Vitamin D: Beyond Bone

Vitamin D: Beyond Bone

Friday, September 21, 2012

The New York Academy of Sciences

Presented By

Presented by the Abbott Nutrition Health Institute, the New York Academy of Sciences, and The Sackler Institute for Nutrition Science

 

Over the past decade, researchers have produced data strongly suggesting that vitamin D and its metabolites contribute to a host of biological processes beyond the control of calcium and bone metabolism. This hypothesis is supported by the fact that the vitamin D receptor is expressed on a variety of cell types including lymphocytes, colonic cells, hepatocytes, and myocytes, including cardiac myocytes.

This 1-day conference will explore recent epidemiological data and the molecular mechanisms of action known to underlie the effects of vitamin D on pregnancy, lactation, and immune, metabolic, muscle, and cardiovascular function. Participants will also explore recent changes to vitamin D dietary guidelines, as well as critical next steps in vitamin D research that will aid the translation of basic research and epidemiological data into public health strategies that support the health and well-being of infants, adults, and the aging population.


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Presented by

This event is sponsored by an unrestricted educational grant from Abbott Nutrition Health Institute.

  • Abbott Nutrition
  • NYAS
  • Sackler

Agenda

* Presentation times are subject to change.


September 21, 2012

8:00 AM

Breakfast and Registration

9:00 AM

Opening Remarks

Mandana Arabi, MD, PhD
The Sackler Institute for Nutrition Science

Amanda Ullman, PhD
The New York Academy of Sciences

Rosemary E. Riley, PhD, LD
Abbott Nutrition Health Institute

Session I: Non-Classical Effects of Vitamin D

Chair: Martin Hewison, PhD, University of California Los Angeles

9:30 AM

Vitamin D Biology Beyond Bone
Sylvia Christakos, PhD, UMDNJ-New Jersey Medical School

10:00 AM

Vitamin D in Immune Function and Disease Prevention
Martin Hewison, PhD, University of California Los Angeles

10:30 AM

Networking Coffee Break

11:00 AM

Role of the Vitamin D Receptor in the Cardiovascular System
David G. Gardner, MD, University of California San Francisco

11:30 AM

Vitamin D during Pregnancy and Lactation: Emerging Concepts
Carol L. Wagner, MD, Medical University of South Carolina

Session II: Early Career Investigator Presentations

Chair: Carol L. Wagner, MD, Medical University of South Carolina

12:00 PM

The Role of Vitamin D in the Regulation of Apoptotic Signaling Pathways in Obesity
Igor N. Sergeev, PhD, DSc, South Dakota State University

12:15 PM

Plasma Vitamin D is Independently Associated with Lung Function in Patients with Chronic Obstructive Pulmonary Disease (COPD)
Erica Rutten, PhD, Ciro+, Centre of Expertise for Chronic Organ Failure, The Netherlands

12:30 PM

Impact of Cholecalciferol Repletion on Erythropoietin Requirements in Vitamin D-deficient Hemodialysis Patients: Pilot Data from a Randomized Controlled Trial
Lily Li, Mount Sinai School of Medicine

12:45 PM

Networking Lunch

Session III: Translating Epidemiological Data into Policy and Clinical Applications in Adult and Aging Populations

Chair: Hawley K. Linke, PhD, Abbott Nutrition

2:00 PM

Vitamin D for Type 2 Diabetes: To D or not to D
Anastassios G. Pittas, MD, Tufts Medical Center

2:30 PM

Molecular Aspects of the Role of Vitamin D in Muscle Function
Ricardo Boland, PhD, Universidad Nacional del Sur, Argentina

3:00 PM

Level of Vitamin D Affects Physical and Cognitive Function in Older Persons
Luigi Ferrucci, MD, PhD, National Institute on Aging

3:30 PM

Networking Coffee Break

4:00 PM

Keynote Address

Vitamin D Dietary Reference Intakes: Navigating the Recommendations
Daniel D. Bikle, MD, PhD, University of California San Francisco and VA Medical Center

4:45 PM

Panel Discussion

What are the Research Gaps and Critical Next Directions in Vitamin D Research?

Moderator
Mandana Arabi, MD, PhD, The Sackler Institute for Nutrition Science

Panelists
Daniel D. Bikle, MD, PhD, University of California San Francisco and VA Medical Center
Luigi Ferrucci, MD, PhD, National Institute on Aging
Anastassios G. Pittas, MD, Tufts Medical Center
Carol L. Wagner, MD, Medical University of South Carolina

5:20 PM

Closing Remarks

Gary Fanjiang, MD, MBA, MS, Abbott Nutrition Health Institute

5:30 PM

Networking Reception with Poster Session

7:00 PM

Conference Adjourns

Speakers

Organizers

Heike Bischoff-Ferrari, MD, MPH

University of Zurich

Martin Hewison, PhD

University of California Los Angeles

Dr Hewison is currently Professor in Residence at the David Geffen School of Medicine UCLA where his group has an established interest in the role of vitamin D in human physiology, and in particular the interaction between vitamin D and the immune system. Dr Hewison gained his PhD in Biochemistry from Guy's Hospital Medical School London and then spent nine years at University College London. He then moved to the University of Birmingham where he established the UK's major vitamin D research group, leading to an appointment as Professor in Molecular Endocrinology in 2004. In 2005 he joined Cedars-Sinai Medical Center Los Angeles but was then recruited to neighboring UCLA at the end of 2007. Dr Hewison has published over 160 peer-reviewed manuscripts focused on various facets of steroid hormone endocrinology. He currently has a team of three postdocs, a clinical fellow and two PhD students and his work supported by NIH and March of Dimes funding.

Nabeeha Mujeeb Kazi, MIA, MPH

Humanitas Global Development

Hawley K. Linke, PhD

Abbott Nutrition

Hawley K. Linke is a Senior Scientist in the Global Discovery Group at Abbott Nutrition. Her early expertise arose from postdoctoral studies in mitochondrial gene identification at Stanford University Medical School and study of human viral gene expression for her PhD from UCLA's Molecular Biology Institute and related investigations at the Salk Institute. She joined Abbott Laboratories Diagnostics Division, Hepatitis-AIDS investigation group, before transferring to Abbott Nutrition. Her contributions to nutrition research include the development and exploitation of industrial scale expression technologies producing genetically modified and unmodified human proteins for nutritional applications; and conduct of clinical studies demonstrating therapeutic innovations in infant formula. As a subject matter expert regarding vitamin D, she advises the division on nutritional products to optimize the pleiotropic health benefits of this molecule and has authored review articles (in press). Innovation areas for which she maintains technical evaluation and theoretical R&D support include technologies for women's health, neurogastroenterology, and manipulation of the microbiome. Dr. Linke enjoys serving annually as a judge for the Collegiate Inventors Competition created by Invent Now.

Rosemary E. Riley, PhD, LD

Abbott Nutrition Health Institute

Rosemary E. Riley, PhD, LD, is senior manager, science programs for the Abbott Nutrition Health Institute, where she is responsible for developing and directing programs that educate health care professionals throughout the world on the importance of nutrition as therapy to improve patient outcomes. While at Abbott, Rosemary has worked on a variety of nutrition initiatives, including a comprehensive, multidisciplinary medically supervised weight management program, geriatric nutrition, sports nutrition, women's health— with a focus on bone health—and diabetes. She also has experience in strategic discovery and evaluation of ingredients and technology to address these same health conditions.

Carol L. Wagner, MD

Medical University of South Carolina

Mandana Arabi, MD, PhD

The Sackler Institute for Nutrition Science

Brooke Grindlinger, PhD

The New York Academy of Sciences

Keynote Speaker

Daniel D. Bikle, MD, PhD

University of California San Francisco and VA Medical Center

Daniel D. Bikle is Professor of Medicine and Dermatology at the University of California, San Francisco, and Co-director of the Special Diagnostic and Treatment Unit of the San Francisco VA Medical Center. He has a long history in the area of vitamin D, performing a number of the initial studies in its metabolism in the kidney and more recently its extrarenal metabolism in the skin. These latter studies enabled Dr. Bikle and his collaborators to clone and sequence the human enzyme, CYP27B1, responsible for 1,25 dihydroxy vitamin D (1,25(OH)2D) production, the most biologically active metabolite of vitamin D. Much of Dr. Bikle's recent research has focused on the molecular mechanisms by which 1,25(OH)2D and its receptor (VDR) regulate gene expression, in particular during normal epidermal differentiation, wound healing, and hair follicle cycling and the pathologic changes underlying epidermal carcinogenesis. Dr. Bikle is also a practicing Endocrinologist with particular interest in metabolic bone disease, and has written extensively on the interface between the laboratory and clinic with respect to the implications of the recent research in vitamin D function and its impact on patient care.

Speakers

Ricardo Boland, PhD

Universidad Nacional del Sur, Argentina

Dr. Ricardo Boland is Superior Investigator of the National Research Council (CONICET) and Director of the Biological Chemistry Laboratories at the Universidad Nacional del Sur, Argentina. Dr. Boland obtained his PhD in Biochemistry at the University of Missouri- Columbia. He completed postdoctoral training at St. Louis University School of Medicine and the Max-Planck Institute for Medical Research, Heidelberg. He served as President of the Argentinean Societies for Biochemistry and Molecular Biology and of Bone and Mineral Research. Dr. Boland´s research career has been mainly focused on the actions of vitamin D3 on skeletal muscle functions. His major contributions are the identification of the vitamin D receptor (VDR) in this tissue, the characterization of signal transduction pathways involved in the regulation of the Ca2+ messenger system and myogenesis by 1α,25(OH)2-vitamin D3, and the demonstration of a functional role of the VDR in these events.

Sylvia Christakos, PhD

UMDNJ–New Jersey Medical School

Sylvia Christakos, PhD, is Professor of Biochemistry and Molecular Biology and at the University of Medicine and Dentistry of New Jersey (UMDNJ)–New Jersey Medical School in Newark, New Jersey, USA. Dr. Christakos received her PhD degree from the State University of New York (SUNY) at Buffalo School of Medicine. She completed her postdoctoral training at the Roswell Park Memorial Institute, Buffalo, NY, SUNY Buffalo School of Medicine Department of Biochemistry, and at the University of California at Riverside, California, Department of Biochemistry. In 1980 she was appointed as Assistant Professor in the Dept of Biochemistry UMDNJ–New Jersey Medical School, Associate Professor from 1985–1990 and Professor from 1990–present. From 1995–2004 Dr. Christakos was the Graduate Program Director of the Department of Biochemistry. Dr. Christakos has received continuous funding from the National Institutes of Health (NIH) and National Science Foundation (NSF) for the past 30 years. Dr. Christakos' laboratory is one of the leading laboratories involved in research related to vitamin D, its function and mechanism of action. For the past 30 years, her laboratory has combined studies related to the functional significance of vitamin D target proteins using animal models with studies related to the molecular mechanism of 1,25(OH)2D3 action.

Dr. Christakos has served on the NSF regulatory biology study panel, NIH study sections (including General Medicine B and Skeletal Biology, Structure and Regeneration) and the Veteran Administration's Endocrinology Merit Review Board. Dr. Christakos was Associate Editor of The Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism (2000–2007) and the Journal of Bone and Mineral Research (2003–2008). She is the author or co-author of 157 publications in peer reviewed journals. Dr. Christakos is a member of the American Society for Bone and Mineral Research (ASBMR) (1980–present) and the Endocrine Society. She is a recipient of the Gideon Rodan Mentorship Award from ASBMR. She has served on numerous ASBMR committees and was ASBMR President (2004–2005).

Luigi Ferrucci, MD, PhD

National Institute on Aging

Dr. Luigi Ferrucci is a geriatrician and an epidemiologist who conducts research on the causal pathways leading to progressive physical and cognitive decline in older persons. Dr. Ferrucci has made major contributions in the design of many epidemiological studies conducted in the U.S. and in Europe, including the European Longitudinal Study on Aging, the "ICareDicomano Study," the AKEA study of Centenarians in Sardinia and the Women's Health and Aging Study. He was also the Principal Investigator of the InCHIANTI study, a longitudinal study conducted in the Chianti Geographical area (Tuscany, Italy) looking at risk factors for mobility disability in older persons. Dr. Ferrucci has refined the design of the BLSA to focus more on normal aging, age-associated frailty and factors associated with exceptionally healthy aging and longevity.

David G. Gardner, MD

University of California San Francisco

Dr. David G. Gardner received an MS (Biochemistry) and MD with Honors and Distinction in Research from the University of Rochester in 1974. He completed his residency training in Internal Medicine at the Massachusetts General Hospital (1974–76) before moving to the NIH to complete his fellowship in the Combined Endocrinology Training Program (1976–79) at that institution. In 1979 he accepted an appointment as Adjunct Instructor in Medicine at the University of California at San Francisco. He is currently the Mount Zion Health Fund Distinguished Professor of Medicine and Chief, Division of Endocrinology and Metabolism at UCSF. His research interests are concentrated in cardiovascular endocrinology—particularly on the regulation of cardiovascular and renal function by vitamin D.

Martin Hewison, PhD

University of California Los Angeles

Dr Hewison is currently Professor in Residence at the David Geffen School of Medicine UCLA where his group has an established interest in the role of vitamin D in human physiology, and in particular the interaction between vitamin D and the immune system. Dr Hewison gained his PhD in Biochemistry from Guy's Hospital Medical School London and then spent nine years at University College London. He then moved to the University of Birmingham where he established the UK's major vitamin D research group, leading to an appointment as Professor in Molecular Endocrinology in 2004. In 2005 he joined Cedars-Sinai Medical Center Los Angeles but was then recruited to neighboring UCLA at the end of 2007. Dr Hewison has published over160 peer-reviewed manuscripts focused on various facets of steroid hormone endocrinology. He currently has a team of three postdocs, a clinical fellow and two PhD students and his work supported by NIH and March of Dimes funding.

Lily Li, BA

Mount Sinai School of Medicine

Lily Li is a third year medical student at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. After receiving her BA with Distinction in Biology from Carleton College, Lily completed a year-long Post-baccalaureate Intramural Research Training Award Program in immunology at the National Institutes of Health. She is currently pursuing a 1-year Doris Duke Clinical Research Fellowship at the Mount Sinai School of Medicine, and is working with Drs. Peter Heeger and Anita Mehrotra in the Department of Medicine.

Anastassios G. Pittas, MD

Tufts Medical Center

Dr. Pittas is an Associate Professor of Medicine at Tufts University School of Medicine, an Adjunct Associate Professor of Nutrition and Policy at Tufts University Friedman School of Nutrition, Science and Policy and a Center Scientist at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. He received his BS degree from Massachusetts Institute of Technology and his MD degree from Cornell University Medical College. After completing his Internal Medicine Residency at the New York Presbyterian Hospital in New York City, NY and his Fellowship in Endocrinology at Tufts Medical Center, Boston, MA, he joined the staff in the Division of Endocrinology, Diabetes, and Metabolism at Tufts Medical Center where he has been active in all three areas of academic medicine: clinical care, research, and teaching, as they relate to the prevention and treatment of diabetes mellitus. Dr. Pittas serves as the Co-director of the Dr. Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research Diabetes Self-education Program and as the Associate Director of the Endocrinology Fellowship program. He also served as the Director of the Endocrine Pathophysiology course at Tufts University School of Medicine from 2000 to 2008. Dr. Pittas earned his MS degree in Clinical Research from Sackler School of Biomedical Sciences at Tufts University in 2006. He is Diplomat of the American Board in Endocrinology and Metabolism. Dr. Pittas was the recipient of a National Institutes of Health K23 Career Development Award. His work on the role of vitamin D and calcium in cardiometabolic disease has been supported by the R01, R21 and U34 mechanisms of the National Institutes of Health (NIDDK and ODS) and the American Diabetes Association. His additional interest is in Comparative Effectiveness Research (CER) as it relates to the care of patients with diabetes. He has co-authored over 60 publications including peer-reviewed journals, books, book chapters, and evidence-based reports. Dr. Pittas has been a peer-reviewer for NIH study sections and for other international research foundations including the Canadian Institutes of Health Research, UK Diabetes, Children's Medical Research Foundation (Australia), and Health Research Council of New Zealand. He has also been a peer reviewer for major medical journals including Annals of Internal Medicine, Archives of Internal Medicine, The Lancet, and The Canadian Medical Association Journal. He is a member of various professional societies.

Erica Rutten, PhD

Ciro +, Centre of Expertise for Chronic Organ Failure

After her study on nutrition in the Catholic University Leuven in Leuven, Belgium, Dr. Rutten moved to Maastricht University in Maastricht, the Netherlands, for a PhD project on amino acid metabolism in patients with chronic obstructive pulmonary disease (COPD). After graduating, she was appointed by the Program Development Centre of the Centre of Expertise for Chronic Organ Failure (CIRO+) in Horn, the Netherlands. She is the theme leader of the topic body composition, nutrition, and metabolism. In 2008, Dr. Rutten received a research grant from the Dutch Asthma Foundation for work titled "Systemic Manifestation and Co-morbidity in COPD are Associated with Markers of Accelerated Aging." She is also interested in malnutrition in COPD, obesity, osteoporosis, vitamin D, and nutritional intake in patients with chronic disease.

Igor N. Sergeev, PhD, DSc

South Dakota State University

Dr. Sergeev has over 25 years of experience in academic research in biochemistry and nutrition. Dr. Sergeev received a PhD in 1984 from Institute of Biomedical Problem, Moscow, Russia and a DSc in 1991 from Institute of Nutrition, Moscow, Russia. As professor of nutritional sciences at South Dakota State University, he directs research program in nutritional biochemistry and molecular nutrition. Dr. Sergeev achieved an international reputation through his work on vitamin D metabolism, vitamin D receptors, and calcium signaling. In the last decade, he has been recognized for his research on the role of cellular calcium and vitamin D in the regulation of apoptosis. Dr. Sergeev's research is featured in over 100 major scientific publications. Among his most cited publications are articles in the Journal of Biological Chemistry, Endocrinology, and the Journal of Steroid Biochemistry and Molecular Biology. Dr. Sergeev has received a number of awards, including prestigious recognitions from the Academy of Medical Sciences (Russia), the Visiting Researcher award from University of California, Riverside, and the Wellcome Trust Senior Research Fellowship in Medical Science.

Carol L. Wagner MD

Medical University of South Carolina

As an academic neonatologist for more than 20 years, Dr. Carol Wagner has been involved in basic science, translational and clinical studies. She is a graduate of Brown University and the Boston School of Medicine, receiving her MD degree in 1986. She then completed both her Pediatric residency and Neonatal–Perinatal fellowship at the University of Rochester, completing her post-doctoral training in 1992. She accepted a faculty position at the Medical University of South Carolina in that same year, where she continues to work as Professor of Pediatrics and Associate Director of the Clinical and Translational Research Center. Dr. Wagner's current research interests are vitamin D requirements during pregnancy and lactation and human milk bioactivity and its effect on gut maturation.

Working with colleague Dr. Bruce Hollis, Drs. Hollis and Wagner undertook a series of ground-breaking pilot studies to ascertain the vitamin D requirements of lactating women and their infants from which three randomized control trials were born: NIH #R01 HD043921; R01 HD047511, and Thrasher Research Fund (#02823). These studies addressed the hormonal and more basic mechanism of vitamin D metabolism during states of both deficiency and sufficiency unique to pregnancy and lactation. Dr. Wagner is also the PI of an ongoing follow-up study of the original NICHD and Thrasher pregnancy cohorts funded by the Thrasher Research Fund with the objective of better understanding the long-term effects of fetal vitamin D status on later development, growth and immune function during childhood. She is a recent recipient of a project funded by the Kellogg Foundation to study the effect of vitamin D repletion on health disparities and outcomes during pregnancy, and to translate these findings into public health policies. Based on the team's ongoing work, Dr. Wagner will present the evidence about vitamin D requirements during pregnancy and lactation and the implication of deficiency during these critical times during the lifecycle.

Sponsors

Presented by

This event is sponsored by an unrestricted educational grant from Abbott Nutrition Health Institute.

  • Abbott Nutrition
  • NYAS
  • Sackler

Promotional Partners

American Society for Nutrition

The Council for Responsible Nutrition (CRN)

Greater New York Dietetic Association

The Journal of Clinical Investigation

Nature Publishing Group
Nutrition & Diabetes

Society for Nutrition Education and Behavior

Vitamin D Council

Abstracts

Session I: Non-Classical Effects of Vitamin D

Vitamin D Biology Beyond Bone
Sylvia Christakos, PhD, UMDNJ-New Jersey Medical School

In recent years vitamin D has received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries together with the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease. The possibility of extraskeletal effects was first noted with the discovery of the presence of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining calcium homeostasis including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the presence of VDR in different tissues is not fully understood and the role of vitamin D in extraskeletal health has been a matter of debate. Evidence in the laboratory, including the use of animal models, indicates that 1,25(OH)2D3 generates a number of extraskeletal effects including inhibition of cancer progression, effects on the cardiovascular system and skin, modulation of innate immunity with subsequent killing of bacteria, and inhibition of certain autoimmune diseases. Although, unlike in the case of vitamin D deficiency and rickets, there is not a causal link between vitamin D deficiency and specific diseases related to extraskeletal effects, the evidence in the laboratory of beneficial effects of 1,25(OH)2D3 beyond bone is convincing. Findings in animal models may suggest mechanisms involving similar pathways in humans that could lead to the identification of new therapies.
 

Vitamin D in Immune Function and Disease Prevention
Martin Hewison, PhD, University of California Los Angeles

Beyond its role in calcium homeostasis and bone metabolism, vitamin D is also known to exert non-classical effects that include potent immunomodulatory properties. Recent studies have shown that this includes actions that enhance innate immune responses to infection whilst simultaneously preventing over-exuberant inflammatory adaptive immune responses. At the innate immune level, conversion of precursor 25-hydroxyvitamin D (25D) to active 1,25-dihydroxyvitamin D (1,25D) via the enzyme CYP27B1 in cells such as macrophages can trigger vitamin D receptor (VDR)-mediated responses that include increased production of antibacterial proteins and enhanced autophagy. These responses are highly dependent on the availability of 25D for intracrine conversion to 1,25D, indicating that impaired vitamin D (25D) status may lead to dysregulated responses to infection. However, innate immune responses to vitamin D are also influenced by T cells from the adaptive immune system that can fine-tune macrophage vitamin D metabolism, with concomitant effects on innate immunity. Vitamin D-mediated innate immunity has been linked to diseases such as tuberculosis and leprosy, but may also be important for more common infectious diseases. The same intracrine vitamin D system reported in macrophages is also present in dendritic cells (DCs) that present antigen to T cells during the adaptive immune response. In this setting localized synthesis of 1,25D acts to suppress DC maturation and therefore inhibit antigen presentation. However, vitamin D is also known to modulate T cell phenotype, most notably promoting T helper 2 (Th2) and regulatory (Treg) cells, whilst suppressing Th1 and Th17 cells. Thus, the overarching effect of vitamin D on adaptive immunity is tolerogenic and anti-inflammatory, prompting a link between vitamin D and the prevention of autoimmune disease. These features of vitamin D-mediated immunity and human disease, along with new developments and translational applications will be discussed in more detail during the presentation.
 

Role of the Vitamin D Receptor in the Cardiovascular System
David G. Gardner, MD, University of California San Francisco

A variety of basic and clinical research studies suggest that vitamin D plays a significant role in the promotion of cardiovascular health. We have generated a mouse model that allows for selective deletion of the vitamin D receptor (VDR) in different cell types. Deletion of the VDR in the cardiac myocyte leads to hypertrophy of the myocyte, activation of a hypertrophy-sensitive gene transcription program, and increased myocardial mass. This is associated with increased expression of the gene encoding modulatory calcineurin interacting protein1, a protein associated with the calcineurin signaling cascade that has been linked to hypertrophy in other models. Combining VDR deficiency with a model of murine myocyte steatosis serves to amplify the pathological phenotype associated with the latter, suggesting that deficiency of VDR or its ligand, 1,25 dihydroxyvitamin D, creates a setting which is more vulnerable to the influence of pathological stimuli affecting the heart. Finally, we have created a model of VDR deficiency in the endothelial cell of the heart (VDRECKO). These mice have normal blood pressure at baseline but show an exaggerated response to chronic angiotensin II infusion. Isolated aortic tissue from the VDRECKO mouse contracts normally in response to phenylephrine but demonstrates a reduced vasorelaxant response to acetylcholine, an effect which appears to be related to reduced endothelial nitric oxide synthase gene expression. Collectively, these data support a role for the liganded VDR in suppressing the effects of pathological stimuli and supporting the maintenance of normal structure and function in the cardiovascular system.
 

Vitamin D during Pregnancy and Lactation: Emerging Concepts
Carol L. Wagner, MD, Medical University of South Carolina

Vitamin D as a preprohormone has effects that extend beyond calcium metabolism and homeostasis throughout life, but this is most vivid during pregnancy when vitamin D metabolism is disengaged from its normal constraints. At no other time during the lifecycle is 25(OH)D, the first vitamin D metabolite, linked directly to 1,25(OH)2D production, which rises more than 2.5 times above nonpregnant levels. This elevation of 1,25(OH)2D likely serves the purpose of immune regulation, but there have been few studies that have evaluated the effect of vitamin D status on immune function during pregnancy to support this premise. In addition, few randomized controlled trials have been conducted in pregnant women to determine what is optimal vitamin D status. Two recent studies, the NICHD trial and the Thrasher Research Fund Trial, indicate that 400 IU vitamin D, the amount found in most prenatal vitamins, is woefully inadequate and that 4000 IU/day is necessary in order to optimize 1,25(OH)2D production, achieved when total circulating 25(OH)D is at least 40 ng/mL. Both studies give evidence that 4000 IU/day is not only safe but that adverse events of pregnancy are lower in the 4000 IU group when compared to 400 IU/day and even 2000 IU/day. Comorbidities of pregnancy appear to be directly linked with lower 25(OH)D, and conversely, increasing 25(OH)D appears to afford protection to the mother and her developing fetus. What we have learned about vitamin D requirements during pregnancy extends to lactation. It was thought for decades that human milk was minimally sufficient in vitamin D yet preliminary results of a recently completed NICHD vitamin D supplementation trial during lactation shows that when mother is vitamin D replete, her milk is replete and that her breastfeeding infant has excellent vitamin D status without infant supplementation. The implications of achieving vitamin D sufficiency solely through lactation is just beginning to be understood and will challenge researchers for decades to come.

 

Session II: Early Career Investigator Presentations

The Role of Vitamin D in Regulation of Apoptotic Signaling Pathways in Obesity
Igor N. Sergeev, PhD, DSc, South Dakota State University

Modulation of apoptosis is emerging as a promising strategy for prevention and treatment of obesity because removal of adipocytes through this process will result in reducing body fat and long-lasting maintenance of weight loss. Effects of 1,25(OH)2-vitamin D3 (1,25D) on apoptotic cell death are mediated via multiple signaling pathways that involve common regulators and effectors converging on cellular Ca2+ (Sergeev, 2005, 2009, 2012). However, the 1,25D-regulated, Ca2+-dependent apoptotic molecular targets have not been identified in adipose tissue. We investigated the mechanism by which 1,25D regulates apoptosis in adipocytes. The results obtained demonstrated that 1,25D induced, in a concentration- and time-dependent fashion, the apoptotic Ca2+ signal (a sustained, prolonged increase in concentration of intracellular Ca2+) in mature mouse 3T3-L1 adipocytes. The 1,25D-induced increase in cellular Ca2+ was associated with activation of the Ca2+-dependent µ-calpain and the Ca2+/calpain-dependent caspase-12. The activation of these proteases was sufficient for effecting morphological and biochemical changes attributed to apoptosis. The 1,25D-induced increase in cellular Ca2+ was also associated with the reduced lipid accumulation in mature adipocytes. A murine diet-induced obesity (DIO) model was used to evaluate the role of vitamin D in adiposity. The DIO mice (C57BL/6J) fed the high-vitamin D and, especially, high-vitamin D plus high-Ca diet demonstrated the decreased body and fat weight gain and improved markers of adiposity and vitamin D status (plasma concentrations of glucose, insulin, adiponectin, 25(OH)D, 1,25(OH)2D, and PTH). The findings obtained imply that the 1,25D-induced cellular Ca2+ signal can act as an apoptotic initiator that directly recruits Ca2+-dependent apoptotic effectors capable of executing apoptosis in adipose tissue. Targeting of Ca2+ signaling and the vitamin D/Ca2+-dependent calpains and caspases in adipocytes can represent an effective approach for chemoprevention and treatment of obesity. These findings also indicate the need to reevaluate the roles of vitamin D and calcium in obesity.
 

Plasma Vitamin D is Independently Associated with Lung Function in Patients with Chronic Obstructive Pulmonary Disease (COPD)
Erica Rutten, PhD, Ciro +, Centre of Expertise for Chronic Organ Failure

Patients with COPD primarily suffer from lung function impairment. Besides this, COPD is more and more believed to be a systemic disease and as such, high prevalence of vitamin D deficiency has been described. An association between lung function parameters and plasma vitamin D levels has been shown previously in the healthy (1), but never in a group of patients with COPD. The objective of the present study was to investigate whether there is an independent association between lung function parameters and plasma vitamin D levels in a group of 157 COPD patients admitted for pulmonary rehabilitation at Ciro+, the Netherlands. Plasma 25(OH)vitamin D levels, body mass index [BMI, weight in kg/(height in m)2] and lung function parameters [forced expiratory volume in 1s (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung (DLCO)] were measured. There were 57% males, mean age was 65±9y, mean FEV1 was 47.2±17.9% predicted, mean FVC was 94.6±20.6% predicted and mean DLCO was 53.2±19.7% predicted. Pearson correlation coefficient showed significant correlations between plasma vitamin D concentration and FEV1 (r=0.29, p<0.01), FVC (r=0.29, p<0.01) and DLCO (r=0.22, p=0.01). Multivariate regression analyses revealed that, after correction for age, gender and BMI, vitamin D concentration was independently associated with FEV1 (beta=0.22, p<0.01), FVC (beta=0.24, p<0.01), DLCO (beta=0.25, p<0.01). In conclusion, there is evidence that vitamin D plays a role in the lung pathology of patients with COPD, which needs further investigation.
 

Impact of Cholecal Ciferol Repletion on Erythropoietin Requirements in Vitamin D-Deficient Hemodialysis Patients: Pilot Data from a Randomized Controlled Trial
Lily Li, BA, Mount Sinai School of Medicine

Vitamin D deficiency is common in hemodialysis patients. Uncontrolled studies suggest correction of Vit D deficiency is associated with decreased erythropoietin (EPO) requirements. To characterize this relationship, we examined the impact of D3 repletion on EPO requirements in 79 Vit D-deficient (25OH-D level <25 ng/mL) hemodialysis patients randomized to receive D3 (n=51) or standard of care (no repletion, n=28) in a 2:1 ratio. Patients randomized to D3 received 50,000 IU/wk to a goal 25OH-D of >35ng/mL. Changes in Vit D level, hemoglobin (Hb), and EPO requirements were assessed at 3 months. EPO (Darbepoetin) doses were adjusted by nursing staff as per dialysis unit protocol (target Hb 10-12 g/dL). Baseline characteristics were similar between groups, as were baseline Vit D levels (median 13.5 vs 13.1, p=0.623), baseline Hb (mean Hb 11.8 g/dL vs 11.4 g/dL, p=0.155), and baseline EPO requirements (median Darbepoetin dose 40 units/wk vs 50 units/wk, p=0.262). Patients randomized to D3 had a rise in 25OH-D levels at 3 months (11.9 to 44.1 ng/mL, p<0.001, n=30), with a corresponding fall in EPO requirements (50.00 to 40.32 units/wk, p=0.029, n=30) despite no change in Hb (11.9 to 11.5 g/dL, p=0.180, n=30). No change in Vit D level, Hb, or EPO dose was observed in control patients at 3 months (n=15). Patients randomized to D3 did not experience hypercalcemia. Our preliminary data from this ongoing randomized controlled trial suggest that treatment of Vit D-deficient dialysis patients with D3 is safe, effective, and may result in lower EPO requirements.

 

Session III: Translating Epidemiological Data into Policy and Clinical Applications in Adult and Aging Populations

Vitamin D for Type 2 Diabetes; to D or not to D
Anastassios G. Pittas, MD, Tufts Medical Center

The most well recognized function of vitamin D is to maintain calcium and phosphorus homeostasis and to promote bone health; however, there is evidence to suggest that optimal vitamin D status may also be important for a variety of non-skeletal outcomes, including type 2 diabetes. Cross-sectional studies have reported consistent associations between lower vitamin D status and prevalent diabetes. In most longitudinal observational studies, lower vitamin D status is associated with increased risk of incident type 2 diabetes but the strengths of associations are attenuated compared to cross-sectional studies. Mechanistic trials have shown that vitamin D supplementation may alter the pathophysiology of type 2 diabetes. Vitamin D is a promising new element in the prevention and management of diabetes. However, because vitamin D is an excellent marker of general health status, the positive results reported in the observational studies and post-hoc analyses of trials might reflect confounding. Therefore, the hypothesis that vitamin D may modify diabetes risk needs to be confirmed in trials specifically designed for that purpose.
 

Molecular Aspects of the Role of Vitamin D in Muscle Function
Ricardo Boland, PhD, Universidad Nacional del Sur, Argentina

Various lines of clinical and experimental data, as well as the presence of the VDR in skeletal muscle, support the notion that Vitamin D3 plays a role in this tissue. There is a wealth of evidence indicating that the hormone 1α,25(OH)2-vitamin D3 [1α,25(OH)2D3] acts in muscle through membrane initiated mechanisms. The purpose of this talk is to review the regulation of signal transduction pathways in skeletal muscle cells by 1α,25(OH)2D3. The hormone induces fast responses, involving transmembrane stimulation of adenylyl cyclase/cAMP/PKA, PLC/DAG + IP3/PKC, Ca2+ messenger system and MAPK cascades. 1α,25(OH)2D3 rapidly induces reverse translocation of the VDR from the nucleus to the plasma membranes. Accordingly, a complex is formed between the VDR and TRCP3, an integral protein of capacitative Ca2+ entry (CCE), suggesting an association between both proteins and a functional role of the VDR in 1α,25(OH)2D3 activation of CCE. In addition, the formation of complexes between the VDR and Src has been involved in the activation of tyrosine phosphorylation paths by hormone. Integration of these mechanisms throw light on the regulation of contractility and myogenesis by 1α,25(OH)2D3.
 

Level of Vitamin D Affects Physical and Cognitive Function in Older Persons
Luigi Ferrucci, MD, PhD, National Institute on Aging, NIH

Vitamin D, the "sunshine vitamin," is recognized for its role in bone health and calcium metabolism. Vitamin D supplementation is generally considered a critical component for the prevention of osteoporosis. Recent research suggest that vitamin D deficiency might also contribute to the pathogenesis and clinical progression of chronic diseases highly prevalent in older persons, including cardiovascular disease, cancer, chronic pulmonary diseases, depressive symptoms, and autoimmune disease. Observational evidence for a role of vitamin D in these conditions is generally strong and consistent, but data on vitamin D in the prevention of specific or multiple morbidity is still limited and different studies often report conflicting findings. Over the last few decades, geriatricians realized that assessing health in older persons should rely on measures of physical and cognitive function rather than on disease diagnoses. Thus, both preventive and therapeutic interventions that target older patients should be evaluated on their ability to prevent or delay physical and cognitive impairment with aging. Through a series of cross-sectional and longitudinal analyses we have demonstrated a strong association of vitamin D deficiency with lower extremity performance, pulmonary function, muscle strength, pain, mobility disability, transition to physical frailty, cognitive decline, dementia, and cardiovascular and all-cause mortality. The mechanisms for these associations are not always fully understood. Because of multifaceted associations with conditions that span across multiple physiological systems and pertain to factors important for quality of life, vitamin D supplementation may be the ideal intervention to slow down the development of major aging phenotypes.
 

Keynote Address
Vitamin D Dietary Reference Intakes: Navigating the Recommendations

Daniel D. Bikle, MD, PhD, University of California San Francisco and VA Medical Center

Recommendations for the appropriate amount of vitamin D to be taken for optimal health, be it for musculoskeletal strength or for the numerous non skeletal presumptive benefits of vitamin D, remain contentious. There is general consensus that the earlier recommendation of 400IU (10µg) of vitamin D per day was insufficient. Recently, an Institute of Medicine (IOM) expert panel to formulate new guidelines has recommended that 600IU per day would suffice for the general public aged 1–70 years with the dose increased to 800IU per day for those older than 70 years. However, doses up to 4000IU per day were considered safe. The task force compiling the Endocrine Society Clinical Practice Guidelines (ESCPG) reached similar conclusions. However, vitamin D status is best assessed by the circulating levels of the vitamin D metabolite 25 hydroxyvitamin D (25OHD). Individuals vary widely as to the serum level of 25OHD that is achieved with a given dose of oral vitamin D and it is the serum level that counts with respect to biologic effect. On this point these two major guidelines differ. The IOM panel concluded that 20ng/ml (50nM) 25OHD is sufficient for normal musculoskeletal strength/function, that 97.5% of the American public was above that level, and that higher levels were not beneficial and might even be detrimental. In contrast, the ESCPG recommend a higher optimal level, namely 30ng/ml (75mM), and point out that many individuals with a variety of conditions including obesity, dark skin, malabsorption, renal failure, lactose intolerance, ingestion of certain drugs, and the institutionalized are likely not to achieve adequate 25OHD levels ingesting only 600IU per day. If 30ng/ml is deemed the optimal level (and neither set of recommendations considers this level unsafe), then the percent of Americans that maintain this level falls well below 50% and across the developing world, the percentage of vitamin D-deficient individuals is much higher. Moreover, 25OHD assays have not proved consistent, making decisions regarding supplementation all that more difficult.
 

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