The Role of Vitamin D and Calcium in type 2 diabetes. A systematic Review and Meta-Analysis (original) (raw)

• Journal List
• HHS Author Manuscripts
• PMC2085234

J Clin Endocrinol Metab. Author manuscript; available in PMC 2007 Nov 21.

Published in final edited form as:

PMCID: PMC2085234

NIHMSID: NIHMS23169

ANASTASSIOS G. PITTAS

1Division of Endocrinology, Diabetes and Metabolism, Tufts-New England Medical Center, Boston, MA

JOSEPH LAU

2Division of Clinical Research, Tufts-New England Medical Center, Boston, MA

FRANK HU

3Harvard School of Public Health and Channing Laboratory, Boston, MA

BESS DAWSON-HUGHES

1Division of Endocrinology, Diabetes and Metabolism, Tufts-New England Medical Center, Boston, MA

4Bone Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA

1Division of Endocrinology, Diabetes and Metabolism, Tufts-New England Medical Center, Boston, MA

2Division of Clinical Research, Tufts-New England Medical Center, Boston, MA

3Harvard School of Public Health and Channing Laboratory, Boston, MA

4Bone Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA

Address all correspondence and reprint requests to: Anastassios G. Pittas, MD MSc, Division of Endocrinology, Diabetes and Metabolism, Tufts-New England Medical Center, 750 Washington Street, #268, Boston, MA 02111, Telephone (617) 636-5694, Fax (617) 636-4719, gro.cmen-stfut@sattipa

Abstract

Context

Altered vitamin D and calcium homeostasis may play a role in the development of type 2 diabetes (t2DM).

Evidence Acquisition and Analyses

MEDLINE review through January 2007 for observational studies and clinical trials in adults with outcomes related to glucose homeostasis. When data was 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 t2DM or metabolic syndrome (OR [95% CI]: t2DM prevalence, 0.36 [0.16 – 0.80] among non-blacks for highest vs. lowest 25-OHD; metabolic syndrome prevalence, 0.71 [0.57 – 0.89] for highest vs. lowest dairy intake). There are also inverse associations with incident t2DM or metabolic syndrome (OR [95% CI]: t2DM 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 t2DM 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 while 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 while combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism.

Key terms: Vitamin D, calcium, type 2 diabetes

Introduction

The incidence of type 2 Diabetes Mellitus (t2DM) is increasing at an alarming rate both nationally and worldwide with more than 1 million new cases per year diagnosed in the US alone (1). Diabetes is the fifth leading cause of death in the US and it is also a major cause of significant morbidity. Although our current methods of treating t2DM and its complications have improved, prevention of the disease is preferable. Indeed, epidemiologic data suggest that 9 out of 10 cases of type 2 diabetes could be attributed to habits and forms of modifiable behavior (2). Potentially modifiable environmental risk factors for t2DM have been identified, the major one being obesity. Although weight-loss (achieved by any means) has been shown to be successful in delaying t2DM, 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 t2DM 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 non-skeletal 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 t2DM. The purpose of our systematic review was to examine: (1) the association between vitamin D and calcium status and risk of t2DM and (2) the effect of vitamin D and/or calcium supplementation on glucose metabolism.

Materials and Methods

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-OHD concentration, and vitamin D, calcium, or dairy intake) and t2DM (prevalence or incidence) and for randomized controlled trials of the effect of vitamin D and/or calcium supplementation in non-pregnant 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 t2DM – 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, beta 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 was performed due to the large heterogeneity in the methods for assessing outcomes among the studies. However, when data was 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 that was asymmetric around the mean, we used a conservative approach and included in the metaanalysis the widest confidence interval reported.

Potential Mechanisms for the Effects of Vitamin D and Calcium on t2DM

For glucose intolerance and t2DM to develop, defects in pancreatic beta-cell function, insulin sensitivity and systemic inflammation are often present (11, 12). There is evidence to support that vitamin D and calcium influence these mechanisms, as summarized next and in Table 1.

Table 1

Potential mechanisms and evidence to support a benefit for vitamin D and calcium in type 2 diabetes

Pancreatic Beta Cell Function

There are several lines of evidence supporting a role for vitamin D in pancreatic beta cell function, as shown in Table 1. Vitamin D appears to affect exclusively the insulin response to glucose stimulation while 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 beta cell vitamin D receptor. Alternatively, activation of vitamin D may occur within the beta cell by the 1-alpha-hydroxylase enzyme, which was recently shown to be expressed in beta 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 beta cell (Table 1). Insulin secretion is a calcium dependent process (16) therefore, alterations in calcium flux can have adverse effects on beta cell secretory function. We speculate that inadequate calcium intake or vitamin D insufficiency may alter the balance between the extracellular and intracellular beta cell calcium pools, which may interfere with normal insulin release, especially in response to a glucose load. Some (17-21) 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 thereby enhancing insulin responsiveness for glucose transport (26), or indirectly via its role in regulating extracellular calcium 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 (27-29) 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 (30-37) via impaired insulin signal transduction (29, 34) leading to decreased GLUT-4 activity (34, 38). Associations between low vitamin D level and decreased insulin sensitivity have been reported in cross-sectional studies (18-23, 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, 41-45) or improvement(46-48) of insulin action with supplementation.

Inflammation

It is currently recognized that t2DM 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 beta cell dysfunction by triggering beta cell apoptosis. Vitamin D may improve insulin sensitivity and promote beta-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 t2DM (48, 51-53).

Evidence from Observational Human Studies

What is the association between vitamin D status and prevalent t2DM or metabolic syndrome?

The role of vitamin D in t2DM is suggested by a seasonal variation in glycemic control reported in patients with t2DM being worse in the winter (54-56), which may, at least in part, be due to prevalent hypovitaminosis D in the winter. In cross-sectional studies (Table 2A), inverse associations between serum 25-OHD and measurements of glycemia or presence of t2DM have been reported in a variety of cohorts (18, 19, 40, 57-59) but the relationship is not consistent (18, 19, 23, 40, 60, 61). In the largest cross-sectional study to date from 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 beta cell function (estimated by HOMA-beta). No correlation between 25-OHD and diabetes prevalence or measures of insulin resistance or beta-cell function was seen in non-Hispanic blacks. This lack of association may be explained by the observation that non-whites exhibit a different vitamin D, calcium and PTH homeostasis compared to whites (62).

Table 2A

Cross-sectional studies reporting an association between vitamin D status, calcium intake, dairy intake and prevalence of type 2 diabetes / metabolic syndrome in non-pregnant adults

Combining data from all studies that reported on the association between 25-OHD level and prevalent t2DM (40, 60, 61, 63), the summary odds ratio (OR) was 0.54 (95% CI, 0.23 – 1.27) for the highest vs. the lowest 25-OHD concentration (25-38 ng/ml vs. 10-23 ng/ml, respectively), but with significant heterogeneity among studies. When we excluded the data on non-Hispanic blacks, there was a statistically significant inverse association between 25-OHD concentration and prevalent t2DM (OR 0.36 [95%CI, 0.16 – 0.80]).

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, 67-72) but not all (69, 73, 74) case-control studies, patients with t2DM or glucose intolerance are found to have lower serum 25-OHD concentration compared to controls without diabetes (Table 2B).

Table 2B

Case-control studies reporting an association between vitamin D status, calcium intake and type 2 diabetes or metabolic syndrome in non-pregnant adults

What is the association between vitamin D status and incident type 2 diabetes or metabolic syndrome?

Two prospective studies have examined the association of vitamin D intake with incident t2DM (Table 2C). In the Women’s Health Study, an intake of 511 IU/day of vitamin D or more was associated with lower risk of incident t2DM compared to an intake of 159 IU/day or less (2.7 vs. 5.6% of the cohort developed t2DM respectively) (66). However, this analysis did not adjust for other risk factors of t2DM or calcium intake. Recently, our group examined the association between vitamin D and calcium intakes and incident t2DM among 83,806 women in the Nurses Health Study, a large prospective observational cohort (52). After adjusting for age, BMI, and non-dietary covariates, we observed a significant inverse association between total (food + supplements) vitamin D intake and risk of t2DM. The association was attenuated after adjusting for dietary factors, in particular, magnesium and calcium.

Table 2C

Prospective studies reporting an association between vitamin D status, calcium intake, dairy intake and incidence of type 2 diabetes / metabolic syndrome in non-pregnant adults

What is the association between calcium intake and prevalent type 2 diabetes or metabolic syndrome?

A potentially important role for calcium status in the development of t2DM is suggested by case control studies where calcium intake was found to be lower in patients with diabetes compared to 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 diabetes or metabolic syndrome?

In prospective studies, low calcium intake is consistently found to be inversely associated with incident t2DM (52, 66, 75, 76) or the metabolic syndrome (77). In the Nurses Health Study, total (food + supplements) calcium intake was inversely associated with incident t2DM 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 ~59,000 women aged 21-69 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 2 studies, the summary OR (95% CI) for incident t2DM was 0.82 [0.72 – 0.93] for the highest vs. the lowest calcium intake (661-1200 mg/day vs. 219-600 mg/day, respectively). The results of these studies highlight an important role for calcium intake.

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

The association between calcium and vitamin D status and t2DM 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/day) vs. lowest (0.9-1.7 servings/day) (66, 78, 79), with no apparent heterogeneity among studies. In prospective studies, a moderate inverse association of dairy intake with incident t2DM (52, 76, 80, 81) or metabolic syndrome (77) is consistently reported. The summary OR for incident t2DM was 0.86 [95% CI 0.79 – 0.93] for the highest vs. lowest dairy intake (3-5 vs. <1.5 servings/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 t2DM 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 prior to 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 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 t2DM 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 t2DM ( Figure ). We observed that, after multivariate adjustment, women with the highest calcium (>1200 mg/day) and vitamin D (>800 IU/day) intake (1.3% of the cohort) had a 33% lower risk of t2DM compared to women with the lowest calcium (<600 mg/day) and vitamin D (<400 IU/day) 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 t2DM risk modifier and the need to take into consideration both nutrients in observational studies.

Adjusted Relative risk of incident type 2 diabetes in the Nurses Health Study by calcium and vitamin D intake (52)

Evidence from Intervention Human Studies

What is the effect of vitamin D supplementation on t2DM?

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 t2DM parameters. Among 18 young healthy men, supplementation with 1,25(OH)2D3 for 7 days did not change fasting glycemia or insulin sensitivity (42). In another small study (n=14) in patients with t2DM, 2 mcg/day IU of 1OHD3 administration daily for 3 weeks enhanced insulin secretion but had no effect on post-load glucose tolerance (24). Ljunghall et al randomized 65 middle-aged men with impaired glucose tolerance or mild diabetes and sufficient vitamin D levels at baseline to 0.75 mcg/day of 1OHD3 or placebo for 3 months and found no effect in fasting or stimulated glucose tolerance (41). In that trial, participants had sufficient vitamin D levels at baseline (mean 25-OHD 38 ng/ml). In a cross-over trial, 20 patients with t2DM and vitamin D deficiency were treated for 4 days with 1 mcg/day 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 t2DM which is supported by more recent data described below (48). Lastly, in a post-hoc analyses of a 2-year trial designed for bone-related outcomes, supplementation with vitamin D3 or 1OHD3 had no effect on fasting glycemia in postmenopausal non-diabetic women (82).

What is the effect of calcium or dairy supplementation on t2DM?

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 3). In 20 non-diabetic patients with essential hypertension, supplementation with 1,500 mg/day of calcium vs. placebo for 8 weeks did not influence fasting glycemia but improved insulin sensitivity, as measured by euglycemic hyperinsulinemic clamp (46). Trials with small numbers of non-diabetic 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 (43-45, 47, 83).

Table 3

Randomized controlled trials of the effect of vitamin D and/or calcium supplementation on glucose tolerance

What is the effect of combined vitamin D and calcium supplementation on t2DM?

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 years compared to 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 t2DM especially in populations at risk for t2DM such as those with glucose intolerance.

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

Currently recommended intakes for calcium are 1,200 mg/day for adults aged >50 years and for vitamin D are 400 IU/day for those aged 51-70 years and 600 IU/day for those aged >70 years (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 non-skeletal outcomes, the most advantageous serum concentration of 25-OHD appears to be 30-40 ng/ml (4). In relation to t2DM, it is difficult to draw definitive conclusion about an optimal level is, 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 concentration above 20 ng/ml are desirable, but those above 40 ng/ml may be better. To achieve such 25-OHD concentration, an intake of approximately 1000 IU/day of vitamin D is needed (4, 86). In relation to calcium intake for type 2 diabetes, the evidence suggests that intakes above 600 mg/day are desirable but intakes above 1200 mg may be optimal (Tables 2and ​3and Figure).

Data from NHANES III show that vitamin D insufficiency (25-OHD <25 ng/ml) may affect up to half of the non-institutionalized adolescent and adult population in the US, 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, 88-90). 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 US population declines with age (708 mg/day for men and 571 mg/day for women 51-70 years; 702 mg/day for men and 517 mg/day for women >70 years) (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/day) and vitamin D (>800 IU/day) that was associated with the lowest risk of incidence t2DM 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 t2DM may, at least in part, be due to suboptimal vitamin D and calcium status of the US 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 Diabetes. Although this may simply reflect confounding, the link between these risk factors and t2DM may, at least partially, be mediated by vitamin D and calcium insufficiency.

Conclusions and Future Directions

There appears to be a relationship between insufficient vitamin D and calcium status and t2DM. However, the available human data are limited because most observational studies are cross-sectional while 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 t2DM. Although the evidence to date suggests that vitamin D and calcium deficiency influences post-prandial 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 beta 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 t2DM and define the individual contributions of each nutrient on t2DM 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 t2DM. The results of future studies will define the clinical role of vitamin D and calcium as potential interventions for prevention and management of t2DM, which will have significant public health implications since vitamin D and calcium insufficiency is common in US adults and both interventions can be implemented easily and inexpensively in clinical practice.

Acknowledgments

Supported by NIH research grants K23 DK61506 and R01 DK76092 (to AGP), U01 AG010353 (to BDH) and U.S.D.A. No. 59-1950-9001 (to BDH).

Footnotes

*This is an un-copyedited author manuscript copyrighted by The Endocrine Society. This may not be duplicated or reproduced, other than for personal use or within the rule of “Fair Use of Copyrighted Materials” (section 107, Title 17, U.S. Code) without permission of the copyright owner, The Endocrine Society. From the time of acceptance following peer review, the full text of this manuscript is made freely available by The Endocrine Society at http://www.endojournals.org/. The final copy edited article can be found at http://www.endojournals.org/. The Endocrine Society disclaims any responsibility or liability for errors or omissions in this version of the manuscript or in any version derived from it by the National Institutes of Health or other parties. The citation of this article must include the following information: author(s), article title, journal title, year of publication and DOI.

Supported by NIH research grants K23 DK61506 and R01 DK76092 (to AGP), U01 AG010353 (to BDH) and U.S.D.A. No. 59-1950-9001 (to BDH).

The authors have no conflict of interest to disclose.

References

1. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289:76–79. [PubMed] [Google Scholar]

2. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345:790–797. [PubMed] [Google Scholar]

3. Benjamin SM, Valdez R, Geiss LS, Rolka DB, Narayan KM. Estimated number of adults with prediabetes in the US in 2000: opportunities for prevention. Diabetes Care. 2003;26:645–649. [PubMed] [Google Scholar]

4. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18–28. [PubMed] [Google Scholar]

5. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353–373. [PubMed] [Google Scholar]

6. Mathieu C, Badenhoop K. Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab. 2005;16:261–266. [PubMed] [Google Scholar]

7. Toma M, McAlister FA, Bialy L, Adams D, Vandermeer B, Armstrong PW. Transition from meeting abstract to full-length journal article for randomized controlled trials. JAMA. 2006;295:1281–1287. [PubMed] [Google Scholar]

8. Bloch CA, Clemons P, Sperling MA. Puberty decreases insulin sensitivity. J Pediatr. 1987;110:481–487. [PubMed] [Google Scholar]

9. Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillil H, Beebe C, Galloway JA, Frank BH, Karrison T, Van Cauter E. Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest. 1988;81:435–441. [PMC free article] [PubMed] [Google Scholar]

10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. [PubMed] [Google Scholar]

11. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787–794. [PMC free article] [PubMed] [Google Scholar]

12. Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes. 2004;53:693–700. [PubMed] [Google Scholar]

13. Bourlon PM, Billaudel B, Faure-Dussert A. Influence of vitamin D3 deficiency and 1,25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat endocrine pancreas. J Endocrinol. 1999;160:87–95. [PubMed] [Google Scholar]

14. Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG. Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. Faseb J. 2003;17:509–511. [PubMed] [Google Scholar]

15. Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, Hewison M. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol. 2004;89-90:121–125. [PubMed] [Google Scholar]

16. Milner RD, Hales CN. The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia. 1967;3:47–49. [PubMed] [Google Scholar]

17. Boucher BJ, Mannan N, Noonan K, Hales CN, Evans SJ. Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in east London Asians. Diabetologia. 1995;38:1239–1245. [PubMed] [Google Scholar]

18. Baynes KC, Boucher BJ, Feskens EJ, Kromhout D. Vitamin D, glucose tolerance and insulinaemia in elderly men. Diabetologia. 1997;40:344–347. [PubMed] [Google Scholar]

19. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820–825. [PubMed] [Google Scholar]

20. Gedik O, Akalin S. Effects of vitamin D deficiency and repletion on insulin and glucagon secretion in man. Diabetologia. 1986;29:142–145. [PubMed] [Google Scholar]

21. Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract. 2003;57:258–261. [PubMed] [Google Scholar]

22. Lind L, Pollare T, Hvarfner A, Lithell H, Sorensen OH, Ljunghall S. 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. 1989;11:141–147. [PubMed] [Google Scholar]

23. Orwoll E, Riddle M, Prince M. Effects of vitamin D on insulin and glucagon secretion in non-insulin-dependent diabetes mellitus. Am J Clin Nutr. 1994;59:1083–1087. [PubMed] [Google Scholar]

24. Inomata S, Kadowaki S, Yamatani T, Fukase M, Fujita T. Effect of 1 alpha (OH)-vitamin D3 on insulin secretion in diabetes mellitus. Bone Miner. 1986;1:187–192. [PubMed] [Google Scholar]

25. Nyomba BL, Auwerx J, Bormans V, Peeters TL, Pelemans W, Reynaert J, Bouillon R, Vantrappen G, De Moor P. Pancreatic secretion in man with subclinical vitamin D deficiency. Diabetologia. 1986;29:34–38. [PubMed] [Google Scholar]

26. Maestro B, Campion J, Davila N, Calle C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J. 2000;47:383–391. [PubMed] [Google Scholar]

27. Ojuka EO. Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle. Proc Nutr Soc. 2004;63:275–278. [PubMed] [Google Scholar]

28. Wright DC, Hucker KA, Holloszy JO, Han DH. Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. Diabetes. 2004;53:330–335. [PubMed] [Google Scholar]

29. Williams PF, Caterson ID, Cooney GJ, Zilkens RR, Turtle JR. High affinity insulin binding and insulin receptor-effector coupling: modulation by Ca2+ Cell Calcium. 1990;11:547–556. [PubMed] [Google Scholar]

30. Draznin B, Sussman K, Kao M, Lewis D, Sherman N. The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem. 1987;262:14385–14388. [PubMed] [Google Scholar]

31. Segal S, Lloyd S, Sherman N, Sussman K, Draznin B. Postprandial changes in cytosolic free calcium and glucose uptake in adipocytes in obesity and non-insulin-dependent diabetes mellitus. Horm Res. 1990;34:39–44. [PubMed] [Google Scholar]

32. Byyny RL, LoVerde M, Lloyd S, Mitchell W, Draznin B. Cytosolic calcium and insulin resistance in elderly patients with essential hypertension. Am J Hypertens. 1992;5:459–464. [PubMed] [Google Scholar]

33. Ohno Y, Suzuki H, Yamakawa H, Nakamura M, Otsuka K, Saruta T. Impaired insulin sensitivity in young, lean normotensive offspring of essential hypertensives: possible role of disturbed calcium metabolism. J Hypertens. 1993;11:421–426. [PubMed] [Google Scholar]

34. Zemel MB. Nutritional and endocrine modulation of intracellular calcium: implications in obesity, insulin resistance and hypertension. Mol Cell Biochem. 1998;188:129–136. [PubMed] [Google Scholar]

35. Draznin B, Sussman KE, Eckel RH, Kao M, Yost T, Sherman NA. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 1988;82:1848–1852. [PMC free article] [PubMed] [Google Scholar]

36. Draznin B, Sussman KE, Kao M, Sherman N. Relationship between cytosolic free calcium concentration and 2-deoxyglucose uptake in adipocytes isolated from 2- and 12-month-old rats. Endocrinology. 1988;122:2578–2583. [PubMed] [Google Scholar]

37. Draznin B, Lewis D, Houlder N, Sherman N, Adamo M, Garvey WT, LeRoith D, Sussman K. Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology. 1989;125:2341–2349. [PubMed] [Google Scholar]

38. Reusch JE, Begum N, Sussman KE, Draznin B. Regulation of GLUT-4 phosphorylation by intracellular calcium in adipocytes. Endocrinology. 1991;129:3269–3273. [PubMed] [Google Scholar]

39. Lind L, Hanni A, Lithell H, Hvarfner A, Sorensen OH, Ljunghall S. Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men. Am J Hypertens. 1995;8:894–901. [PubMed] [Google Scholar]

40. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27:2813–2818. [PubMed] [Google Scholar]

41. Ljunghall S, Lind L, Lithell H, Skarfors E, Selinus I, Sorensen OH, Wide L. Treatment with one-alpha-hydroxycholecalciferol in middle-aged men with impaired glucose tolerance--a prospective randomized double-blind study. Acta Med Scand. 1987;222:361–367. [PubMed] [Google Scholar]

42. Fliser D, Stefanski A, Franek E, Fode P, Gudarzi A, Ritz E. No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects. Eur J Clin Invest. 1997;27:629–633. [PubMed] [Google Scholar]

43. Barr SI, McCarron DA, Heaney RP, Dawson-Hughes B, Berga SL, Stern JS, Oparil S. Effects of increased consumption of fluid milk on energy and nutrient intake, body weight, and cardiovascular risk factors in healthy older adults. J Am Diet Assoc. 2000;100:810–817. [PubMed] [Google Scholar]

44. Bowen J, Noakes M, Clifton PM. Effect of calcium and dairy foods in high protein, energy-restricted diets on weight loss and metabolic parameters in overweight adults. Int J Obes (Lond) 2005;29:957–965. [PubMed] [Google Scholar]

45. Thompson WG, Rostad Holdman N, Janzow DJ, Slezak JM, Morris KL, Zemel MB. Effect of energy-reduced diets high in dairy products and fiber on weight loss in obese adults. Obes Res. 2005;13:1344–1353. [PubMed] [Google Scholar]

46. Sanchez M, de la Sierra A, Coca A, Poch E, Giner V, Urbano-Marquez A. Oral calcium supplementation reduces intraplatelet free calcium concentration and insulin resistance in essential hypertensive patients. Hypertension. 1997;29:531–536. [PubMed] [Google Scholar]

47. Zemel MB, Thompson W, Milstead A, Morris K, Campbell P. Calcium and dairy acceleration of weight and fat loss during energy restriction in obese adults. Obes Res. 2004;12:582–590. [PubMed] [Google Scholar]

48. Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The Effects of Calcium and Vitamin D Supplementation on Blood Glucose and Markers of Inflammation in Non-diabetic Adults. Diabetes Care. 2007 in press. [PubMed] [Google Scholar]

49. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–334. [PubMed] [Google Scholar]

50. Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes. 2003;52:1799–1805. [PubMed] [Google Scholar]

51. Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2006;29:722–724. [PubMed] [Google Scholar]

52. Pittas AG, Dawson-Hughes B, Li T, Van Dam RM, Willett WC, Manson JE, Hu FB. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006;29:650–656. [PubMed] [Google Scholar]

53. Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? Qjm. 2002;95:787–796. [PubMed] [Google Scholar]

54. Campbell IT, Jarrett RJ, Keen H. Diurnal and seasonal variation in oral glucose tolerance: studies in the Antarctic. Diabetologia. 1975;11:139–145. [PubMed] [Google Scholar]

55. Behall KM, Scholfield DJ, Hallfrisch JG, Kelsay JL, Reiser S. Seasonal variation in plasma glucose and hormone levels in adult men and women. Am J Clin Nutr. 1984;40:1352–1356. [PubMed] [Google Scholar]

56. Ishii H, Suzuki H, Baba T, Nakamura K, Watanabe T. Seasonal variation of glycemic control in type 2 diabetic patients. Diabetes Care. 2001;24:1503. letter. [PubMed] [Google Scholar]

57. Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care. 2005;28:1228–1230. [PubMed] [Google Scholar]

58. Need AG, O’Loughlin PD, Horowitz M, Nordin BE. Relationship between fasting serum glucose, age, body mass index and serum 25 hydroxyvitamin D in postmenopausal women. Clin Endocrinol (Oxf) 2005;62:738–741. [PubMed] [Google Scholar]

59. Hypponen E, Power C. Vitamin D status and glucose homeostasis in the 1958 British birth cohort: the role of obesity. Diabetes Care. 2006;29:2244–2246. [PubMed] [Google Scholar]

60. Wareham NJ, Byrne CD, Carr C, Day NE, Boucher BJ, Hales CN. Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality. Metabolism. 1997;46:1171–1177. [PubMed] [Google Scholar]

61. Snijder M, van Dam R, Visser M, Deeg D, Seidell J, Lips P. 2006 [PubMed] [Google Scholar]Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia. 2005;48:1247–1257. [PubMed] [Google Scholar]Diabetologia. 49:217–218. [Google Scholar]

62. Bell NH, Greene A, Epstein S, Oexmann MJ, Shaw S, Shary J. Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest. 1985;76:470–473. [PMC free article] [PubMed] [Google Scholar]

63. Scragg R, Holdaway I, Singh V, Metcalf P, Baker J, Dryson E. Serum 25-hydroxyvitamin D3 levels decreased in impaired glucose tolerance and diabetes mellitus. Diabetes Res Clin Pract. 1995;27:181–188. [PubMed] [Google Scholar]

64. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72:690–693. [PubMed] [Google Scholar]

65. Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, Yanovski JA. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 2004;89:1196–1199. [PubMed] [Google Scholar]

66. Liu S, Song Y, Ford ES, Manson JE, Buring JE, Ridker PM. Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005;28:2926–2932. [PubMed] [Google Scholar]

67. Christiansen C, Christensen MS, McNair P, Nielsen B, Madsbad S. Vitamin D metabolites in diabetic patients: decreased serum concentration of 24,25-dihydroxyvitamin D. Scand J Clin Lab Invest. 1982;42:487–491. [PubMed] [Google Scholar]

68. Stepan J, Wilczek H, Justova V, Havranek T, Skrha F, Wildtova Z, Formankova J, Pacovsky V. Plasma 25-hydroxycholecalciferol in oral sulfonylurea treated diabetes mellitus. Horm Metab Res. 1982;14:98–100. [PubMed] [Google Scholar]

69. Nyomba BL, Bouillon R, Bidingija M, Kandjingu K, De Moor P. Vitamin D metabolites and their binding protein in adult diabetic patients. Diabetes. 1986;35:911–915. [PubMed] [Google Scholar]

70. Pietschmann P, Schernthaner G, Woloszczuk W. Serum osteocalcin levels in diabetes mellitus: analysis of the type of diabetes and microvascular complications. Diabetologia. 1988;31:892–895. [PubMed] [Google Scholar]

71. Aksoy H, Akcay F, Kurtul N, Baykal O, Avci B. Serum 1,25 dihydroxy vitamin D (1,25(OH)2D3), 25 hydroxy vitamin D (25(OH)D) and parathormone levels in diabetic retinopathy. Clin Biochem. 2000;33:47–51. [PubMed] [Google Scholar]

72. Isaia G, Giorgino R, Adami S. High prevalence of hypovitaminosis D in female type 2 diabetic population. Diabetes Care. 2001;24:1496. [PubMed] [Google Scholar]

73. Ishida H, Seino Y, Matsukura S, Ikeda M, Yawata M, Yamashita G, Ishizuka S, Imura H. Diabetic osteopenia and circulating levels of vitamin D metabolites in type 2 (noninsulin-dependent) diabetes. Metabolism. 1985;34:797–801. [PubMed] [Google Scholar]

74. Heath H, 3rd, Lambert PW, Service FJ, Arnaud SB. Calcium homeostasis in diabetes mellitus. J Clin Endocrinol Metab. 1979;49:462–466. [PubMed] [Google Scholar]

75. Colditz GA, Manson JE, Stampfer MJ, Rosner B, Willett WC, Speizer FE. Diet and risk of clinical diabetes in women. Am J Clin Nutr. 1992;55:1018–1023. [PubMed] [Google Scholar]

76. van Dam RM, Hu FB, Rosenberg L, Krishnan S, Palmer JR. Dietary calcium and magnesium, major food sources, and risk of type 2 diabetes in U.S. black women. Diabetes Care. 2006;29:2238–2243. [PubMed] [Google Scholar]

77. Pereira MA, Jacobs DR, Jr, Van Horn L, Slattery ML, Kartashov AI, Ludwig DS. Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA Study. JAMA. 2002;287:2081–2089. [PubMed] [Google Scholar]

78. Mennen LI, Lafay L, Feskens EJM, Novak M, Lepinay P, Balkau B. Possible protective effect of bread and dairy products on the risk of the metabolic syndrome. Nutrition Research. 2000;20:335–347. [Google Scholar]

79. Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi F. Dairy consumption is inversely associated with the prevalence of the metabolic syndrome in Tehranian adults. Am J Clin Nutr. 2005;82:523–530. [PubMed] [Google Scholar]

80. Choi HK, Willett WC, Stampfer MJ, Rimm E, Hu FB. Dairy consumption and risk of type 2 diabetes mellitus in men: a prospective study. Arch Intern Med. 2005;165:997–1003. [PubMed] [Google Scholar]

81. Liu S, Choi HK, Ford E, Song Y, Klevak A, Buring JE, Manson JE. A prospective study of dairy intake and the risk of type 2 diabetes in women. Diabetes Care. 2006;29:1579–1584. [PubMed] [Google Scholar]

82. Nilas L, Christiansen C. Treatment with vitamin D or its analogues does not change body weight or blood glucose level in postmenopausal women. Int J Obes. 1984;8:407–411. [PubMed] [Google Scholar]

83. Zemel MB, Richards J, Milstead A, Campbell P. Effects of calcium and dairy on body composition and weight loss in African-American adults. Obes Res. 2005;13:1218–1225. [PubMed] [Google Scholar]

84. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403. [PMC free article] [PubMed] [Google Scholar]

85. Food and Nutrient Board IoM. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D and fluoride. Washington, DC: National Academy Press; 2003. [PubMed] [Google Scholar]

86. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005;135:317–322. [PubMed] [Google Scholar]

87. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone. 2002;30:771–777. [PubMed] [Google Scholar]

88. McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. Am J Med. 1992;93:69–77. [PubMed] [Google Scholar]

89. Gloth FM, 3rd, Gundberg CM, Hollis BW, Haddad JG, Jr, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA. 1995;274:1683–1686. [PubMed] [Google Scholar]

90. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777–783. [PubMed] [Google Scholar]

91. Fleming KH, Heimbach JT. Consumption of calcium in the U.S.: food sources and intake levels. J Nutr. 1994;124:1426S–1430S. [PubMed] [Google Scholar]

92. Subar AF, Krebs-Smith SM, Cook A, Kahle LL. Dietary sources of nutrients among US adults, 1989 to 1991. J Am Diet Assoc. 1998;98:537–547. [PubMed] [Google Scholar]

93. Nusser SM, Carriquiry AL, Dodd KW, Fuller WA. A semiparametric transformation approach to estimating usual daily intake distributions. J Am Stat Assoc. 1996;91:1440–1449. [Google Scholar]

94. Johnson JA, Grande JP, Roche PC, Kumar R. Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28k in human and rat pancreas. Am J Physiol. 1994;267:E356–360. [PubMed] [Google Scholar]

95. Maestro B, Davila N, Carranza MC, Calle C. Identification of a Vitamin D response element in the human insulin receptor gene promoter. J Steroid Biochem Mol Biol. 2003;84:223–230. [PubMed] [Google Scholar]

96. Maestro B, Molero S, Bajo S, Davila N, Calle C. Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D(3) Cell Biochem Funct. 2002;20:227–232. [PubMed] [Google Scholar]

97. Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science. 1980;209:823–825. [PubMed] [Google Scholar]

98. Kadowaki S, Norman AW. Dietary vitamin D is essential for normal insulin secretion from the perfused rat pancreas. J Clin Invest. 1984;73:759–766. [PMC free article] [PubMed] [Google Scholar]

99. Tanaka Y, Seino Y, Ishida M, Yamaoka K, Yabuuchi H, Ishida H, Seino S, Seino Y, Imura H. Effect of vitamin D3 on the pancreatic secretion of insulin and somatostatin. Acta Endocrinol (Copenh) 1984;105:528–533. [PubMed] [Google Scholar]

100. Cade C, Norman AW. Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo. Endocrinology. 1986;119:84–90. [PubMed] [Google Scholar]

101. Chertow BS, Sivitz WI, Baranetsky NG, Clark SA, Waite A, Deluca HF. Cellular mechanisms of insulin release: the effects of vitamin D deficiency and repletion on rat insulin secretion. Endocrinology. 1983;113:1511–1518. [PubMed] [Google Scholar]

102. Clark SA, Stumpf WE, Sar M. Effect of 1,25 dihydroxyvitamin D3 on insulin secretion. Diabetes. 1981;30:382–386. [PubMed] [Google Scholar]

103. Sooy K, Schermerhorn T, Noda M, Surana M, Rhoten WB, Meyer M, Fleischer N, Sharp GW, Christakos S. Calbindin-D(28k) controls [Ca(2+)](i) and insulin release. Evidence obtained from calbindin-d(28k) knockout mice and beta cell lines. J Biol Chem. 1999;274:34343–34349. [PubMed] [Google Scholar]

104. Beaulieu C, Kestekian R, Havrankova J, Gascon-Barre M. Calcium is essential in normalizing intolerance to glucose that accompanies vitamin D depletion in vivo. Diabetes. 1993;42:35–43. [PubMed] [Google Scholar]

105. Yasuda K, Hurukawa Y, Okuyama M, Kikuchi M, Yoshinaga K. Glucose tolerance and insulin secretion in patients with parathyroid disorders. Effect of serum calcium on insulin release. N Engl J Med. 1975;292:501–504. [PubMed] [Google Scholar]

106. Gedik O, Zileli MS. Effects of hypocalcemia and theophylline on glucose tolerance and insulin release in human beings. Diabetes. 1977;26:813–819. [PubMed] [Google Scholar]

107. Fujita T, Sakagami Y, Tomita T, Okamoto Y, Oku H. Insulin secretion after oral calcium load. Endocrinol Jpn. 1978;25:645–648. [PubMed] [Google Scholar]

108. Hochberg Z, Borochowitz Z, Benderli A, Vardi P, Oren S, Spirer Z, Heyman I, Weisman Y. Does 1,25-dihydroxyvitamin D participate in the regulation of hormone release from endocrine glands? J Clin Endocrinol Metab. 1985;60:57–61. [PubMed] [Google Scholar]

109. Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab. 2003;88:5766–5772. [PubMed] [Google Scholar]

110. Simpson RU, Thomas GA, Arnold AJ. Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle. J Biol Chem. 1985;260:8882–8891. [PubMed] [Google Scholar]

111. Dunlop TW, Vaisanen S, Frank C, Molnar F, Sinkkonen L, Carlberg C. The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol. 2005;349:248–260. [PubMed] [Google Scholar]

112. Luquet S, Gaudel C, Holst D, Lopez-Soriano J, Jehl-Pietri C, Fredenrich A, Grimaldi PA. Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes. Biochim Biophys Acta. 2005;1740:313–317. [PubMed] [Google Scholar]

113. Plehwe WE, Williams PF, Caterson ID, Harrison LC, Turtle JR. Calcium-dependence of insulin receptor phosphorylation. Biochem J. 1983;214:361–366. [PMC free article] [PubMed] [Google Scholar]

114. Zemel MB, Shi H, Greer B, Dirienzo D, Zemel PC. Regulation of adiposity by dietary calcium. Faseb J. 2000;14:1132–1138. [PubMed] [Google Scholar]

115. McCarty MF, Thomas CA. PTH excess may promote weight gain by impeding catecholamine-induced lipolysis-implications for the impact of calcium, vitamin D, and alcohol on body weight. Med Hypotheses. 2003;61:535–542. [PubMed] [Google Scholar]

116. Levy J. Abnormal cell calcium homeostasis in type 2 diabetes mellitus: a new look on old disease. Endocrine. 1999;10:1–6. [PubMed] [Google Scholar]

117. Riachy R, Vandewalle B, Kerr Conte J, Moerman E, Sacchetti P, Lukowiak B, Gmyr V, Bouckenooghe T, Dubois M, Pattou F. 1,25-dihydroxyvitamin D3 protects RINm5F and human islet cells against cytokine-induced apoptosis: implication of the antiapoptotic protein A20. Endocrinology. 2002;143:4809–4819. [PubMed] [Google Scholar]

118. Gysemans CA, Cardozo AK, Callewaert H, Giulietti A, Hulshagen L, Bouillon R, Eizirik DL, Mathieu C. 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology. 2005;146:1956–1964. [PubMed] [Google Scholar]

119. van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005;97:93–101. [PubMed] [Google Scholar]

120. D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia F, Panina-Bordignon P. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998;101:252–262. [PMC free article] [PubMed] [Google Scholar]

121. Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin Endocrinol Metab. 2004;89:447–452. [PubMed] [Google Scholar]

122. Rabinovitch A, Suarez-Pinzon WL, Sooy K, Strynadka K, Christakos S. Expression of calbindin-D(28k) in a pancreatic islet beta-cell line protects against cytokine-induced apoptosis and necrosis. Endocrinology. 2001;142:3649–3655. [PubMed] [Google Scholar]

123. Kadowaki S, Norman AW. Pancreatic vitamin D-dependent calcium binding protein: biochemical properties and response to vitamin D. Arch Biochem Biophys. 1984;233:228–236. [PubMed] [Google Scholar]

124. Christakos S, Barletta F, Huening M, Dhawan P, Liu Y, Porta A, Peng X. Vitamin D target proteins: Function and regulation. J Cell Biochem. 2003;88:238–244. [PubMed] [Google Scholar]