Update on vitamin D and type 2 diabetes

Emerging Science Update on vitamin D and type 2 diabetes Christy S Maxwell and Richard J Wood The prevalence of type 2 diabetes mellitus continues to climb in many parts of the globe in association with the rise in obesity. Although the latter is clearly a predominant factor in the pathogenesis of type 2 diabetes, other modifiable lifestyle factors such as exercise, alcohol consumption, smoking, and certain nutritional factors, such as vitamin D deficiency, are also believed to play a role. In contrast to the findings of observational studies, information pooled from vitamin D intervention trials lack conclusive evidence in support of vitamin D supplementation and changes in diabetes risk or measures of glucose intolerance, although an effect on insulin resistance may exist. Well-designed trials that focus on intermediate biomarkers of diabetes risk in response to increased vitamin D intake are still needed. It will be important to include in the design of these studies selection of insulin-resistant study subjects who have a low (<50 nmol/l) initial serum vitamin D (25-hydroxyvitamin D) status and administration of sufficient vitamin D to adequately increase their vitamin D status to >75 nmol/l serum 25-hydroxyvitamin D. nure_393 291..295 2011 International Life Sciences Institute INTRODUCTION Type 2 diabetes is the most common noncommunicable disease on a global scale and is being fueled by the worldwide obesity epidemic. Currently, there are 285 million people worldwide living with diabetes, and 90 95% have type 2 diabetes. 1 This number is expected to reach 439 million by 2030. The prevalence of impaired glucose tolerance, or insulin resistance, is even higher. In the United States alone, the prevalence of diabetes has tripled in the past 25 years, with nearly 26 million people currently affected. 2 However, other parts of the world, such as the Middle East and Southeast Asia, including Saudi Arabia, India, Pakistan, and Sri Lanka, have the dubious distinction of being the world leaders in diabetes prevalence, with a combined total of 85.3 million diabetics. Other geographical areas, such as Central America, Northern Africa, Indonesia, and New Zealand also have high diabetes rates. Since insulin resistance is a risk factor for diabetes, which is an important risk factor for cardiovascular disease (CVD), understanding the role of various nutritional or other modifiable risk factors that may contribute to the pathogenesis of diabetes and impaired glucose tolerance is important in the effort to combat the rising tide of diabetes and CVD worldwide. Potential causes of diabetes have been investigated for decades and many diabetes risk factors have been identified. Obesity is clearly the predominant factor in the pathogenesis of diabetes, while other modifiable lifestyle factors such as exercise, alcohol consumption, smoking, and certain dietary habits can also play an important role. 3 A novel association with diabetes that has received considerable attention recently is vitamin D deficiency. Mounting evidence indicates a surprisingly high prevalence of vitamin D deficiency worldwide. Vitamin D deficiency is usually caused by low dietary vitamin D intake and reduced cutaneous production of vitamin D. The latter condition is associated with reduced sunlight exposure due to geographic location, genetic background affecting skin color, age, and cultural or religious practices. Obesity is also known to be associated with reduced vitamin D status, which may reflect some of the lifestyle factors mentioned above, but another may be increased Affiliation: CS Maxwell and RJ Wood are with the Department of Nutrition, University of Massachusetts, Amherst, Massachusetts, USA. Correspondence: RJ Wood, Department of Nutrition, 100 Holdsworth Way, University of Massachusetts, Amherst, MA 01003, USA. E-mail: rwood@nutrition.umass.edu, Phone: 413-545-1687, Fax: 413-545-1074. Key words: aging, calcium, dietary supplements, vitamin D doi:10.1111/j.1753-4887.2011.00393.x Nutrition Reviews Vol. 69(5):291 295 291

sequestration of vitamin D in adipose tissue. 4 Consistent with the hypothesis that vitamin D deficiency and diabetes are related, areas with a high prevalence of vitamin D insufficiency and deficiency have been associated with a higher prevalence of diabetes. While it is generally accepted that frank vitamin D deficiency is associated with levels of serum 25- hydroxyvitamin D (25(OH)D), a biomarker of vitamin D status, that are below 25 nmol/l (10 ng/ml), there is uncertainty concerning the appropriate serum 25(OH)D concentration cutoff value that should be used to define optimal vitamin D status. This has led to the emergence of a variable gray zone of vitamin D status, often referred to as vitamin D insufficiency, which lies between vitamin D deficiency and apparent optimal vitamin D status. For example, in a 2007 editorial, a group of well-respected researchers in the vitamin D field suggested, based on consideration of a variety of health-related endpoints, that an optimal level of serum 25(OH)D is 75 nmol/l (30 ng/ml) and urged the need for a reexamination of the current dietary vitamin D recommendations so as to better achieve this level of serum 25(OH)D in the population. 5 A high prevalence of vitamin D insufficiency and deficiency has been reported in African Americans, Hispanic/Mexican Americans, Southeast Asians, and in populations from parts of the Middle East. 6 However, it should be pointed out that optimal levels of vitamin D status may vary according to the outcome being evaluated. There is no a priori reason to believe that a level of vitamin D status (e.g., serum 25(OH)D ~75 nmol/l) that may be sufficient to maintain low serum parathyroid hormone concentrations, one potential measure of bone health, will necessarily be optimal for another functional outcome measure, such as glucose metabolism. One of the limitations in this area of investigation that can confound interpretation in many observational or case-control studies is that a higher vitamin D status may reflect a healthier overall lifestyle, which would be associated with better health outcomes. There is consequently a need for well-designed clinical trials that demonstrate a positive change in important intermediate biomarkers of disease in response to intentional changes in vitamin D intake. Recent progress has been made in this area related to the proposed linkage between vitamin D status and diabetes. THE VITAMIN D/CHRONIC DISEASE CONNECTION Epidemiological evidence supports an association between hypovitaminosis D and increased risk of mortality due to CVD, 7 9 as well as an increased risk of hypertension, 10,11 stroke, 12 metabolic syndrome, 13,14 and diabetes. 7,15 For example, in an analysis of data from the National Health and Nutrition Examination Survey (NHANES) III, which is a representative survey from the United States, Ginde et al. 7 stratified elderly subjects into five groups based on serum 25(OH)D concentration (<25 nmol/l, 25.0 49.9 nmol/l, 50.0 74.9 nmol/l, 75.0 99.9 nmol/l, and 100 nmol/l) and found that the low (<50 nmol/l) serum 25(OH)D groups, when compared to the high ( 100 nmol/l) serum 25(OH)D group, had a significantly higher risk for CVD (hazard ratio [HR] = 1.6 3.1) and all-cause (HR = 1.5 2.5) mortality. There was also a significant linear trend between increasing serum 25(OH)D and these outcomes. Interestingly, the association between serum 25(OH)D and all-cause mortality was stronger in people with diabetes compared to those without diabetes (HR = 0.86 and 0.96 for every 10 nmol/l increase in serum 25(OH)D, respectively). This observation in diabetic patients suggests that raising serum 25(OH)D concentrations in this patient group may be of particular benefit in reducing mortality. Recently, Parker et al. 16 reviewed the association of vitamin D status and cardiometabolic disorders (CVD, diabetes, and metabolic syndrome) in a meta-analysis of 28 independent, cross-sectional, case-control, and cohort studies published between 1990 and 2009 with a sample population of 99,745 participants. These investigators found a significant 55% reduction in risk of diabetes (9 studies), a 33% reduction in risk of cardiovascular disease (16 studies), and a 51% reduction in metabolic syndrome (8 studies) associated with high serum 25(OH)D concentration. Although there appears to be a significant association between high serum 25(OH)D concentration and reduced risk of diabetes in observational studies, clinical intervention trials in which vitamin D status is increased by giving vitamin D supplements should provide a powerful test of the potential relationship between vitamin D and diabetes risk. VITAMIN D INTERVENTION TRIALS In contrast to the findings of observational studies, information pooled from vitamin D intervention trials lack conclusive evidence in support of vitamin D supplementation and changes in diabetes risk or measures of glucose intolerance. In a meta-analysis by Pittas et al. 17 published in 2007, among the six intervention trials reviewed, none were able to elicit a remarkable change in measures of glucose intolerance. However, the authors pointed out that there were multiple inconsistencies within the reported trials. For example, three of the six trials were very short term ( 3 weeks) and two of these three supplemented subjects with the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3), 292 Nutrition Reviews Vol. 69(5):291 295

while the other used the 1-hydroxyvitamin D 3 analog. These observations may only indicate that acute increases in blood 1,25(OH) 2D 3 active hormone concentration are insufficient to bring about a sustained change in glucose metabolism.also, these trials were not primarily designed to investigate the effects of vitamin D intake on glucose metabolism. The current Institute of Medicine recommendations for adequate vitamin D intakes are 600 IU (15 mg) per day for men and women ages 19 through 70 years and 800 IU (20 mg) per day for those >70 years old. 18 Interestingly, in one clinical trial 19 it was observed that supplementation with 700 IU vitamin D 3 and 500 mg calcium daily for 3 years caused a significant decrease in fasting blood glucose and an improvement in insulin resistance, but only in the subjects that had evidence of impaired glucose tolerance, defined as a fasting glucose level of 5.6 6.9 mmol/l (100 124 mg/dl) at baseline. The absence of an effect of vitamin D supplementation in subjects with normal fasting glucose levels was supported by an earlier observation in a clinical trial 20 in which healthy, nondiabetic postmenopausal women were supplemented with 2,000 IU vitamin D 3 dailyfor2years to assess bone effects. In this study, no significant change was observed between fasting blood glucose at the start and end of supplementation in the vitamin D-treated group. Pittas et al. 21 recently revisited the question of vitamin D supplementation and plasma glucose as part of a meta-analysis of vitamin D and cardiometabolic outcomes. This time, the authors were able to accumulate six randomized controlled trials 19,20,22 25 in which vitamin D supplementation was used, including the two previously mentioned studies by Nilas and Christiansen 20 and Pittas et al. 19 to assess the effects of vitamin D supplementation on fasting glucose. Of the six studies considered, only three studies 23 25 administered vitamin D alone and measured fasting plasma glucose. Treatment time and protocols varied among these studies. One study 23 utilized a weekly dose of 40,000 IU (1,000 mg) vitamin D for 26 weeks in diabetics, while two of the studies used daily doses of 3,333 IU 24 (83.3 mg) and 4,000 IU 25 (100 mg) for 1 year and 26 weeks, respectively, in non-diabetic subjects. These latter two studies 24,25 are notable because they used healthy, overweight, nondiabetic men and women 24 and non-diabetic women with insulin resistance. 25 However, none of the six studies 19,20,22 25 evaluated found a significant change in fasting glucose concentration due to vitamin D supplementation. Overall, these observations suggest there is no convincing evidence from clinical intervention trials that widespread vitamin D supplementation in the population will have favorable effects on blood glucose control in either diabetics or subjects with insulin resistance. However, a closer look at the more recent studies in non-diabetics 24,25 indicate some potential benefits of vitamin D supplementation. VITAMIN D SUPPLEMENTATION IN NON-DIABETIC, INSULIN-RESISTANT SUBJECTS Pittas et al. 19 reported in 2007 that there may be some benefit of vitamin D supplementation in non-diabetic subjects with impaired fasting glucose (plasma glucose, 5.6 6.9 mmol/l; 101 124 mg/dl) because they observed a significant deterioration in insulin resistance in placebo-treated elderly subjects over a 3-year supplementation trial, but no change in vitamin D-treated subjects. With this lesson in mind, a closer look at the recent studies 24,25 in non-diabetic, insulin-resistant subjects appears warranted despite the lack of effect of vitamin D treatment on fasting plasma glucose. In one of these studies, Zittermann et al. 24 randomized 200 overweight (body mass index score, >27) men and women, who were attempting to lose weight, to receive 3,333 IU (83 mg) daily for 12 months. The vitamin D status of the group was relatively low at baseline (mean serum 25(OH)D, 30 nmol/l or 12 ng/ml), although this was not a study inclusion criterion. Supplementation increased mean serum 25(OH)D to 86 nmol/l (34.4 ng/ ml), whereas the mean serum 25(OH)D was 42 nmol/l (16.8 ng/ml) in the placebo group at the conclusion of the 12-month study. As mentioned above, vitamin D supplementation had no effect on fasting serum glucose (FSG), but it did result in a significant 13% reduction in serum triglycerides. On the other hand, a significant 5% increase in serum LDL-cholesterol was also observed, which warrants further investigation. Unfortunately, no measures of serum insulin or insulin resistance were reported from this study. In the second study, von Hurst et al. 25 conducted a randomized, placebo-controlled trial specifically designed to investigate the effects of vitamin D supplementation on insulin resistance in subjects who were chosen because they exhibited both insulin resistance and low vitamin D status, i.e., serum 25(OH)D, <50 nmol/l (20 ng/ml) at baseline. The study population included women of South Asian descent (mean age, 42 years; 91% Indian) living in New Zealand, who as a group were at high risk of vitamin D deficiency. 26 Previous studies had also found a threefold higher prevalence of self-reported diabetes in this population compared with the general New Zealand population. One hundred and six insulin-resistant women were entered into the 6-month randomized, placebocontrolled, double-blind, vitamin D supplementation trial. Insulin resistance was ascertained at baseline by homeostasis model assessment of insulin resistance (HOMA-IR 1.93) and/or the triglyceride to HDL Nutrition Reviews Vol. 69(5):291 295 293

cholesterol ratio (TG/HDL 3.0). An elevated TG/HDL ratio has been accepted as a reliable predictor of insulin resistance and metabolic syndrome. 27 Study exclusion criteria included a diagnosis of diabetes, including FSG 7.2 mmol/l (130 mg/dl) and/or taking medication for diabetes. In addition, participants were excluded if they were taking 1,000 IU (25 mg) of vitamin D 3 per day. Eligible subjects were pair-matched by age and body mass index (BMI) and randomized to either a control group or to the vitamin D treatment group. Fasting blood samples and anthropometric data were collected at baseline and at the end of the 6-month study. A slightly different homeostasis model assessment (HOMA2) was used to evaluate the insulin resistance study outcomes. HOMA2 assessment utilized computerized, non-linear equations that, when solved, determined insulin sensitivity (HOMA2 %S) from FSG and fasting serum insulin (FSI), and b-cell function (HOMA2 %B) from FSG and C-peptide. C-peptide is an index of total insulin secretion. Both HOMA2 measures are reported as a percentage, with 100% being normal. Insulin resistance (HOMA2-IR) is then reported as the reciprocal of percent insulin sensitivity, with 1.0 being normal. Therefore, as insulin sensitivity increases, insulin resistance decreases. The median baseline serum 25(OH)D level was similar and in the deficient range in both groups, i.e., 21 nmol/l (8.4 ng/ml) in the vitamin D group and 19 nmol/l (7.6 ng/ml) in the placebo group. At the conclusion of the study, as expected, women in the vitamin D treatment group showed a significant increase in serum 25(OH)D compared to those taking the placebo (median change, 49 nmol/l [19.6 ng/ml] and 8 nmol/l [3.2 ng/ ml], respectively). Thus, 4,000 IU vitamin D daily was able to raise the vitamin D status of the group to near optimal recommended levels (serum 25(OH)D > 75 nmol/l). The investigators found a significant inverse association between baseline serum 25(OH)D and change in serum 25(OH)D over the 6-month period. In other words, those with the lowest serum 25(OH)D at baseline experienced the greatest change in serum 25(OH)D concentration by the end of the trial. As mentioned above, there was no change in FSG as a result of vitamin D treatment in these subjects (median baseline FSG, 4.8 mmol/l [86.4 mg/dl]). Importantly, however, the measurement for insulin sensitivity (HOMA2 %S) increased significantly in the vitamin D group (median change, 5.9%), due to a significant decrease in FSI concentration (median change in insulin, -1.3 mu/l, which was about 10% from baseline), whereas no change in this measure of insulin sensitivity was observed in the placebo group. The observed improvement in insulin sensitivity in the vitamin D supplementation group was reflected in a significant improvement in insulin resistance (HOMA2-IR median change, -0.2), while no significant change in insulin resistance was observed in the placebo group. Additional parameters often associated with metabolic syndrome, serum high sensitivity-c-reactive protein (a biomarker of inflammation), total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride were also measured in this study, but no significant differences over time or between treatment groups were noted. CONCLUSION There are relatively few vitamin D supplementation trials that have measured glucose and insulin metabolism. Overall, a recent meta-analysis 21 of available studies indicates there is no evidence that vitamin D supplementation has significant effects on FSG in either stable type 2 diabetics or in insulin-resistant, non-diabetic subjects. However, closer inspection of a recent study by von Hurst et al. 25 demonstrates that vitamin D-deficient South Asian women with evidence of insulin resistance had improved insulin sensitivity after 6 months following high-dose vitamin D supplementation, which was sufficient to raise vitamin D status from low to more optimal levels. The apparent favorable effects found in this vitamin D intervention study on fasting insulin may be due to the researchers selection of insulin-resistant study subjects who had low initial vitamin D status (<50 nmol/l) and received a relatively high daily dose of vitamin D, sufficient to increase their vitamin D status to near optimal levels. Additional studies with similar study designs in other population groups are needed to confirm these findings and to investigate the extent to which vitamin D supplementation in these groups may influence the development of type 2 diabetes. Acknowledgment Declaration of interest. The authors have no relevant interests to declare. REFERENCES 1. International Diabetes Federation. IDF Diabetes Atlas. Global Burden. Epidemiology and Morbidity. Diabetes and Impaired Glucose Tolerance. Available at: http://www.diabetesatlas. org/content/diabetes-and-impaired-glucose-tolerance. Accessed 29 March 2010. 2. Centers for Disease Control and Prevention. Diabetes Public Health Resources. Fact Sheet. 2011 National Diabetes Fact Sheet. Diagnosed and Undiagnosed Diabetes in the United States, All Ages, 2010. Available at: http://www.cdc.gov/ diabetes/pubs/estimates11.htm#1. Accessed 29 March 2011. 3. Van Dam RM. The epidemiology of lifestyle and risk for type 2 diabetes. Eur J Epidemiol. 2003;18:1115 1125. 294 Nutrition Reviews Vol. 69(5):291 295

4. Blum M, Dolnikowski G, Seyoum E, et al. Vitamin D(3) in fat tissue. Endocrine. 2008;33:90 94. 5. Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007;85:649 650. 6. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353 373. 7. Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am Geriatr Soc. 2009;57:1595 1603. 8. Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ. Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination survey 2001 to 2004). Am J Cardiol. 2008;102:1540 1544. 9. Kendrick J, Targher G, Smits G, Chonchol M. 25- hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the third National Health and Nutrition Examination survey. Atherosclerosis. 2009;205: 255 260. 10. Martini LA, Wood RJ. Vitamin D and blood pressure connection: Update on epidemiologic, clinical, and mechanistic evidence. Nutr Rev. 2008;66:291 297. 11. Judd SE, Nanes MS, Ziegler TR, Wilson PW, Tangpricha V. Optimal vitamin D status attenuates the age-associated increase in systolic blood pressure in white Americans: Results from the third National Health and Nutrition Examination survey. Am J Clin Nutr. 2008;87:136 141. 12. Pilz S, Dobnig H, Fischer JE, et al. Low vitamin D levels predict stroke in patients referred to coronary angiography. Stroke. 2008;39:2611 2613. 13. Chiu KC, Chu A, Go VL, Saad M. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820 825. 14. Martini LA, Wood RJ. Vitamin D status and the metabolic syndrome. Nutr Rev. 2006;64:479 486. 15. Mattila C, Knekt P, Mannisto S, et al. Serum 25- hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes Care. 2007;30:2569 2570. 16. Parker J, Hashmi O, Dutton D, et al. Levels of vitamin D and cardiometabolic disorders: Systematic review and metaanalysis. Maturitas. 2010;65:225 236. 17. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92:2017 2029. 18. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press; 2010. 19. 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 nondiabetic adults. Diabetes Care. 2007;30:980 986. 20. 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. 21. Pittas AG, Chung M, Trikalinos T, et al. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010;152:307 314. 22. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115:846 854. 23. Jorde R, Figenschau Y. Supplementation with cholecalciferol does not improve glycaemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels. Eur J Nutr. 2009;48:349 354. 24. Zittermann A, Frisch S, Berthold HK, et al. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr. 2009;89:1321 1327. 25. Von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient A randomised, placebo-controlled trial. Br J Nutr. 2010;103:549 555. 26. Von Hurst PR, Stonehouse W, Coad J. Vitamin D status and attitudes towards sun exposure in South Asian women living in Auckland, New Zealand. Public Health Nutr. 2010;13:531 536. 27. Reaven GM. The insulin resistance syndrome: Definition and dietary approaches to treatment. Annu Rev Nutr. 2005;25:391 406. Nutrition Reviews Vol. 69(5):291 295 295