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Diabetes and Vitamin D Stefania Maggi CNR Center on Aging Padua, Italy.

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Presentation on theme: "Diabetes and Vitamin D Stefania Maggi CNR Center on Aging Padua, Italy."— Presentation transcript:

1 Diabetes and Vitamin D Stefania Maggi CNR Center on Aging Padua, Italy

2 Vitamin D metabolism and actions Epidemiology of hypovitaminosis D Association of low Vitamin D status and chronic diseases Association of low vitamin D and diabetes: – epidemiological evidence, – pathophysiological plausibility, – efficacy of interventions Diabetes and Vitamin D

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4 The primary function of calcitriol or 1,25 (OH)2D3 in the intestine is increased absorption of calcium and phosphorous. Vitamin D is carried into the nucleus of the enterocyte, where it binds to receptor proteins and acts as a steroid hormone, resulting in the stimulation and synthesis of new messenger RNA molecules. These messenger RNA molecules are then translated to produce a protein, Calbindin, a calcium binding protein in the intestinal mucosa that is synthesized in response to the action of calcitriol (active vit. D). This calcium binding protein is needed for Ca transport across the cell membranes

5 Calcitriol and the Bone: PTH, alone or with calcitriol, directs the mobilization of Ca and P from the bones to help achieve a normal blood Ca concentration. The body’s needs for calcium is regulated by the production of calcitriol by the kidneys. “Hypocalcemia” increases the secretion of parathyroid hormone, which in turn: a) Stimulates the conversion of some of the circulating 25(OH)2D3 to 1,25(OH)2D3 (calcitriol) in the kidneys. b) This active 1,25(OH)2D3 (calcitriol) then causes elevation of serum Ca and P by acting on kidney, bone, and G.I. Tract

6 Vitamin D metabolism and actions Maalouf NM, Current opinion in Nephrology and hypertension, 2008

7 Vitamin D metabolism and actions Epidemiology of hypovitaminosis D Association of low Vitamin D status and chronic diseases Association of low vitamin D and diabetes: – epidemiological evidence, – pathophysiological plausibility, – efficacy of interventions Diabetes and Vitamin D

8 Suggested terminology to describe vitamin D status according to circulating 25(OH)D concentrations Stages of vitamin D status 25(OH)D concentrations (ng/mL) Deficiency0–12 Insufficiency>12–30 Adequacy>30 to 100 Toxicity>100 Souberbielle JC et al, Autoimmune reviews, 2010

9 Causes of hypovitaminosis D Reduced skin synthesis –Sunscreen use, skin pigment, aging, season, latitude Decreased bioavailability –Malabsorption, obesity Increased catabolism –Antconvulsants, glucocorticoids (binding to the steroid receptor) Breast feeding –Poor vit D content in human milk Decreased synthesis of 25(OH)D –Liver failure Increased urinary loss of 25(OH)D –Nephrotic syndrome Decreased synthesis of 1,25(OH)D –Chronic kidney failure

10 50-97% 35-73% 80% in aged, 42% in adolescents 30-80% Hypovitaminosis D: a global perspective Bandeira et al, Arq Bras Endocrinol Metab 50, 2006 Mithal et al, Osteop Int, 2009 Van der Meer M et al, Ospeop Int, 2011 Midle East and Africa register the highest rates of hypovitaminosis D worldwide. Turkish, Moroccan, Indian and Sub-Sahara African immigrants in Europe have higher level of hypovitaminosis D compared to indigenous European populations 89% in adolescents

11 Copyright ©2001 The Endocrine Society Lips, P. Endocr Rev 2001;22:477-501 Serum 25(OH)D measured in elderly people in 16 European centers participating in the Euronut SENECA Study. The lowest values were found in Greece, Spain, and Italy

12 Vitamin D metabolism and actions Epidemiology of hypovitaminosis D Association of low Vitamin D status and chronic diseases Association of low vitamin D and diabetes: – epidemiological evidence, – pathophysiological plausibility, – efficacy of interventions Diabetes and Vitamin D

13 Vitamin D deficiency Rickets--------------Children Osteomalacia------ Adults Osteoporosis-------Adults ……….. And much more!!

14 Vitamin D deficiency

15 Copyright restrictions may apply. Dobnig, H. et al. Arch Intern Med 2008;168:1340-1349. Independent Association of Low Serum 25-Hydroxyvitamin D Levels With All- Cause and Cardiovascular Mortality DobnigDobnig H et al, Arch Intern Med. 2008;168(12):1340-1349. Dobnig Prospective cohort study of 3258 patients undergoing coronary angiography

16 Copyright restrictions may apply. Dobnig, H. et al. Arch Intern Med 2008;168:1340-1349. Cox proportional hazards regression model ratios (including 95% confidence intervals [CI]) for cardiovascular mortality are shown for 25-hydroxyvitamin D (A) and 1,25- dihydroxyvitamin D (B) quartiles (Q) for the following 3 different statistical models (M): (1) M1 (unadjusted), (2) M2 (adjusted for age, sex, body mass index, and physical activity level), and (3) M3 (variables of M2 plus active smokers, diabetes mellitus, albumin level, cystatin C level, triglyceride level, N-terminal pro-BNP level, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol levels, and the use of statins, aspirin, -blockers, bronchodilators, and angiotensin-converting enzyme inhibitors) Low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are independently associated with all-cause and CVD mortality

17 Copyright restrictions may apply. Martins, D. et al. Arch Intern Med 2007;167:1159-1165. Age-, Sex-, and Race-Adjusted Prevalence and ORs of Select Cardiovascular Disease Risk Factors Between the First and Fourth Quartiles of Serum 25(OH)D Levels Data From the Third National Health and Nutrition Examination Survey (15088 participants >20 yrs)

18 Vit D and Metabolic Syndrome Relation of 25-hydroxyvitamin D and PTH levels with metabolic syndrome among US adults JP Reis, D. von Muhlen, ER Miller European Journal of Endocrinology, 159, 2008 We have strong evidences of hypovitaminosis D in MetS patients, independent of Ca intake, PTH, BMI, or renal function The potential mechanisms to explain the protective effect of vitamin D against MetS is based on the effect on glucose homeostasis (insulin resistance, β cell function): Vit D increases insulin receptor capacity and responsiveness for glucose transport

19 Vitamin D metabolism and actions Epidemiology of hypovitaminosis D Association of low Vitamin D status and chronic diseases Association of low vitamin D and diabetes: – epidemiological evidence, – pathophysiological plausibility, – efficacy of interventions Diabetes and Vitamin D

20 Association between type 1 diabetes mellitus and risk of hip fracture in case-control and cohort studies. Janghorbani M et al. Am. J. Epidemiol. 2007;166:495-505 American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

21 Association between type 2 diabetes mellitus and risk of hip fracture in case-control and cohort studies. Janghorbani M et al. Am. J. Epidemiol. 2007;166:495-505 American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

22 Tuominen et al, Diabetes Care, 1999 P<0.05 P<0.005 Bone Mineral Density (BMD) at the hip in subjects with diabetes type 1, diabetes type 2 and without diabetes

23 Diabetes is associated with a decrease in bone strength that is not reflected in the measurement of BMD Despite having a higher bone density, on average, patients with T2D have a higher risk of fractures. Other factors, associated with frailty and falls, including age, physical activity and BMI do not account for the association between T2D and fracture. Bone quality vs bone density

24 Has Fat a Protective Role for the Skeleton? “Pros & Cons” Rosen CJ et al. Nature, 2006 Decreased Vit D bioavailability

25 Role of vitamin D in the pathogenesis of type 2 Diabetes Mellitus Palomer et al, Diabetes, Obesity and Metabolism, 2008

26 Serum Vitamin D and Subsequent Occurrence of Type 2 Diabetes Study- and sex-specific and pooled age-adjusted relative odds of type 2 diabetes comparing highest and lowest quartiles of serum vitamin D. The black squares and horizontal lines represent study- and sex-specific ORs and 95% CIs, respectively. The area of the black squares reflects the study- and sex-specific weight (inverse of the standard error). The diamond represents the pooled ORs and 95% CI. The vertical dashed line represents the pooled relative risk. Knekt: Epidemiology, Volume 19(5).September 2008.666-671 Two nested case-control studies, collected by the Finnish Mobile Clinic in 1973–1980. During a follow- up period of 22 years, 412 incident type 2 diabetes cases occurred, and 986 controls were selected by individual matching.

27 Pittas AG et al, Diabetes Care, 33(9) 2010

28 Levels of vitamin D and cardiometabolic disorders: Systematic review and meta-analysis Levels of vitamin D and cardiometabolic disorders: Systematic review and meta-analysis Parker J et al, Maturitas, 2009

29 Factors Contributing to Low Vitamin D Levels in Diabetes Penckofer et al, 2008

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31 Diabetes Care, 33(10), 2010

32 Vitamin D and diabetes The metabolically active form of vitamin D, 1,25(OH)2D3, and its analogues have been shown to have effects on the major players involved in the pathogenesis of type 1 and type 2 diabetes. Beta cell function has been shown to be improved by 1,25(OH)2D3 in vitro and in vivo, and the avoidance of vitamin D deficiency is essential for normal beta cell function. In NOD mice, 1,25(OH)2D3 protects against insulitis, diabetes and disease recurrence after islet transplantation, primarily through immunomodulatory effects. Review Vitamin D and diabetes C. Mathieu et al, Diabetologia, 2005

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34 Evidence of the efficacy of Vit D supplementation Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels J. A. Sugden, J. I. Davies, M. D. Witham,et al DIABETIC Medicine, 2007 Daily consumption of vitamin D-or vitamin D + calcium fortified yogurt drink improved glycemic control in patients with type 2 diabetes: a randomized clinical trial Nikooyeh B, Neyestani TR, Farvid M et al AJCN, 2011 Vitamin D as an analgesic for patients with T2D and neuropathic pain Lee P, Chen R. Arch Intern Med 2008

35 Schematic representation of the multitude of other potential physiologic action of vitamin D for cardiovascular health, cancer prevention, regulation of immune function and decreased risk of autoimmune diseases Holick, Am J Clin Nutr, 2004

36 November, 2010

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38 Major challenges Measuring 25(OH)D –Techniques available –Clinical reporting of circulating 25(OH)D concentrations Defining doses of Vitamin D supplements

39 Recommendations for clinical practice Souberbielle JC et al, Autoimmunity reviews, 2010

40 Copyright ©2011 The Endocrine Society Heaney, R. P. et al. J Clin Endocrinol Metab 2011;96:E447-E452 Vitamin D3 is more potent than Vitamin D2 in humans D2 D3

41 Conclusions The role of Vitamin D in diabetes is not limited to the autoimmune form of diabetes The relationship between vitamin D and diabetes is complicated, involving various mechanisms not yet fully elucidated Clinical trials are required to identify individuals with or at risk of T2D that will most benefit from Vitamin D supplementation and the dose and formulation which would be most effective


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