on anthropometric measurements and blood pressure in T2DM patients with insufficient vitamin D level.
In this randomized, placebo-controlled clinical trial, eighty T2DM patients were randomly assigned into 4 groups receiving (1) 500 mg/day curcuminoids; (2) 50,000 IU/week vitamin D₃; (3) 50,000 IU/week vitamin D₃ plus 500 mg/d curcuminoids; or (4) placebos for 12 weeks. Blood pressure and anthropometric measurements were evaluated before and after intervention.
Intergroup comparisons showed that Vitamin D (main effect) significantly reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) (P = 0/000). Curcuminoids (main effect) significantly reduced DBP (P = 0/001). Interaction effects showed that curcuminoids significantly prevented the effect of vitamin D on the reduction of SBP (P = 0.006). Whereas, vitamin D and curcuminoids had a synergistic effect on DBP reduction (P = 0.006). The comparison of changes in anthropometric measurements between the four groups showed no significant differences in the raw and adjusted models. In-group comparisons showed that SBP, DBP, waist to hip circumference (WHR), body fat mass (BFM), percent body fat (PBF) and visceral fat area (VFA) values were significantly reduced in all groups except the placebo group compared to baseline values. Only in the CR-D group, there was a significant reduction in body weight (P = 0/047).
Curcuminoids and vitamin D may have beneficial effects on blood pressure and anthropometric measurements in T2DM patients.
http://www.IRCT.ir:IRCT2017041213678N22.
The molecular mechanisms by which vitamin D improve glucose homeostasis: A mechanistic review
2020, Life Sciences
Diabetes mellitus (DM) is a complex metabolic disorder involving multiple deleterious molecular pathways and cellular defects leading to disturbance in the biologic milieu. It is currently a global health concern with growing incidence, especially among younger adults. There is an unmet need to find new therapeutic targets for the management of diabetes. Vitamin D is a promising target in the pathophysiology of DM, especially since vitamin D deficiency is common in patients with diabetes compared to people without diabetes. Evidence suggests that it can play significant roles in improving peripheral insulin sensitivity and glucose metabolism, however, the exact pathophysiological mechanism is not clarified yet. In this current study, we have reviewed the evidence on the effect of vitamin D in improving insulin resistance via distinct molecular pathways.

View all citing articles on Scopus

^☆: Conflicting or financial interests: Nothing to declare.

^☆☆: Clinical Trial Registration Number: ID: NCT00812578.

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Clinical ScienceEffects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency – a double-blind, randomized, placebo-controlled trial☆,☆☆

Abstract

Objectives

Materials/methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Author contributions

Funding

Disclosures

Acknowledgments

Lancet

Am J Clin Nutr

Am J Clin Nutr

Metabolism

Maturitas

Am J Hypertens

Gend Med

Metabolism

Diabetes and the vitamin D connection

Curr Diab Rep

Vitamin D supplement in early childhood and risk for type 1 (insulin-dependent) diabetes mellitus

Diabetologia

Use of cod liver oil during pregnancy associated with lower risk of type 1 diabetes in the offspring

Diabetologia

Vitamin D and calcium intake in relation to type 2 diabetes in women

Diabetes Care

Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the third national health and nutrition examination survey

Diabetes Care

Baseline serum 25-hydroxy vitamin D is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990–2000

Diabetes

Effects of vitamin D deficiency and repletion on insulin and glucagon secretion in man

Diabetologia

Long-term treatment with active vitamin D (alphacalcidol) in middle-aged men with impaired glucose tolerance. Effects on insulin secretion and sensitivity, glucose tolerance and blood pressure

Diabetes Res

The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients

Int J Clin Pract

The effects of calcium and vitamin D supplementation on blood glucose and markers and inflammation in nondiabetic adults

Diabetes Care

A double-blind, randomized, placebo-controlled trial of the short term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men

Diabet Med

Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient – a randomized, placebo-controlled trial

Br J Nutr

Hypovitaminosis D in Chinese type 2 diabetes: lack of impact on clinical metabolic status and biomarkers of cellular inflammation

Diab Vasc Dis Res

Supplementation with cholecalciferol does not improve glycemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels

Eur J Nutr

Vitamin D, insulin secretion, sensitivity, and lipids

Diabetes

Vitamin D and cardiometabolic outcomes: a systematic review

Ann Intern Med

Clinical Science
Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency – a double-blind, randomized, placebo-controlled trial☆,☆☆

The effect of vitamin D₃ on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients

A double-blind, randomized, placebo-controlled trial of the short term effect of vitamin D₃ supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men