Vitamin D 3. Classical Vitamin D 3 Pathway. Vitamin D

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1 Vitamin D Matthew J. Rowling, Ph.D. Department of Food Science and Human Nutrition, Iowa State University, Ames, IA Vitamin D 3 Steroid hormone Derivative of cholesterol Acquired by sunlight exposure or diet Dietary Sources: Supplements, fortified foods, fatty fish, cod liver oil Classical Vitamin D 3 Pathway Cholesterol (skin) Diet Target Tissues UV Vitamin D 3 Liver Kidney 1

2 Proposed Physiological Roles of Vitamin D 3 Calcium and phosphorus homeostasis (proven) Insulin secretion and sensitivity Immunity Cancer prevention: Regulation of cell growth, differentiation, and apoptosis Cardiovascular health Updated View of Vitamin D 3 Pathway Vitamin D 3 Liver Target Cell Kidney 2

3 Endocytosis of - in Kidney-not proven elsewhere 25- (OH)D3 Megalin Cubilin Endocytosis 25 - (OH)D3 25(OH) D 3 25(OH) D 3 Proximal Tubule Blood Target Tissues Mechanism of Vitamin D 3 Actions in Target Cells Target Cell Immune System VDR Ca 2+ Homeostasis Growth, Differentiation, Apoptosis Vitamin D 3 metabolism and actions Whiting and Calvo, 2005, J. Nutr., 135:

4 Reasoning Behind Current Vitamin D Recommendations Intake enough to ensure adequate serum levels for bone health Based on no UVB exposure Upper limits- are conservative estimates Cautious of soft tissue calcification Lack of clinical trials that demonstrate vitamin D prevents chronic disease Life stage group 1997 IOM Adequate Intake (AI)a Endocrine Endocrine Society Upper Level 2011 IOM Adequate 1997 IOM 2011 IOM Society Daily Tolerable of Intake Recommende Intake values Tolerable Tolerable Requirement Upper Intake Values for d Dietary for Australia Upper Intake Upper Intake for patients at Level for Australia and Allowance and New Level (UL)a Level (UL)b risk for patients at New Zealand (RDA)b Zealand (AI) vitamin D risk for (UL) deficiencyc vitamin D deficiencyc 0 through , (AI) 1, ,000 2, ,000 months 7 through , (AI) 1, ,000 2, ,000 months 1 through , , ,000 4, ,200 4 through , , ,000 4, ,200 9 through , , ,000 4, , through , ,000 1,500 2,000 10, , through , ,000 1,500 2,000 10, ,200 > , ,000 1,500 2,000 10, ,200 Pregnancy , , ,000 4, , through , ,000 1,500 2,000 10, ,200 Lactation , , ,000 4, , through , ,000 1,500 2,000 10, ,200 Factors influencing vitamin D 3 synthesis and bioavailability 20 minutes in the sun: equivalent to taking 10,000-25,000 IU (25-60 vitamin D 3 supplement pills, 400 IU). Factors influencing vitamin D 3 synthesis and bioavailability: Age, melanin pigmentation, latitude, clothing, obesity. 4

5 Serum levels of vitamin D 3 metabolites Serum synthesized only in kidney Very tightly regulated Only drops when individuals are severely vitamin D deficient!!! Not regulated Reflects vitamin D intake and sun exposure. Recommendations for serum 25D concentrations Definition of vitamin D status (based on 25(OH)D concentrations) Institute of Medicine a Endocrine Society b Deficient <30 nmol/l <12 ng/ml <50 nmol/l <20 ng/ml Insufficient nmol/l ng/ml nmol/l ng/ml Sufficient >50 nmol/l >20 ng/ml >75 nmol/l >30 ng/ml Potential adverse effects >125 nmol/l >50 ng/ml No cutoff value defined 1. a Institute of Medicine, b Holick et al., Urial-Adams, et al., (2013) Vitamin D 3 Dose Response ng/ml=2.4 nm Barger-Lux, et al., 1998, Osteoporosis Intl., 8: Haddad and Chyu, 1971, Clin. Endocrinol. Metab., 33:

6 When should vitamin D recommendations be adjusted? Renal insufficiency Cannot reabsorb 25D 3 Increased urinary loss of 25D 3 and 1,25D 3 Uncontrolled diabetics-poor renal function Children Northern Latitudes Lactating women Obesity and Serum Lowest quartile of obesity Highest quartile of obesity Bolland, et al. (2007) AJCN Endocytosis of - in Kidney During Renal Failure 25- (OH)D3 Megalin Cubilin Diabetes Urine Endocytosis 25 - (OH)D3 Vitamin D Deficiency 25(OH) D 3 1,25(OH) 2 D Proximal Tubule 3 Target Tissues Blood 6

7 Vitamin D Status in Diabetes Mellitusinduced Chronic Renal Failure Ishimura, et al. (1999) Kidney Int, 55(3): Vitamin D and maternal and child health: Overview and implications for dietary requirements Birth Defects Research Part C: Embryo Today: Reviews Volume 99, Issue 1, pages 24-44, 30 MAY 2013 DOI: /bdrc Total circulating 25(OH)D concentration (nmol/l) by treatment (400 IU vs 6400 IU groups) of breastfeeding mothers: A, through V4; B, through V7; and of breastfeeding infants: C, through V4; D, through V7. Mothers Infants Bruce W. Hollis et al. Pediatrics 2015;136: by American Academy of Pediatrics 7

8 Extrarenal activation of? Extra renal tissues express and can make Big question: Is it accessible??? The more serum, the more tissue 1,? vitamin D 3 VDR Target Cell Kidney Growth, Differentiation, Apoptosis Extra-renal Tissues that express (1α-hydroxylase) Mammary Colon T cells Prostate Skin Ovary Placenta, adrenal medulla, brain, and pancreas Vitamin D 3 and Breast Cancer 1 ng/ml=2.4 nm Garland, C.F., et al. 2007, J Steroid Biochem Mol Biol. 103:

9 Vitamin D 3 and Colon Cancer Bischoff-Ferrari, et al., 2006, Amer. J. Clin. Nutr. 84: Sunlight Exposure and Prostate Cancer Mortality Prostate Cancer Mortality UV Exposure Hanchette, C.L. and Schwartz, G.G., 1992 Cancer, 70: Vitamin D 3 deficiency and autoimmunity Cantorna and Mahon, 2004, Exp. Biol. Med., 229:

10 Vitamin D 3 and Multiple Sclerosis Munger, K. L. et al., 2006, JAMA 296: Issue with studies such as these Not controlled clinical trials. Only associations have been made. Cause vs. effect? Variation in vitamin D status over time. Several trials completed or underway cleid= #jvp150014t1 What needs to happen to change recommendations? More mechanistic evidence for why vitamin D may prevent or treat illness. Long-term (length is debatable), wellcontrolled vitamin D clinical trials. Studies that demonstrate early life exposure to vitamin D is beneficial to longterm outcomes. No small feat. Feasibility is quite low. 10

11 From: Vitamin D Research and Clinical Practice: At a Crossroads JAMA. 2015;313(13): doi: /jama Table Title: Ongoing Large-Scale Randomized Trials (N Participants) of Vitamin D Supplementation Worldwide a Copyright 2016 American Medical Association. All rights reserved. Risk vs. Reward??? Whiting and Calvo, 2005, J. Nutr., 135: Continuum of Vitamin D 3 Status in Relation to Disease Whiting and Calvo, 2005, J. Nutr., 135:

12 Time Course Response 10,000 IU 5,000 IU Heaney, et al., 2003, Amer. J. Clin. Nutr. 77: Serum Calcium Levels Heaney, et al., 2003, Amer. J. Clin. Nutr. 77: How Much is Safe?? Zittermann, A. 2006, Br. J. Nutr. 89,

13 Can Dietary Vitamin D Suffice? Vitamin D3 in Food Cod liver oil (1 tbsp): ~1400 IU vit. D Catfish (3 oz): ~400 IU vit. D Salmon (3 oz): ~400 IU vit. D Fortified Milk (8 oz): ~100 IU vit. D. Fortified Cereal (8 oz): ~75 IU vit. D. Hands, E. Food Finder Vitamin and Mineral Source (1995) ESHA Research, 3 rd edition. Achieving optimal serum through the Diet. Not practical without supplemental vitamin D or sun exposure. Not practical in elderly or individuals with darker skin pigmentation. Putting Dietary Vitamin D into Perspective Achieving adequate through dietary means (2000 IU vitamin D/day) 2 tablespoons cod liver oil/day-vit A toxicity? 5 servings salmon or catfish/day 20 servings milk/day 25 bowls of fortified cereal/day 13