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Keywords:

  • 25-hydroxyvitamin D;
  • diabetes;
  • evidence-based medicine;
  • hypovitaminosis;
  • vitamin D

Summary

  1. Top of page
  2. Summary
  3. What is known and objective
  4. Comment
  5. What is new and conclusions
  6. References

What is known and Objective

The deleterious effect of vitamin D deficiency on bone health has long been known. More recent studies suggest a deleterious effect of low vitamin D (hypovitaminosis D) on general health. And specific studies propose an association between hypovitaminosis D and the aetiology and progression of type 2 diabetes (T2DM). Given a commonly assumed lack of toxicity of vitamin D, routine measurement of plasma vitamin D and supplementation is rapidly becoming accepted general practice.

Comment

Authoritative practice guidelines have raised the level of vitamin D that is to be considered minimal for optimum health. This recommendation was based on a wealth of information and definitive evidence for skeletal benefits of vitamin D, but there was a lack of compelling evidence that hypovitaminosis D is causally related to extra-skeletal health outcomes such as diabetes. Hence, vitamin D supplementation for the purpose of achieving a level consistent with good health is evidence based, but measurement and supplementation for the purpose of preventing or treating T2DM is not.

What is new and Conclusion

Although the maintenance of adequate vitamin D levels is desirable for all patients, we conclude that routine measurement of vitamin D level in every patient or initiating high-dose supplementation for the purpose of preventing or treating T2DM is not evidence based.


What is known and objective

  1. Top of page
  2. Summary
  3. What is known and objective
  4. Comment
  5. What is new and conclusions
  6. References

The following scenario is becoming increasingly common. A healthy young adult goes to their family physician for an annual examination. The physical is normal, and all laboratory test results are within normal limits – except for vitamin D, which is 27 ng/mL instead of the recommended minimum of 30 ng/mL.[1, 2] Aware of a purported connection between low vitamin D and (pre)diabetes and other health issues, the patient is placed on a regimen of 2000 units per day.

We consider the following questions to inform decision making regarding the management of type 2 diabetes mellitus (T2DM): why has the measurement of plasma vitamin D level become so routine? What prompted this practice? Is there an evidence-based connection between vitamin D and T2DM? Is vitamin D supplementation safe and effective?

Comment

  1. Top of page
  2. Summary
  3. What is known and objective
  4. Comment
  5. What is new and conclusions
  6. References

Type 2 diabetes mellitus

More than 26 million Americans have diabetes mellitus (DM),[3] which is defined by the American Diabetes Association as a haemoglobin A1C (HgA1c) level ≥6·5%,[4] and an additional 80 million have ‘pre-diabetes’, which is defined as an HgA1c higher than normal, but not high enough to be classified as DM. Any measure that could reduce the numbers of those in these categories would be a boon, because DM has long been recognized as contributory to increased morbidity (e.g. kidney failure, non-traumatic limb amputations, new cases of blindness, cardiovascular disease and stroke) and mortality.[5] T2DM (‘non insulin-dependent’ or ‘adult-onset’) accounts for the majority of cases of diabetes (about 90–95%) in the United States.[6] Risk factors for T2DM include ageing, obesity, a family history of diabetes, impaired glucose metabolism, lack of physical activity and race/ethnicity, among other factors.[3] Approximately 90% of T2DM cases are associated with poor lifestyle choices, the major being obesity (BMI > 30), but it is difficult for patients to reach and sustain weight-loss goals.[7] Preventative interventions are more cost-effective than are medications and DM care.[3] Thus, there is significant motivation to find ways to help reduce the progression as well as possibly delay the onset of T2DM.

Vitamin D

‘Vitamin D’ refers to a mixture of substances, but in particular to the two secosteroids ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). We use here vitamin D without a subscript to indicate D2, D3 or both. Vitamin D is unusual as a vitamin in that it can be obtained not only from exogenous (dietary) sources, but it can also be produced from endogenous sources, specifically UVB irradiation (sunlight)-mediated hepatic/renal hydroxylation of its precursor, 7-dehydrocholesterol. The active form of vitamin D, calcitriol, binds to a vitamin D receptor (VDR). VDR acts as a transcription factor that modulates gene expression of at least two transport factors involved in the absorption of calcium from the intestine: TRPV6 (a transient receptor potential cation channel) and calbindin (calcium-binding protein).[8] If vitamin D levels are too low, low calcium absorption leads to osteoporosis and bone brittleness, which is a contributing factor for bone fractures during falls.[9] As dietary sources generally contain relatively small amounts of vitamin D (except fatty fish and liver oils), the diet is not usually the major source of vitamin D (unless the food is fortified with the vitamin). Therefore, exposure to sunshine, which promotes endogenous synthesis of vitamin D from cholesterol,[10] is important and limited exposure to the sun can lead to low vitamin D levels.[11]

It is easy to see that both endogenous and exogenous sources of vitamin D are sub-optimal in populations that have a reduced dietary source and limited exposure to sunlight – such as the ageing and institutionalized – and that pro-active efforts to prevent or reverse hypovitaminosis D levels are justified. The association of vitamin D with T2DM is less intuitive.

Vitamin D and T2DM

Beneficial effects of vitamin D on Type 1 DM (‘insulin-dependent’) (T1DM) are generally widely accepted (see reviews in Ref. [12, 13]), based on findings in animal models[14-16] and in humans.[17, 18] The mechanistic connection is thought to be the immunomodulatory actions of vitamin D.[13] Beneficial effects of vitamin D on T2DM are less definitive, as revealed in a systematic review of English-language studies of longitudinal cohort studies reporting associations between vitamin D status and incident T2DM and randomized controlled trials of vitamin D supplementation.[19] The review authors conclude that ‘lower vitamin D status and intake are associated with higher risk of incident T2DM in observational studies; however, the effect of vitamin D supplementation on glycemic outcomes was not evident in small underpowered trials or post hoc analyses of larger trials. Overall, the available data are currently insufficient to support the contention that T2DM can be improved by raising [calcidiol] concentration’ and that ‘confirmation of a potential beneficial effect of vitamin D on T2DM is needed in large trials … specifically designed to test the hypothesis that vitamin D status is a direct contributor to T2DM pathogenesis’. While such studies are awaited, it is constructive to consider whether there is a physiological basis for such an effect.

Postulated physiological connections between vitamin D and T2DM have been recently comprehensively reviewed[20] and are summarized here from that source: hypovitaminosis D reduces pancreatic insulin secretion (possibly by a rise in intracellular Ca2+ concentration via Ca2+ influx through non-selective voltage-dependent Ca2+ channels), without altering glucagon secretion, in rats and humans, and its replenishment improves pancreatic β-cell function and glucose tolerance and correction of insulin secretion in response to glucose[21-24]; allelic variations in VDR and DBP (vitamin D-binding protein)[25-27] could partly explain the genetic predisposition in T2DM, although mixed results have been obtained using transgenic VDR knockout mice; circulating vitamin D is reduced in streptozotocin-induced diabetic rats (attributed to an inhibitory effect of insulin deficiency on renal hydroxylase activity)[28, 29]; and vitamin D stimulates insulin synthesis by activating protein biosynthesis in pancreatic islets,[30] among others.

From the above, it seems clear that there is the potential for an association of vitamin D and T2DM and if there is one, what the physiological links underlying such an association might be. The evidence for an actual, clinically relevant, association is less clear.

Impetus for vitamin D supplementation

A widely publicized comparison of mean serum levels of 25-hydroxyvitamin D (25[OH]D) culled from National Health and Nutrition Examination Survey (NHANES) data revealed a significant reduction from the 30 ng/mL obtained during the period 1988–1994 (~19 000 participants) to the 24 ng/mL obtained during the period 2001–2004 (~13 000 participants).[31] The authors concluded that: ‘This drop was associated with an overall increase in vitamin D insufficiency to nearly three of every four adolescent and adult Americans’ and, even more alarmingly, that ‘Nearly all non-Hispanic blacks (97%) and most Mexican-Americans (90%) now have vitamin D insufficiency’. Despite the fact that the decline was unlikely as large as reported – because there had been a change in the test used to measure the levels – it was at least qualitatively consistent with other studies that showed (i) a decline,[32] (ii) greater insulin resistance in patients with low levels of vitamin D,[33] (iii) children of mothers with 25(OH)D levels lower than 54 nm having double the risk of type 1 diabetes[34] and (iv) other similar associations.[7, 35-40] The perception of almost universal hypovitaminosis D has influenced clinical practice.

A subsequent authoritative and extensive review by the Institute of Medicine (IOM) of the National Academies of more than 1000 scientific studies and reports and testimony (Ref. [41] comprehensively reviewed in Ref. [42]) clarified the voluminous literature, but might have inadvertently reinforced inaccurate perceptions if not read closely. The report concluded that there was definitive evidence for skeletal benefits of vitamin D and raised the recommended level of 25(OH) D from that required to ‘maintain skeletal health’ to that required for ‘optimal health’ (30 ng/mL), but that ‘The data do not, however, provide compelling evidence that [vitamin D] is causally related to extra-skeletal health outcomes or that intakes greater than those established in the dietary reference intakes process have benefits for health’. Thus, raising serum 25(OH) D to 30 ng/mL for the purpose of ‘optimal health’ comports with evidence-based medicine, whereas vitamin D supplementation for the purpose of treating or preventing T2DM does not.

Vitamin D baseline status and effective dose is still a matter of scientific debate[43] and subject of editorials in prestigious medical journals.[44] Two recent developments further add to the uncertainty: (i) evidence for a condition of subclinical micronutrient deficiency,[42] and difficulty diagnosing it[45] and (ii) the recognition of a prediabetic state,[46] which arguably might be more sensitive than would fully developed T2DM to vitamin supplementation.

Vitamin D safety profile

Serum levels of 25(OH)D >30 ng/mL are not consistently associated with increased benefit, and concern has been expressed regarding levels >50 ng/mL.[41] The tolerable daily intake of vitamin D is estimated to be 4000 IU for those older than 9 years (except in certain clinical situations),[1] including pregnant or lactating women.[47] The intake of up to 10 000 IU per day has not been associated with acute intoxication or hypercalcemia,[41] but more than 50 000 IU (1250 μg) over several months can produce overt toxicity, the main symptoms of which involve hypercalcemia.[48]

What is new and conclusions

  1. Top of page
  2. Summary
  3. What is known and objective
  4. Comment
  5. What is new and conclusions
  6. References

In answer to the questions raised in the clinical scenario we posed at the beginning; our review suggests that the following factors/events influenced clinical perception:

  1. Several studies prior to 2009 reported associations of vitamin D ‘deficiency’ with negative health outcomes beyond poor bone health (e.g. heart disease, cancer and diabetes). [However, a comprehensive review requested by the United States and Canadian governments did not find compelling evidence to support a role for vitamin D in non-bone health conditions[41]].
  2. A widely publicized study of data of the United States population reported that there is a ‘growing epidemic of vitamin D insufficiency’ with ‘an overall increase in vitamin D insufficiency to nearly three of every four adolescent and adult Americans’.[31] [Although methodological factors led to a large overestimate in this study, the perception was widely disseminated that nearly everyone had insufficient vitamin D].
  3. These reports prompted a change in viewpoint away from ‘adequate’ vitamin D levels (viz., enough to avoid ‘deficiency’), to ‘sufficient’ levels (i.e. consistent with overall healthiness). [The transition to thinking that vitamin ‘insufficiency’ and not only ‘deficiency’ can have negative health consequences is consistent with physiological arguments that cells operate at a point of compromise between the differential advantage of increased amount of a vital substance and the energetics required to achieve it, such that the ‘adequate’ level is far below the ‘optimal’ level.[49]]
  4. Based on factor 3, new guidelines raised the level of recommended daily intake of vitamin D. [Identification of subclinical disease (e.g. prediabetes) and subclinical deficiency[42] was further impetus for raising the minimal recommended amount].
  5. Some misinterpreted the recommendations for an increase in recommended daily intake of vitamin D as evidence that factors 1 and 2 must be true. [Even if the same source specifically stated otherwise, for example Ref. [41]].

Thus, regarding the clinical scenario posed at the beginning, routine measurement of vitamin D level based on a perception that deficiency is common is not evidence based (at least not for most countries); a belief that there is an established causal or ameliorative association between vitamin D and T2DM is not evidence based (at least not currently); and caution must be exercised to avoid excess amounts. However, the recent raising of the recommended level of daily intake to avoid an ‘insufficiency’ (vs. merely avoiding a ‘deficiency’) is evidence based. In addition, certain populations are more at risk of insufficiency and should be appropriately monitored. These include persons who have an inadequate endogenous biochemical supply capacity (e.g. due to polymorphism, premature birth or other factor), insufficient exposure to the sun (e.g. due to latitude, clothing style, institutionalization or other factor) or a drug–vitamin interaction. Further, basic science and clinical study is required to more definitively address this issue.

References

  1. Top of page
  2. Summary
  3. What is known and objective
  4. Comment
  5. What is new and conclusions
  6. References