VITAMINA D COME FATTORE DI RISCHIO POTENZIALE

NELL’OBESITA’

Massimiliano Andrioli

EndocrinologiaOggi, Roma, Lecce

Endocrinologia, Istituto Auxologico Italiano, Milano

TIPI DI VITAMINA D

• vitamina D3 o Colecalciferolo (animale)

• vitamina D2 o Ergocalciferolo (vegetale)

• 80-90% produzione endogena

• 10-20% alimentare (animale/ vegetale)

7-Dehydrocholesterol7-Dehydrocholesterol Pre-Vitamin DPre-Vitamin D33 Vitamin DVitamin D33

EpidermisEpidermis

LatitudeLatitudePollutionPollutionClothingClothingMelanin pigmentationMelanin pigmentationDuration of exposureDuration of exposure

FISIOLOGIA

FISIOLOGIA

calcifediolo

calcitriolo

colecalciferolo

Colecalciferolo (vitamina D3) • Di-base gtt 10.000 UI/ml (1 gtt = 250 IU, 1 mcg = 40 UI)• Di-base flaconcino 25.000 IU • Di-base fl os/im 100.000-300.000 UI

Calcifediolo (25-OH-colecalciferolo)• Didrogyl gtt (uso selettivo) NB 5 ug (200 IU) colecalciferolo = 1 ug (40 IU) calcifediolo

Calcitriolo (1,25 OH vitamina D3)• Rocaltrol 0,25-0,50 ug cpr (uso selettivo)• 1-alfa-OH-colecalciferolo (alfa-calcidolo)• Dediol/Diserinal cpr 0,25-1 ug (uso selettivo)

Ergocalciferolo (Vitamina D2 )• Ostelin fl os/im 400.000 UI (meno efficace, poco utilizzata)

FARMACI

FUNZIONE

1,25(OH)1,25(OH)22DD

BoneBoneDietary calciumDietary calcium IntestinesIntestines

Bone Density and Fractures

– Risk of osteoporosis may be reduced with adequate intake of vitamin D and calcium.

– Studies support the concept that vitamin D at doses between 700 and 800 IU/d with calcium supplementation effectively increase hip bone density and reduced fracture risk, whereas lower vitamin D doses may have less effect.

VITAMINA D - OSSO

Cells containing 25OH-VitD3-1-alpha-OHaseBreast, prostate, lung, skin, lymph nodes, colon, pancreas, adrenal

medulla, brain, placenta» Holllick MF. Am J Clin Nutr. 2004. 79(3):362.» Zehnder et al. J Clin Endocrin Metab. 2001;86(2)

Cells containing Nuclear VDRPancreatic islet cells, monocytes, transformed B cells, activated T

cells, neurons, prostate, ovaries, pituitary, aortic endothelium, placenta, skeletal muscle cells.

» Zittermann A. Br J Nutr. 2003;89(5):552.» Bischoff HA, et al. Histochem J 2001;33:19.

EFFETTI EXTRASCHELETRICI

• Involved in cellular growth, differentiation and apoptosis• Simulates insulin secretion• Modulates the immune system. • Reduces inflammation• Muscle development

EFFETTI EXTRASCHELETRICI

Role in Cancer Prevention

– Low intake of vitamin D and calcium has been associated with an increased risk of non-Hodgkin lymphomas, colon, ovarian, breast, prostate, and other cancers.

– The anti-cancer activity of vitamin D is thought to result from its role

as a nuclear transcription factor that regulates cell growth, differentiation, apoptosis and a wide range of cellular mechanisms central to the development of cancer. These effects may be mediated through vitamin D receptors expressed in cancer cells.

– Vitamin D is not currently recommended for reducing cancer risk

VITAMINA D - TUMORI

Role in All Cause Mortality

–Researches concluded that having low levels of vitamin D (<17.8 ng/mL) was independently associated with an increase in all-cause mortality in the general population.

VITAMINA D – MORTALITA’

Autoimmune Disease

– Vitamin D supplementation is associated with a lower risk of autoimmune diseases.

– In a Finnish birth cohort study of 10,821 children, supplementation with vitamin D at 2000 IU/d reduced the risk of type 1 diabetes by approximately 78%, whereas children who were at risk for rickets had a 3-fold higher risk for type 1 diabetes.

– In a case-control study of 7 million US military personnel, high circulating levels of vitamin D were associated with a lower risk of multiple sclerosis.

– Similar associations have also been described for vitamin D levels and rheumatoid arthritis.

VITAMINA D – AUTOIMMUNITA’

Role in Cardiovascular Diseases

– Vitamin D deficiency activates the renin-angiotensin-aldosterone system and predisposes to hypertension and left ventricular hypertrophy.

– Vitamin D deficiency increases PTH, which increases insulin resistance secondary to down regulation of insulin receptors and is associated with diabetes, hypertension, inflammation, and increased cardiovascular risk.

VITAMINA D - CARDIOVASCOLARE

Role in Reproductive Health

– Vitamin D deficiency early in pregnancy is associated with a five-fold increased risk of preeclampsia.

VITAMINA D - RIPRODUZIONE

Robert P. 2008. Vitamin D in Health and Disease. Clin J Am Soc Nephrol 3:1535-1541.

Disorder Strength of Evidence

Osteoporosis ++++

Falls ++++

Type 1 DM ++

Cancer ++++

Autoimmune diseases ++

Hypertension +++

Periodontal disease ++++

Multiple sclerosis ++

Susceptibility/poor response to infection

++++

Osteoarthritis ++

DISORDINI CAUSATI O AGGRAVATI DA IPOVITAMINOSI D

VITAMINA D - PUBBLICAZIONI

VITAMINA D- OBESITA’

VITAMINA D

OBESITA’

RISCHIO CARDIOVASCOLARE

(Rizzoli R. Current Medical Research & Opinion 2013)

DEFINIZIONE

- increased age - female sex- darker skin pigmentation- reduced sun exposure- seasonal variation - distance from the equator- inter-assay and inter-laboratory 25(OH)D variability

25OHD ASSESSMENT

• Poor dietary intake of vitamin D

• Lower sun exposure

• Sedentary lifestyle

• Clothing practices

• Decreased oral absorption

• Decreased cutaneous synthesis

• Increased clearance

• Enhanced production of 1,25(OH) D. Negative feedback on 25(OH)D

• 25(OH)D may increase glucocorticoid which regulates adipose tissue

• Vitamin D decreases PPAR-gamma, leading to other metabolic processes in the preadipocyte.

EZIOLOGIA

• Olson et al JCEM 2011– 92% of obese subjects had a 25(OH)D level below 30 ng/ml vs

68% in non overweight children– 50% of obese subjects were below 20 ng/l vs 22% in non

overweight children

• Alemzedeh et al Metabolism 2008– 74% had 25(OH)D levels less than 30 ng/ml and 32.3% had

25(OH)D < 20 ng/ml

EPIDEMIOLOGIA

– selective deposition of vitamin D, a lipophilic molecule, in subcutaneous and visceral adipose tissue

– BMI and body fat were inversely related to serum 25(OH) vitamin D

– positive correlation between serum and fat tissue 25(OH) vitamin

– visceral compartment volume more closely associated with vitamin D deficiency compared with subcutaneous fat

– independent association between hypovitaminosis D and dysmetabolic conditions such as MS, T2D, hypertension and liver steatosis

– hypovitaminosis D has been hypothesized as a primary cause of obesity

VITAMINA D - OBESITA’

- obesity leads to lower vitamin D levels and not the other way around

Vimaleswaran, PLoS Med. 2013

Proteins linking vitamin D to obesity:

- vitamin D receptor- toll-like receptors- renin-angiotensin system- apolipoprotein E- vascular endothelial growth factor- poly (DP-ribose) polymerase-1

IPOVITAMINOSI D – GENETICA

Vitamin D cell-signaling mechanisms:

- matrix metalloproteinases- mitogen-activated protein kinase pathways- reduced form of nicotinamide

IPOVITAMINOSI D – SINDROME METABOLICA

– Vitamin D insufficiency involves more than 75% of patients with metabolic syndrome (MS)

– serum 25(OH) vitamin D3 levels are significantly lower in obese patients affected by MS than in obese subjects without MS

– A powerful association between hypovitaminosis D and MS in obese patients independently from body fat mass and its clinical correlates.

– The association between low 25(OH) D3 levels and MS is not merely induced by vitamin D deposition in fat tissue

– active form of vitamin D3 exerts an insulinsensitizing action by increasing the expression of insulin receptors in peripheral tissues and facilitating insulin-mediated glucose transport.

– In addition, vitamin D3 directly regulates the free fatty acids (FFA) metabolism acting on the PPAR and improves insulin resistance induced by FFA.

– Hypovitaminosis D represent a crucial independent determinant of MS.

IPOVITAMINOSI D – ADIPONECTINA

– Lower vitamin D and adiponectin levels were strongly associated with metabolic risk factors and obesity in Turkish children and adolescent

IPOVITAMINOSI D – IPERTENSIONE

- inverse association of vitamin D levels with the renin-angiotensin-aldosterone system activity - endothelial function - secondary hyperparathyroidism

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25 OH(D) (ng/mL)

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Johnson et al, Journal of Pediatrics 2010

VITAMINA D - GLICEMIA

VITAMINA D - DIABETE

– low vitamin D levels high risk of developing diabetes in the future – VDR, 1-α-hydroxylase expressed in pancreatic beta cells, potential role of vitamin

D on beta cell function – calcium crucial for insulin synthesis and secretion – vitamin D-induced stimulation of osteocalcin, which may improve insulin sensitivity – the currently available literature on vitamin D does not support the notion that

vitamin D supplementation is useful for the prevention and/or treatment of diabetes mellitus

– Vitamin D treatment of animals with diabetes mellitus type 1 slows the progression of diabetes

– High doses of vitamin in high risk-group children reduces diabetes incidence

VITAMINA D - DIABETE

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25 OH(D) (ng/mL)

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VITAMINA D – COLESTEROLO HDL

– association of vitamin D deficiency with lower high density lipoprotein (HDL) – higher triglycerides– higher apolipoprotein E levels– no significant effect on blood lipids when vitamin D supplementation

IPOVITAMINOSI D – TRATTAMENTO

In generale: forme inattive (non 1-alfa-idrossilate)•Colecalciferolo•Calcifediolo (25OHD3)

Tre indicazioni alla terapia con forme attive (1-alfa-idrossilate)•Calcitriolo•1-alfa-calcidolo:- IRC in stadio avanzato - ipoparatiroidismo cronico- malassorbimento grave

Adami S et al, Reumatismo 2011

IPOVITAMINOSI D – TRATTAMENTO

CONCLUSIONI

- ipovitaminosi D è frequente in obesità- ipovitaminosi D è una conseguenza- ipovitaminosi D si associa a: MS, ipertensione, diabete, ipercolesterolemia, rischio CV- trattamento integrativo

GRAZIE PER L’ATTENZIONE…..

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