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The Role of Vitamin D and Calcium in Type 2 Diabetes. A Systematic Review and Meta-Analysis

Divisions of Endocrinology, Diabetes and Metabolism (A.G.P., B.D.-H.), and Clinical Research (J.L.), Tufts-New England Medical Center, Boston, Massachusetts 02111; Harvard School of Public Health and Channing Laboratory (F.B.H.), Boston, Massachusetts 02115; and Bone Metabolism Laboratory (B.D.-H.), Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111

Address all correspondence and requests for reprints to: Anastassios G. Pittas, M.D., M.Sc., Division of Endocrinology, Diabetes and Metabolism, Tufts-New England Medical Center, 750 Washington Street, #268, Boston, Massachusetts 02111. E-mail: apittas{at}tufts-nemc.org.

	Abstract

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Context: Altered vitamin D and calcium homeostasis may play a role in the development of type 2 diabetes mellitus (type 2 DM).

Evidence Acquisition and Analyses: MEDLINE review was conducted through January 2007 for observational studies and clinical trials in adults with outcomes related to glucose homeostasis. When data were available to combine, meta-analyses were performed, and summary odds ratios (OR) are presented.

Evidence Synthesis: Observational studies show a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalent type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM prevalence, 0.36 (0.16–0.80) among nonblacks for highest vs. lowest 25-hydroxyvitamin D; metabolic syndrome prevalence, 0.71 (0.57–0.89) for highest vs. lowest dairy intake]. There are also inverse associations with incident type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM incidence, 0.82 (0.72–0.93) for highest vs. lowest combined vitamin D and calcium intake; 0.86 (0.79–0.93) for highest vs. lowest dairy intake]. Evidence from trials with vitamin D and/or calcium supplementation suggests that combined vitamin D and calcium supplementation may have a role in the prevention of type 2 DM only in populations at high risk (i.e. glucose intolerance). The available evidence is limited because most observational studies are cross-sectional and did not adjust for important confounders, whereas intervention studies were short in duration, included few subjects, used a variety of formulations of vitamin D and calcium, or did post hoc analyses.

Conclusions: Vitamin D and calcium insufficiency may negatively influence glycemia, whereas combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism.

	Introduction

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THE INCIDENCE OF type 2 diabetes mellitus (type 2 DM) is increasing at an alarming rate both nationally and worldwide, with more than 1 million new cases per year diagnosed in the United States alone (1). Diabetes is the fifth leading cause of death in the United States, and it is also a major cause of significant morbidity. Although our current methods of treating type 2 DM and its complications have improved, prevention of the disease is preferable. Indeed, epidemiological data suggest that nine of 10 cases of type 2 DM could be attributed to habits and forms of modifiable behavior (2). Potentially modifiable environmental risk factors for type 2 DM have been identified, the major one being obesity. Although weight loss (achieved by any means) has been shown to be successful in delaying type 2 DM, it is difficult to achieve and maintain long term. Therefore, identification of environmental and easily modified risk factors is urgently needed to prevent development of type 2 DM in the 41 million Americans who are at risk of the disease (3).

The major and most well-known function of vitamin D is to maintain calcium and phosphorus homeostasis and promote bone mineralization. However, recent evidence suggests that vitamin D and calcium homeostasis may also be important for a variety of nonskeletal outcomes including neuromuscular function and falls, psoriasis, multiple sclerosis, and colorectal and prostate cancer (4, 5). Based on basic and animal studies, vitamin D and calcium have also been suspected as modifiers of diabetes risk. Vitamin D insufficiency has long been suspected as a risk factor for type 1 diabetes based on animal and human observational studies (6). More recently, there is accumulating evidence to suggest that altered vitamin D and calcium homeostasis may also play a role in the development of type 2 DM. The purpose of our systematic review was to examine: 1) the association between vitamin D and calcium status and risk of type 2 DM; and 2) the effect of vitamin D and/or calcium supplementation on glucose metabolism.

	Materials and Methods

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We searched MEDLINE for English-language literature through January 2007 for observational studies on the association between vitamin D/calcium status (defined by serum 25-hydroxyvitamin D (25-OHD) concentration, and vitamin D, calcium, or dairy intake) and type 2 DM (prevalence or incidence) and for randomized controlled trials of the effect of vitamin D and/or calcium supplementation in nonpregnant adults on outcomes related to glucose homeostasis. We also examined metabolic syndrome (prevalence or incidence) as an outcome of interest, given that insulin resistance, a feature of type 2 DM, is considered to be a central mechanism underlying the metabolic syndrome. Search terms included diabetes, hyperglycemia, glucose, glycohemoglobin, metabolic syndrome, insulin resistance, homa, homeostasis model assessment, ß-cell function, insulin secretion, vitamin D, calcium, dairy, milk and related terms. Additional publications were identified from citations from the recovered articles, review articles, and personal reference lists. We excluded letters, abstracts, and conference proceedings that were not published in full in peer-reviewed journals (7). We excluded studies in children because insulin dynamics are evolving during childhood, especially during puberty (8, 9). We excluded studies of type 1 diabetes (or insulin-requiring diabetes of unclear type), hemodialysis, hyperparathyroidism, and other conditions or medications that affect vitamin D metabolism (e.g. epilepsy). Qualitative synthesis of available data were performed due to the large heterogeneity in the methods for assessing outcomes among the studies. However, when data were available to combine, meta-analyses using a random-effects model (10) were performed, and summary odds ratios (OR) are presented. For certain studies that reported a confidence interval (CI) that was asymmetric around the mean, we used a conservative approach and included in the meta-analysis the widest CI reported.

	Potential Mechanisms for the Effects of Vitamin D and Calcium on Type 2 DM

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For glucose intolerance and type 2 DM to develop, defects in pancreatic ß-cell function, insulin sensitivity, and systemic inflammation are often present (11, 12). There is evidence that vitamin D and calcium influence these mechanisms, as summarized next and in Table 1.

There are several lines of evidence supporting a role for vitamin D in pancreatic ß-cell function, as shown in Table 1. Vitamin D appears to affect exclusively the insulin response to glucose stimulation, whereas it does not appear to influence basal insulinemia (13, 14). The direct effect of vitamin D may be mediated by binding of its circulating active from, 1,25-OHD, to the ß-cell vitamin D receptor. Alternatively, activation of vitamin D may occur within the ß-cell by the 1--hydroxylase enzyme, which was recently shown to be expressed in ß-cells (15). The indirect effects of vitamin D may be mediated via its important and well-recognized role in regulating extracellular calcium and calcium flux through the ß-cell (Table 1). Insulin secretion is a calcium-dependent process (16); therefore, alterations in calcium flux can have adverse effects on ß-cell secretory function. We speculate that inadequate calcium intake or vitamin D insufficiency may alter the balance between the extracellular and intracellular ß-cell calcium pools, which may interfere with normal insulin release, especially in response to a glucose load. Some (17, 18, 19, 20, 21), but not all (22, 23), studies in several cohorts with varied baseline vitamin D status have reported an association between vitamin D deficiency and impaired glucose-mediated insulin release. Vitamin D supplementation improved insulin release in some (17, 21, 23, 24), but not all (21, 23, 25), small-scale short-term randomized trials.

Insulin resistance

Vitamin D may have a beneficial effect on insulin action either directly, by stimulating the expression of insulin receptor and thereby enhancing insulin responsiveness for glucose transport (26), or indirectly via its role in regulating extracellular calcium and ensuring normal calcium influx through cell membranes and adequate intracellular cytosolic calcium [Ca²⁺]_i pool (Table 1). Calcium is essential for insulin-mediated intracellular processes in insulin-responsive tissues such as skeletal muscle and adipose tissue (27, 28, 29), with a very narrow range of [Ca²⁺]_i needed for optimal insulin-mediated functions (30). Changes in [Ca²⁺]_i in primary insulin target tissues may contribute to peripheral insulin resistance (30, 31, 32, 33, 34, 35, 36, 37) via impaired insulin signal transduction (29, 34), leading to decreased glucose transporter-4 activity (34, 38). Associations between low vitamin D level and decreased insulin sensitivity have been reported in cross-sectional studies (18, 19, 20, 21, 22, 23, 39, 40). Some (19, 40), but not all (23), observational studies have shown an inverse association between vitamin D or calcium status and insulin resistance. Results from randomized trials on the effect of vitamin D and/or calcium supplementation on insulin resistance show either no effect (23, 41, 42, 43, 44, 45) or improvement (46, 47, 48) of insulin action with supplementation.

Inflammation

It is currently recognized that type 2 DM is associated with systemic inflammation (12, 49, 50). Systemic inflammation has been linked primarily to insulin resistance, but elevated cytokines may also play a role in ß-cell dysfunction by triggering ß-cell apoptosis. Vitamin D may improve insulin sensitivity and promote ß-cell survival by directly modulating the generation and effects of cytokines (Table 1). There are very limited and conflicting data from human studies that have directly examined the relationship between vitamin D or calcium status and systemic inflammation in relation to type 2 DM (48, 51, 52, 53).

	Evidence from Observational Human Studies

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What is the association between vitamin D status and prevalent type 2 DM or metabolic syndrome?

The role of vitamin D in type 2 DM is suggested by a seasonal variation in glycemic control reported in patients with type 2 DM being worse in the winter (54, 55, 56), which may, at least in part, be due to prevalent hypovitaminosis D in the winter. In cross-sectional studies (Table 2), inverse associations between serum 25-OHD and measurements of glycemia or presence of type 2 DM have been reported in a variety of cohorts (18, 19, 40, 57, 58, 59), but the relationship is not consistent (18, 19, 23, 40, 60, 61). In the largest cross-sectional study to date from National Health and Nutrition Examination Survey (NHANES) data, serum 25-OHD concentration (after multivariate adjustment) was inversely associated with diabetes prevalence in a dose-dependent pattern in non-Hispanic whites and Mexican-Americans (40, 57). In the same study, 25-OHD concentration also correlated with measures of insulin resistance [estimated by homeostatic model assessment (HOMA-R) based on fasting glucose and insulin levels] but did not correlate with ß-cell function (estimated by HOMA-ß). No correlation between 25-OHD and diabetes prevalence or measures of insulin resistance or ß-cell function was seen in non-Hispanic blacks. This lack of association may be explained by the observation that nonwhites exhibit a different vitamin D, calcium, and PTH homeostasis compared with whites (62).

Vitamin D intake and 25-OHD concentration have also been inversely associated with prevalence of metabolic syndrome (19, 57). In the largest study using NHANES data, serum 25-OHD concentration (after multivariate adjustment, but not including calcium intake) was inversely associated with having the metabolic syndrome (57) among both sexes and all three major racial or ethnic groups (57). The components of the metabolic syndrome that were independently associated with low 25-OHD were abdominal obesity and hyperglycemia; therefore, the results of this study may simply reflect the inverse association between serum 25-OHD and body weight or fatness (40, 64, 65). In a recent cross-sectional analysis of the Women’s Health Study, a large randomized trial designed to evaluate the effects of low-dose aspirin and vitamin E in cardiovascular disease, the inverse association between vitamin D intake and prevalence of metabolic syndrome was dissipated after adjustment for calcium intake (66).

In most (17, 51, 59, 63, 67, 68, 69, 70, 71, 72), but not all (69, 73, 74), case-control studies, patients with type 2 DM or glucose intolerance are found to have lower serum 25-OHD concentration compared with controls without diabetes (Table 3).

Two prospective studies have examined the association of vitamin D intake with incident type 2 DM (Table 4). In the Women’s Health Study, an intake of 511 IU/d of vitamin D or more was associated with lower risk of incident type 2 DM compared with an intake of 159 IU/d or less (2.7 vs. 5.6% of the cohort developed type 2 DM, respectively) (66). However, this analysis did not adjust for other risk factors of type 2 DM or calcium intake. Recently, our group examined the association between vitamin D and calcium intakes and incident type 2 DM among 83,806 women in the Nurses Health Study, a large prospective observational cohort (52). After adjusting for age, BMI, and nondietary covariates, we observed a significant inverse association between total (food + supplements) vitamin D intake and risk of type 2 DM. The association was attenuated after adjusting for dietary factors, in particular, magnesium and calcium.

A potentially important role for calcium status in the development of type 2 DM is suggested by case control studies in which calcium intake was found to be lower in patients with diabetes compared with controls (72). In the analysis from the Women’s Health Study, calcium intake (after adjustment for vitamin D intake) was inversely associated with prevalence of metabolic syndrome (66).

What is the association between calcium intake and incident type 2 DM or metabolic syndrome?

In prospective studies, low calcium intake is consistently found to be inversely associated with incident type 2 DM (52, 66, 75, 76) or the metabolic syndrome (77). In the Nurses Health Study, total (food + supplements) calcium intake was inversely associated with incident type 2 DM after complete multivariate adjustment, including vitamin D intake (52). A similar inverse association was seen in the Black Women’s Health Study, a prospective cohort of approximately 59,000 women aged 21–69 yr at baseline (76). In the latter study, there was no adjustment for vitamin D status, but the association was attenuated after adjustment for magnesium intake. After combining data from the latter two studies, the summary OR (95% CI) for incident type 2 DM was 0.82 (0.72–0.93) for the highest vs. the lowest calcium intake (661–1200 vs. 219–600 mg/d, respectively). The results of these studies highlight an important role for calcium intake.

What is the association between dairy intake and type 2 DM or metabolic syndrome?

The association between calcium and vitamin D status and type 2 DM can also be assessed from studies that report the effects of intake of dairy products on measurements of glycemia and metabolic syndrome. After combining data from cross-sectional studies, the summary OR for prevalence of metabolic syndrome was 0.71 (95% CI, 0.57–0.89) for the highest dairy intake (3–4 servings per day) vs. lowest (0.9–1.7 servings per day) (66, 78, 79), with no apparent heterogeneity among studies. In prospective studies, a moderate inverse association of dairy intake with incident type 2 DM (52, 76, 80, 81) or metabolic syndrome (77) is consistently reported. The summary OR for incident type 2 DM was 0.86 (95% CI, 0.79–0.93) for the highest vs. lowest dairy intake (3–5 vs. <1.5 servings per day, respectively) (52, 76, 80, 81) with no apparent heterogeneity among studies. It is important to note that although calcium and vitamin D are important components of dairy products, their contribution to the measured outcomes cannot be separated from other components in dairy products.

Summary of evidence from human observational studies and future directions

The evidence from observational studies suggests an association between low vitamin D status and calcium intake (including low dairy intake) and risk of type 2 DM or metabolic syndrome. However, definite conclusions from these studies are limited for a variety of reasons. 1) In cross-sectional or case-control studies, vitamin D or calcium status was measured in patients with glucose intolerance or established diabetes; therefore, these measures may not reflect vitamin D or calcium status before diagnosis and, as a result, the causative nature of the observed associations cannot be established. 2) There is considerable variability in studied cohorts [normal glucose tolerance vs. diabetes (newly diagnosed vs. established), ethnicity, latitude etc.]. 3) In most studies, there is a lack of adjustment for important confounders, such as adiposity, physical activity, and importantly, vitamin D or calcium status (for calcium or vitamin D studies, respectively). To clarify the individual contribution of each nutrient to future type 2 DM risk, in the Nurses Health Study, our group examined the combined effects of total (food + supplements) vitamin D and calcium intake on risk of incident type 2 DM (Fig. 1). We observed that, after multivariate adjustment, women with the highest calcium (>1200 mg/d) and vitamin D (>800 IU/d) intake (1.3% of the cohort) had a 33% lower risk of type 2 DM compared with women with the lowest calcium (<600 mg/d) and vitamin D (<400 IU/d) intakes. The lower risk seen with the combined intake was more than that seen with the highest intake of each nutrient separately, which highlights the importance of both nutrients as potential type 2 DM risk modifiers and the need to take into consideration both nutrients in observational studies.

View larger version (35K): [in this window] [in a new window]   FIG. 1. Adjusted relative risk of incident type 2 DM in the Nurses Health Study by calcium and vitamin D intake (52 ).

	Evidence from Intervention Human Studies

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There are four small-scale short-term and two long-term controlled trials that have examined the effect of supplementation with a variety of formulations of vitamin D on type 2 DM parameters. Among 18 young healthy men, supplementation with 1,25-(OH)₂D₃ for 7 d did not change fasting glycemia or insulin sensitivity (42). In another small study (n = 14) in patients with type 2 DM, 2 µg/d IU of 1-OHD₃ administration daily for 3 wk enhanced insulin secretion but had no effect on post-load glucose tolerance (24). Ljunghall et al. (41) randomized 65 middle-aged men with impaired glucose tolerance or mild diabetes and sufficient vitamin D levels at baseline to 0.75 µg/d of 1-OHD₃ or placebo for 3 months and found no effect in fasting or stimulated glucose tolerance. In that trial, participants had sufficient vitamin D levels at baseline (mean 25-OHD, 38 ng/ml). In a crossover trial, 20 patients with type 2 DM and vitamin D deficiency were treated for 4 d with 1 µg/d of 1,25-OHD, and no change was seen in fasting or stimulated glucose, insulin, or C-peptide concentrations, but an improvement in insulin and C-peptide secretion was seen in patients with diabetes of short duration (23). The intervention period in this trial was too short to draw definitive conclusions, but it does suggest that vitamin D supplementation at an early stage in the development of diabetes (i.e. glucose intolerance) may be of benefit in delaying progression to clinical type 2 DM, which is supported by more recent data described below (48). Lastly, in a post hoc analyses of a 2-yr trial designed for bone-related outcomes, supplementation with vitamin D₃ or 1-OHD₃ had no effect on fasting glycemia in postmenopausal nondiabetic women (82).

What is the effect of calcium or dairy supplementation on type 2 DM?

There is limited evidence of an effect of calcium supplementation on diabetes-related parameters from trials that have examined the effects of calcium either alone or as a component of dairy products (Table 5). In 20 nondiabetic patients with essential hypertension, supplementation with 1,500 mg/d of calcium vs. placebo for 8 wk did not influence fasting glycemia but improved insulin sensitivity, as measured by euglycemic hyperinsulinemic clamp (46). Trials with small numbers of nondiabetic participants that have examined the effects of calcium supplementation as a component of dairy products in relation to glycemia or insulin resistance have shown conflicting results, but most studies show a neutral effect (43, 44, 45, 47, 83).

In a recent report from our group, post hoc analyses of a trial designed for bone-related outcomes showed that combined supplementation with 700 IU of vitamin D₃ and 500 mg of calcium as calcium citrate malate had no effect on glycemia or insulin resistance in 221 adults over age 65 with normal glucose tolerance at baseline (48). However, among participants with impaired fasting glucose at baseline, those who took combined vitamin D₃ and calcium supplements had a significantly lower rise in fasting glycemia and insulin resistance at 3 yr compared with those on placebo (0.4 vs. 6.1 mg/dl, respectively) (48). The effect size with combined vitamin D and calcium supplementation seen in this high-risk group was similar in magnitude to the progression of fasting glycemia seen in the Diabetes Prevention Program with intensive lifestyle or metformin (0.2 mg/dl in the lifestyle and 0.2 mg/dl in the metformin arm vs. 5.5 mg/dl in placebo) (84).

Summary of evidence from human intervention studies and future directions

It is difficult to draw definitive conclusions from the available intervention studies with vitamin D and/or calcium supplementation because most studies were short in duration, included few subjects, used a variety of formulations and combinations of vitamin D and calcium among various cohorts, or used post hoc analyses. Furthermore, the contribution of vitamin D and/or calcium in studies with dairy are difficult to interpret because dairy may have additional components affecting glucose metabolism. However, the overall evidence suggests that vitamin D alone probably has no effect in healthy individuals, but combined vitamin D and calcium supplementation may have a role in the prevention of type 2 DM, especially in populations at risk for type 2 DM such as those with glucose intolerance.

	Optimal Intake of Vitamin D and Calcium in Relation to Type 2 DM

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Currently recommended intake for calcium is 1200 mg/d for adults older than 50 yr, and for vitamin D, 400 IU/d for those aged 51–70 yr and 600 IU/d for those older than 70 yr (85). However, there is growing consensus that vitamin D intakes above the current recommendations may be associated with better health outcomes. Optimal levels of 25-OHD have not been defined, but for a variety of skeletal and nonskeletal outcomes, the most advantageous serum concentration of 25-OHD appears to be 30–40 ng/ml (4). In relation to type 2 DM, it is difficult to draw a definitive conclusion about an optimal level because available studies were done in a variety of cohorts with a large range of 25-OHD levels (Table 2). However, the data suggest that serum 25-OHD concentrations above 20 ng/ml are desirable, but those above 40 ng/ml may be better. To achieve such a 25-OHD concentration, an intake of approximately 1000 IU/d of vitamin D is needed (4, 86). In relation to calcium intake for type 2 DM, the evidence suggests that intakes above 600 mg/d are desirable, but intakes above 1200 mg may be optimal (Tables 2–5 and Fig. 1).

Data from NHANES III show that vitamin D insufficiency (25-OHD < 25 ng/ml) may affect up to half of the noninstitutionalized adolescent and adult population in the United States, even in the southern latitudes during the winter (87). Additional studies have shown a prevalence of vitamin D insufficiency ranging from 36–100% in a variety of populations including healthy young adults to hospitalized elderly individuals (52, 88, 89, 90). Insufficiency of calcium status is difficult to document biochemically, but there is concern that Americans are not meeting the recommended intake for calcium (91, 92). Adjusted for day-to-day variation, the median reported intake of calcium in the U.S. population declines with age (ages 51–70 yr, 708 mg/d for men and 571 mg/d for women; older than 70 yr, 702 mg/d for men and 517 mg/d for women) (85, 93). Combined insufficiency in vitamin D and calcium intake may be even more prevalent. In the Nurses Health Study, the group of female nurses with the highest intake of calcium (>1200 mg/d) and vitamin D (>800 IU/d) that was associated with the lowest risk of incidence type 2 DM was only 1.3% of the cohort (52).

Therefore, given the potential link between vitamin D, calcium, and diabetes described above, it is plausible that the rising incidence of type 2 DM may, at least in part, be due to suboptimal vitamin D and calcium status of the U.S. adult population. Furthermore, certain determinants of adequate vitamin D and calcium status (aging, physical inactivity, dark skin, and obesity) are also strong risk factors for type 2 DM. Although this may simply reflect confounding, the link between these risk factors and type 2 DM may, at least partially, be mediated by vitamin D and calcium insufficiency.

	Conclusion and Future Directions

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There appears to be a relationship between insufficient vitamin D and calcium status and type 2 DM. However, the available human data are limited because most observational studies are cross-sectional, whereas prospective studies have not measured 25-OHD concentration, and there is a paucity of randomized controlled trials with vitamin D and/or calcium supplementation specifically designed for outcomes related to type 2 DM. Although the evidence to date suggests that vitamin D and calcium deficiency influences postprandial glycemia and insulin response while supplementation may be beneficial in optimizing these processes, our understanding of the exact mechanisms by which vitamin D and calcium may promote ß-cell function or ameliorate insulin resistance and systemic inflammation is incomplete. It is also not clear whether the effects are additive or synergistic.

Future research should focus on studies within prospective observational cohorts to clarify and quantify the association between calcium intake and 25-OHD concentration, rather than self-reported intake of vitamin D, and incident type 2 DM and should define the individual contributions of each nutrient on type 2 DM risk. Additionally, there is a need for randomized trials to examine the effects of vitamin D and/or calcium supplementation with intermediary endpoints (glucose tolerance, insulin secretion, insulin sensitivity) and ultimately with incident type 2 DM. The results of future studies will define the clinical role of vitamin D and calcium as potential interventions for prevention and management of type 2 DM, which will have significant public health implications because vitamin D and calcium insufficiency is common in U.S. adults, and both interventions can be implemented easily and inexpensively in clinical practice.

	Footnotes

 
This work was supported by National Institutes of Health research grants K23 DK61506 and R01 DK76092 (to A.G.P.), U01 AG010353 (to B.D.-H.) and U.S. Department of Agriculture Grant 59-1950-9001 (to B.D.-H.).

The authors have no conflict of interest to disclose.

First Published Online March 27, 2007

Abbreviations: [Ca²⁺]_i, Intracellular cytosolic calcium; CI, confidence interval; HOMA, homeostatic model assessment; OHD, hydroxyvitamin D; OR, odds ratio(s); type 2 DM, type 2 diabetes mellitus.

Received February 8, 2007.

Accepted March 19, 2007.

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