1a. Objectives (from AD-416):
1. Conduct clinical studies to determine the effects of vitamin D in the prevention of physical dysfunction, oral disease, and diabetes, and other chronic diseases in older adults. 2. Conduct clinical studies to determine the effects of dietary protein and dietary acid-base balance on bone and muscle metabolism and function, respectively, in older adults. 3. Determine the role and mechanisms of action for calcium, magnesium, and other dietary components in the maintenance of bone health and the progression of related diseases.
1b. Approach (from AD-416):
The Bone Metabolism Laboratory uses a variety of approaches to carry out its clinical and translational research program. Observational studies such as the publicly available cross-sectional National Health and Nutrition Examination Survey Nutrition, Exercise Physiology and Sarcopenia Laboratory, and external. These collaborations allow us to expand our reach to examine the effect of vitamin D on risk of other chronic diseases such as periodontal disease and diabetes. They also allow us access to basic research technologies, such as gene array analysis, that enable us to identify mechanisms by which nutrients affect bone and muscle.
3. Progress Report:
We have established that administration of potassium bicarbonate, a compound that neutralizes the acid load of the diet, has favorable effects on muscle performance and bone turnover markers over a 3-month period. In the future, it will be important to determine whether the bone and muscle benefits persist with longer term use of potassium bicarbonate. Before proceeding to a long-term trials however, it is necessary to identify the dose of potassium bicarbonate that is optimal for men and women. We have obtained funding from the NIH to conduct a large dose-finding trial to identify the optimal dose of bicarbonate for bone and muscle health in 276 healthy older men and women. Vitamin D affects muscle tissue, but the mechanism(s) have not been delineated. We have recently completed a study in frail older women to determine the effects of 4000 IU of vitamin D per day versus placebo on muscle fiber number and area and on vitamin D receptors in muscle biopsy samples taken from the thigh. Initial analyses reveal that vitamin D supplementation increased the fiber number and the proportion of muscle cell nuclei staining positively for vitamin D receptors. Final data analyses and manuscript preparation are in progress. A study to determine the effects of calcium, vitamin D, the two combined, and placebo on insulin secretion and sensitivity in adults at high risk for diabetes (adults with pre-diabetes) has revealed that vitamin D but not calcium supplementation significantly increased the Disposition Index (the product of insulin secretion and sensitivity), suggesting that vitamin D may retard the progression to type 2 diabetes in high risk adults. This finding led to an initiative to test this possibility in a large prospective study. Under a Planning Grant from the NIH, we have developed and submitted an application to do a 3-year vitamin D versus placebo intervention trial involving 25 clinical sites across the country. We have recently completed a randomized controlled trial to assess the effect of 2000 IU of vitamin D per day, compared with placebo, on progression of knee osteoarthritis. The data are analyzed and indicate that vitamin D supplementation did not have a significant effect on progression of knee osteoarthritis. The paper will soon be submitted for publication. In a secondary analysis of our STOP/IT trial study, we noted that the serum 25OHD increment in response to 700 IU per day of vitamin D was influenced by the fat composition of the diet. The increment was enhanced by dietary mono-unsaturated fatty acids (MUFAs) and decreased by poly-unsaturated fatty acids (PUFAs). We are currently in the process of exploring this possibility further in two prospective studies that are currently underway. One study will determine whether the amount of fat is important and the other study will directly assess the effect of the dietary MUFA: PUFA ratio on vitamin D absorption.
1. Vitamin D improves glucose tolerance in adults at high risk for type 2 diabetes. Adults with lower blood levels of vitamin D are thought to be at increased risk of developing type 2 diabetes. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, in collaboration with scientists at Tufts Medical Center in Boston, MA conducted a study to examine the effect of 2000 IU of vitamin D per day compared with placebo on insulin secretion and insulin sensitivity in a group of mainly Caucasian adults at high risk for developing type 2 diabetes. Over a 16-week period, supplementation significantly improved glucose tolerance, mainly by increasing insulin secretion. This study suggests a favorable effect of vitamin D on glucose handling and it provides the evidence needed to justify a large trial to determine whether longer-term supplementation with vitamin D will in fact lower risk of risk of developing type 2 diabetes in high-risk adults.
2. Vitamin D does not change the pathophysiology of prediabetes in African Americans. African-Americans have low vitamin D levels and a high incidence of type 2 diabetes. Prior evidence from this laboratory suggested that vitamin D supplementation can mitigate the progression from prediabetes to type 2 diabetes in Caucasian individuals, but it was unknown whether a similar effect would be observed in African Americans. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, conducted a randomized controlled trial to examine the effect of a 4000 international units per day (IU/d) dose of vitamin D on insulin secretion and related measures in overweight and obese African Americans with prediabetes. Supplementation successfully corrected vitamin D insufficiency and had divergent effects on insulin secretion and sensitivity with no overall effect on blood sugar levels. Thus, vitamin D supplementation for three months did not change the risk for progressing to diabetes in overweight and obese African Americans.
3. Dietary fat may influence the bioavailability of dietary vitamin D. The process of vitamin D replacement is complicated by the fact that the increase in the blood level of vitamin D in response to a given dose of the vitamin varies greatly from person to person. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, recently analyzed data from an intervention trial, and found that the increase in the blood level of vitamin D in response to 700 IU per day of vitamin D was influenced by the fat composition of the diet. The increment was enhanced by dietary mono-unsaturated fatty acids (MUFAs) and decreased by poly-unsaturated fatty acids (PUFAs). Understanding the nature of nutrient-nutrient interactions with vitamin D may lead to guidance on how to increase the bioavailability of this important vitamin.