A randomised controlled trial of high dose vitamin D in recent-onset type 2 diabetes

https://doi.org/10.1016/j.diabres.2014.08.030Get rights and content

Highlights

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    Vitamin D deficiency has been associated with impaired pancreatic beta-cell function.

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    We conducted a randomised trial of high dose vitamin D3 in people with recent-onset type 2 diabetes.

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    D3 was associated with transient improvement in glycaemia but not beta-cell function.

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    High dose D3 appears to offer little or no therapeutic benefit in type 2 diabetes.

Abstract

Aims

Vitamin D insufficiency has been associated with impaired pancreatic beta-cell function. We aimed to determine if high dose oral vitamin D3 (D) improves beta-cell function and glycaemia in type 2 diabetes.

Methods

Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000 IU D (n = 26) or placebo (n = 24) daily for 6 months. Beta-cell function was measured by glucagon-stimulated serum C-peptide (delta C-peptide [DCP], nmol/l). Secondary outcome measures were fasting plasma glucose (FPG), post-prandial blood glucose (PPG), HbA1c and insulin resistance (HOMA-IR).

Results

In the D group, median serum 25D (nmol/l) increased from 59 to 150 (3 months) and 128 (6 months) and median serum 1,25D (pmol/l) from 135 to 200 and 190. After 3 months, change in DCP from baseline in D (+0.04) and placebo (−0.08) was not different (P = 0.112). However, change in FPG (mmol/l) was significantly lower in D (−0.40) compared to placebo (+0.1) (P = 0.007), as was the change in PPG in D (−0.30) compared to placebo (+0.8) (P = 0.005). Change in HbA1c (%) between D (−0.20) and placebo (−0.10) was not different (P = 0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups.

Conclusion

Oral D3 supplementation in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function this effect is unlikely to be biologically significant. High dose D3 therefore appears to offer little or no therapeutic benefit in type 2 diabetes.

Introduction

With few dietary sources of vitamin D, sufficiency of this pluripotent steroid depends on its synthesis in the skin in response to ultraviolet B radiation. Indoor lifestyles and active protection against sun exposure have contributed to an increased prevalence of vitamin D insufficiency, even in sun-abundant countries [1]. Emerging evidence suggests that vitamin D insufficiency may be a risk factor for both type 1 and type 2 diabetes [2], [3], [4] and associated with reduced beta-cell function in type 2 diabetes (reviewed in Ref. [3]). Pancreatic beta cells not only express the nuclear vitamin D receptor (VDR) [5] but also 1-alpha-hydroxylase which converts 25-hydroxyvitamin D (25D3) to the active metabolite 1,25-dihydroxyvitamin D3 (1,25D3) [6]. Vitamin D supplementation may promote beta-cell function [3], [7] by a direct effect on insulin secretion or beta-cell survival, or by an indirect effect to inhibit production of inflammatory cytokines that impair beta-cell function [8] and induce beta-cell apoptosis [9]. Despite indications that vitamin D insufficiency may increase the risk of type 2 diabetes [3], [4], the potential therapeutic effect of vitamin D has not been widely tested in randomised controlled trials. We aimed to determine if high dose oral vitamin D3 supplementation improves beta-cell function and glycaemic indices in recent-onset type 2 diabetes.

Section snippets

Participants

A randomised, double blind placebo-controlled clinical trial of oral vitamin D3 (D) was conducted in 50 Caucasians sequentially diagnosed with type 2 diabetes. Participants gave written informed consent and the study was approved by the Royal Melbourne Hospital Human Research Ethics Committee. Participants were recruited from the community through a national diabetes register (National Diabetes Services Scheme, Australia). They were eligible for enrolment if they had diabetes diagnosed

Recruitment

Of the 50 participants, 26 were randomly allocated to the D group and 24 to placebo, with males and females being equally represented. Only 3 required modification of their diabetes therapy due to hyperglycaemia during the trial, with one requiring insulin. There were no adverse events related to the study treatments, in particular no participant developed hypercalcemia. Similar numbers of D and placebo participants were enrolled in all seasons. Randomisation commenced in January 2008 and the

Discussion

High dose D supplementation substantially increased both 25D and 1,25D concentrations without toxicity. It has been shown previously that oral D increases serum 25D in people with diabetes [8], [15], [16], [17], but its effect on serum 1,25D has not been reported. The significant increase in 1,25D in response to oral D challenges the traditional view that 1,25D production is tightly regulated by renal 1-alpha hydroxylase to maintain calcium homeostasis. It indicates that oral D has broader

Funding

This work was funded by grants from The Munro Foundation, Melbourne, and Diabetes Australia Research Trust, and supported by Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS. SE was a Postgraduate Scholar of the National Health and Medical Research Council of Australia (NHMRC) and received a Basser Family Scholarship from the Royal Australasian College of Physicians. LCH is a Senior Principal Research Fellow of the NHMRC.

Conflict of interest statement

There is no conflict of interest for any of the authors.

Contribution statement

Study concept and design LCH, SF, SE; acquisition of data: SE, NM, PGC, JMW; analysis and interpretation of data: SE, SF, TS, LCH; drafting of manuscript SE, SF, LCH.

Acknowledgements

The authors thank Diabetes Australia for assistance in recruiting participants and Professor John Wark and Dr Mark Stein, Royal Melbourne Hospital, for advice on vitamin D dosing and comments on the manuscript.

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