[ Above: Artwork from the title page of Francis Glisson's De Rachitide published in 1650. Image available for re-use from Wikimedia Commons. ]
[ Cover image: Coloured X-ray of bowed legs from a child recovering from rickets. Credit: Biophoto Associates/Science Photo Library. ]
This month we have three papers related to vitamin D and diabetes and a pertinent discussion of some of the issues in Naveed Sattar’s exciting Dorothy Hodgkin Lecture that he presented to Diabetes UK earlier this year on ‘Biomarkers for diabetes prediction, pathogenesis or pharmacotherapy guidance? Past present and future possibilities’.
The effects of extreme vitamin D deficiency causing rickets have been known since the 17th century. Although not the first description, Professor Francis Glisson (1597–1677) wrote the most comprehensive exposition on the subject, of which the cover illustration of his book is illustrated on this page. He concluded that its cause was neither infectious nor hereditary. The closest he came to a nutritional aetiology was to blame excess feeding, which, even then, was known to be associated with diabetes. The link with vitamin D and rickets was established by Sir Edward Mellanby, who, between 1919 and 1921, working with dogs reared indoors, established that cod liver oil (which contains both vitamin D and vitamin A) prevented rickets. It is now internationally accepted that 25-hydroxyvitamin D [25(OH)D] levels of greater than 25 nmol/l (10 ng/ml) are required to prevent rickets and that this, in large part, can be accomplished by nutritional supplementation. Nonetheless, rickets is still seen in the UK.
It is also clear that 25(OH)D levels are associated with a number of disease processes other than related to bone health, and 25(OH)D levels less than 75 nmol/l (30 ng/ml) may be deleterious to health. Of relevance to diabetes and associated disease, there is reasonable evidence, extending over 40 years, that hypovitaminosis D predisposes to Type 2 diabetes, cardiovascular disease and Type 1 diabetes. However, as Naveed Sattar points out in his review article (page 5), an association does not prove reverse causality—that must wait for well-designed randomized controlled trials, which are adequately powered from the outset and achieve adequate levels of repletion; these are currently in progress and results awaited eagerly.
An association between diabetic neuropathy and Type 2 diabetes is described in the National Health and Nutrition Examination Survey (NHANES) from the USA by Sodestrom and colleagues (page 50) and a study from Kuwait by Shehab and colleagues (page 43). In both study populations, there was a high prevalence of hypovitaminosis D, which, in common with many studies, was almost universal in the ethnic minorities; in the NHANES study, vitamin D levels < 75 nmol/l (30 ng/ml) were present in 92% Hispanic and 98% non-Hispanic black people, compared with 76% in non-Hispanic white people. In the NHANES and Kuwaiti studies, the odds ratios for peripheral neuropathy were 2.12 (95% CI 1.17–3.85) and 3.47 (95% CI 1.04–11.56), respectively. Whilst both studies are comparatively small, the trend is clear.
The third paper in this issue, from Mozaffari-Khosravi and colleagues in Iran (page 36), is a pilot study of vitamin D supplementation (a single intramuscular dose of 300 000 IU of D3) post-partum in gestational diabetes after delivery. Three months later they found a beneficial effect on vitamin D status and insulin resistance. Although this study has many limitations, it is sufficient to demonstrate the need for an adequately powered and well-designed randomized controlled trial over a longer time period and with hard outcomes.