outline of the thesis

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Vitamin D for the prevention of type 2 diabetes Oosterwerff, M.M.

2015

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Oosterwerff, M. M. (2015). Vitamin D for the prevention of type 2 diabetes.

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Chapter 1

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General introduction and

outline of the thesis

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1.1 Diabetes mellitus type 2 and the metabolic syndrome

Type 2 diabetes mellitus has become a significant global health care problem. World- wide the prevalence has increased substantially over the past decades due to the increasing incidence of overweight and longevity. In addition, more alertness leads to earlier detection.(1) In the Netherlands, approximately 800,000 inhabitants were known to have diabetes in 2011 and estimations have been made that the number of diabetic patients in the Netherlands will increase to 1,3 million (8.4 % of the population) in 2025. (2)

Diabetes mellitus type 2 is a chronic metabolic disease, which is characterized by chronic hyperglycemia caused by insulin resistance and β cell dysfunction (insulin deficiency).(3) Besides chronic hyperglycemia, there is disturbance in protein and fat metabolism. More important, diabetes mellitus is associated with serious long term morbidity (i.e. retinopathy, neuropathy, nephropathy, micro-angiopathy and cardiovascular disease) and increased mortality.(4-6) Although therapies for type 2 diabetes and its complications have been improved, the increasing burden of type 2 diabetes causes a strong need for preventative approaches of the disease.

The clustering of risk factors for diabetes type 2 and cardiovascular disease, which occur together more often than by chance alone, is well known as the insulin resistance syndrome or the metabolic syndrome, i.e. obesity, hypertension, dyslipidemia and hyper- glycaemia and was first described by Reaven. (7) Various diagnostic criteria have been proposed by different organizations. (8-10) A harmonized definition of the metabolic syndrome was established by an international committee in 2009 and is displayed in Table 1.

The metabolic syndrome is present in case of three or more of the following risk factors:

abdominal overweight, high triglycerides concentration, low HDL-concentration, hypertension and high fasting plasma glucose. Insulin resistance and abdominal overweight are independent factors in the clustering of metabolic abnormalities.(11) Diabetes mellitus is defined according to the American Diabetes Association (ADA) as follows: a HbA1c level

≥ 6.5 % (48 mmol/mol), fasting plasma glucose ≥ 7.0 mmol/l, 2-hr glucose during an oral glucose tolerance test of ≥ 11.1 mmol/l, or classic symptoms and a random glucose ≥ 11.1 mmol/l and the first three criteria should be confirmed by repeat testing. (12) Since 2011, the World Health Organization (WHO), also added HbA1c as diagnostic criterium following the ADA in addition to abnormal glucose levels. In the Netherlands however, only abnormal glucose levels are used to diagnose diabetes mellitus currently.

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Table 1. Criteria for Clinical Diagnosis of the Metabolic Syndrome(11) Criteria metabolic syndrome ( presence of any 3 of 5 risk factors)

Men Women

Waist circumference (Population- and country- specific definitions)

≥ 94 cm for Middle East/African origin

≥ 90 cm for Asian origin

≥ 102 cm or ≥ 94 cm for European origin

≥ 80 cm for Middle East/African origin

≥ 80 cm for Asian origin

≥ 88 cm or ≥ 80 cm for European origin Triglycerides ≥ 1.7 mmol/l or medication for

high triglycerides

≥ 1.7 mmol/l or medication for high triglycerides

HDL cholesterol < 1.0 mmol/l or medication for low HDL cholesterol

< 1.3 mmol/l or medication for low HDL cholesterol

Hypertension ≥ 130/85 mmHg or

antihypertensive medication

≥ 130/85 mmHg or antihypertensive medication

Glucose ≥ 5.6 mmol/l or glucose

lowering medication

≥ 5.6 mmol/l or glucose lowering medication

1.2 Non-western immigrants and diabetes

Next to a sedentary lifestyle and obesity, ethnicity and migration are important risk factors for diabetes. (13) It has been demonstrated that African and Asian immigrants in the USA and the United Kingdom have a higher prevalence of diabetes than the indigenous populations.(14;15) In the Netherlands, immigrants from Turkey, Morocco and Su- rinam are the largest ethnic minority groups. In 2012, the Netherlands comprised around 16.7 million inhabitants, and the absolute numbers of Turkish, Moroccan and Surinam migrants were 392,933, 362,954 and 346,797 respectively. (16) The prevalence rates of diabetes in Turkish and Moroccan inhabitants in the Netherlands, respectively, are two and over three times higher than in the indigenous Dutch population. Moreover diabetes occurs at younger ages in Turkish and Moroccan inhabitants.(17;18) The difference in prevalence can be explained on the one hand by lower socioeconomic status and higher prevalence of obesity and probably on the other hand by genetic susceptibility, (17) other endogenous factors such as hypertension and dyslipidemia and other environmental factors, such as vitamin D deficiency. Vitamin D deficiency is highly prevalent among the different non-western ethnicities living in the Netherlands compared to the indigenous population. Serum 25-hydroxyvitamin D (25[OH]D) levels were lower than 25 nmol/l in 41 % of the Turkish and 36% of the Moroccan immigrants. Insufficient exposure to direct sunlight, covering of the skin, a low calcium and vitamin D diet, and high fat mass are contributors to this high prevalence. (19)

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1.3 Vitamin D

Vitamin D is a generic term for a group of fat soluble prohormones, including vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Vitamin D3 is the animal source vitamin and is synthesized in the skin from 7-dehydrocholesterol under the influence of ultraviolet radiation of the sun during the summer months from April to September in the Nether- lands. The other source of vitamin D3 is food, mainly fatty fish, such as herring, mackerel and salmon. Vitamin D2, the vegetable form, can be produced industrially through ultraviolet exposure of the plant sterol ergosterol, found in fungi and yeast. Vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D (25[OH]D) (20) and is the major circulating storage form of vitamin D in the body (Figure 1). After a second hydroxylation, mainly in the kidney, the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25[OH]2D) is gener- ated. (21) This active form of vitamin D acts as a hormone: its formation is stimulated by parathyroid hormone (PTH), with a negative feedback through calcium, phosphate and 1,25(OH)2D itself. The active metabolite 1,25(OH)2D enters the cell and binds to the nu- clear vitamin D receptor (VDR), which forms a heterodimer with the vitamin A receptor (RXR). This complex binds to the vitamin D responsive element in the genome, leading to transcription and translation and proteins are formed. More than 300 genes are up- or downregulated by the active vitamin D metabolite.(22) The vitamin D receptor is present in many organs, for example the gut, bone, muscle, parathyroid gland, prostate, mamma, brain and lymphocytes. Furthermore, in extra renal cells and tissues, 25(OH)D can also be hydroxylated into 1,25(OH)2D under the influence of cytokines and this appears to be important for the paracrine regulation of cell differentiation and function. (23)

Severe vitamin D deficiency (serum 25(OH)D < 15 nmol/l) may cause rickets in children, characterized by deficient mineralization at the growth plate, which increases in size. Rickets has become rare in Western countries, although it still exists in populations with low sun exposure and low vitamin D intake, including minorities in the Netherlands.

(24) On the other hand sub clinical vitamin D deficiency (or insufficiency, serum 25(OH) D 25-50 nmol/l) is rather common nowadays and has also been described among adoles- cents (25) and the elderly (26) and may contribute to the development of osteoporosis and increases the risk of falls and fractures in the elderly.(27-29) Moreover, severe long- standing vitamin D deficiency may lead to osteomalacia (“bone weakness”) in adults and older persons.(22) Osteomalacia is characterized by poor mineralization of newly synthesized bone matrix, the osteoid, during bone remodeling.

1.4 Vitamin D deficiency

In the literature there is neither consensus on the diagnosis of vitamin D deficiency, nor on the optimal serum 25(OH)D level. The Dutch Health Council concluded that a serum 25(OH)D level above 30 nmol/l is sufficient for children (based on risk of rachitis) and

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adults, with a recommended supplementation dose of 400 IU for children, women between 50 and 70 years old and people with dark skin. Furthermore, 800 IU is recommended for the elderly (>70 years), based on research on fracture and fall risk. It also stated that a level above 50 nmol/l is required for the elderly.(30) In 2011, the Institute of Medicine (IOM) (which focused on the general population) concluded that a serum 25(OH)D level of 50 nmol/l or higher was sufficient, <30 nmol/l as deficient and advised 600 IU/day as recommended dietary intake for the age ≤ 70 years and 800 IU/day for ages 71 year and older to obtain the required 25(OH)D level.(31) However, the latest Endocrine Society Guide- line (Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline) (focusing on at-risk individuals) defined 25(OH)D < 50 nmol/l as vitamin D deficient and 50-75 nmol/l as vitamin D insufficient and recommended 400 IU/d to all infants aged 0-1 year, 600 IU/d for all persons aged 1-50 year, with the remark that to raise the blood level consistently above 75 nmol/l at least 1500-2000 IU/d is required.

For adults aged 50-70 yr and above 70 yr, the recommendation is at least 600-800 IU/d with the same remark as above mentioned. In case of vitamin D deficiency (serum 25(OH) D < 50 nmol/l), 2000 IU/d for infants and children is recommended for at least 6 weeks, followed by a maintenance dose of 600-1000 IU/d. For adults with vitamin D deficiency Figure 1. Vitamin D metabolism

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50,000 IU once a week for 8 weeks, followed by 1500-2000 IU/d as maintenance therapy is recommended.(32) In Table 2, the main agreements and disagreements between the two recent guidelines are shown, including both differences in recommended intake, and maximum tolerable doses. This leads to confusion among clinicians, researchers and the general population. (33) Based on the existing evidence for classical outcomes as fractures and falls, to my opinion 800 IU/day should be advised to the elderly and patients with osteoporosis. (34) With 600-800 IU/day, most healthy postmenopausal women reached serum 25(OH)D levels of 50 nmol/l, based on a multi-dose study.(35)

1.5 Non-skeletal effects of vitamin D

Vitamin D status is the main determinant of active calcium absorption from the gut, which is important for bone mineralization. The precise action of vitamin D and the full spectrum Table 2. The main differences between the IOM and the Endocrine Practice Guidelines Committee.

Adequate intake: When the evidence base is insufficient for development of the EAR (estimated average intake=median intake needs of the population)/RDA, an adequate intake (AI) level was estimated instead.

Recommended dietary allowance (RDA): Intake that covers the needs of 97.5% of the population, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter). RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer.

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of activities have been extensively studied in VDR-knockout mice. We know that VDR is widely expressed in mammals and men, that there is extra renal production of 1,25(OH)2D by CYP27B1, and that multiple genes (about 3% of the mouse and human genome) are regulated by VDR all suggesting a more widespread function of vitamin D. For example, VDR-deficient mice develop total alopecia, increased sensitivity to autoimmune diseases, more susceptibility to chemo carcinogenic tumors, high renin hypertension, cardiac hy- pertrophy and increased thrombogenicity. In humans with vitamin D resistance, gener- alized alopecia has been observed as well. Moreover, there are many epidemiological links between vitamin D deficiency in humans and colon cancer, breast cancer, prostate cancer, and autoimmune diseases such as type 1 diabetes and multiple sclerosis. Vitamin D deficiency has been associated with an increased cardiovascular risk and the metabolic syndrome as well, but causality has to be proven by intervention studies. (36)

1.6 Vitamin D and type 2 diabetes mellitus

As earlier mentioned, much knowledge about vitamin D metabolism and function has been obtained by animal models. This applies also to the relation between vitamin D and diabetes and the metabolic syndrome. An impaired insulin secretory capacity was found in mice lacking a functional VDR. (37) Treatment with 1,25 dihydroxyvitamin D3 improved de novo insulin biosynthesis in rats.(38) Further evidence on this topic came from a large number of human cross-sectional studies reporting an inverse association between vitamin D status and insulin resistance (39;40), the metabolic syndrome (41;42) and diabetes (43), with similar results from longitudinal observational studies. (44-46) However, intervention studies have shown conflicting results, so causality has not been proven. (47) In chapter 7, the general discussion, the intervention studies will be extensively summarized.

1.7 Vitamin D and physical performance

Many observational studies found a clear link between vitamin D status and muscle strength, and physical performance (48-50) and an inverse association with risk of falls (51), especially in the elderly. In some clinical trials, vitamin D supplementation in older adults with vitamin D deficiency resulted in improvements of muscle performance (52) and reduction of falls (53;54), while other trials showed no effect or an increase of fall incidence in an Australian study with a large supplementation dose once per year.(55;56) The underlying mechanisms can be caused by an indirect effect via calcium and phosphate on muscle strength or directly via activation of the VDR in muscle cells by 1,25(OH)2D (57).

VDR activation regulates transcription of genes involved in calcium handling and muscle cell differentiation and proliferation. Also membrane-associated VDR activates intracel- lular pathways involved in calcium handling, signaling and myogenesis. (58;59)

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1.8 Testosterone and vitamin D

VDRs have been observed in the human male reproductive system. Also vitamin D metabolizing enzymes are expressed in the male reproductive tract.(60) Furthermore VDR is found in the male reproductive system in rats while VDR knockout mice present with gonadal insufficiency. (61;62) In recent literature low serum levels of 25(OH)D have been associated with lower testosterone levels in males.(63;64) One randomized trial found (65) an increase in serum testosterone concentration after vitamin D supplementation with 3332 IU/d for 1 year, but another study did not find such an effect (vitamin D supplementation dose 20,000-40,000 IU/wk for 6 months to 1 year).(66) In conclusion, the main question is whether the positive association between vitamin D and testosterone is causal or not, and randomized trials are needed to answer this question.

1.9 Osteocalcin and type 2 diabetes mellitus

Osteocalcin is a non-collagenous bone matrix protein synthesized by osteoblasts during bone formation. It plays a role during bone mineralization and it is used as a biochemi- cal marker of late phase osteoblastic bone formation. Osteocalcin undergoes vitamin K dependent posttranslational γ-carboxylation (adding three carboxyl groups), which fa- cilitates the binding to hydroxyapatite and retention in the bone. Both carboxylated and un(der)carboxylated forms of osteocalcin are present in the circulation, and are measured as plasma total osteocalcin. (67) Currently, there is some evidence that osteocalcin plays a role in glucose regulation and fat metabolism, linking bone metabolism with energy metabolism.(68;69) It was found in mice that osteocalcin was involved in glucose metabolism by pancreatic β-cell proliferation and increasing insulin secretion and improving insulin sensitivity by up regulating the expression of insulin-sensitizing adipokines in adipocytes.

Figure 2 shows a schematic overview. Subsequent human studies showed a negative association between serum osteocalcin and plasma glucose and body fat mass. (70) Further- more, a positive association between serum osteocalcin and insulin secretion (71), insulin sensitivity (70-72) and serum adiponectin concentration have been described in epidemiological studies.(72) However, the relationship between energy expenditure and bone is still controversial and the data from humans studies are scant. Above all, osteocalcin is an interesting new marker for further research in relation to diabetes and the metabolic syndrome. Further research is needed to answer the question whether un(der)carboxylated osteocalcin is the active form in humans, or the carboxylated form. Animal and in vi- tro data suggest that only the un(der)carboxylated form of osteocalcin influences glucose homeostasis and energy metabolism. (68;73) In contrast, carboxylated osteocalcin was associated with insulin resistance in humans, not un(der)carboxylated osteocalcin. (72)

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1 Aim and outline of the thesis

Type 2 diabetes has become a significant global health care problem, with increased morbidity and mortality, which requires innovative approaches for prevention. The main object of this thesis was to investigate the role of vitamin D in glucose metabolism, and to investigate if vitamin D supplementation could improve beta cell function and insulin sensitivity, and thereby contribute to the prevention of type 2 diabetes mellitus. Furthermore, the association between the bone marker osteocalcin and the metabolic syndrome was explored.

In Chapter 2 the association between vitamin D and the metabolic syndrome was investigated in a large population study in the Netherlands, the Longitudinal Aging Study Amsterdam (LASA).

The aim of the main study described in this thesis was to test the hypothesis that vitamin D supplementation has a positive effect on insulin sensitivity in non-western immigrants in the Netherlands. To this end, a randomized, placebo-controlled trial was performed in vitamin D deficient, non-western immigrants at high risk for diabetes. The title of the trial was “The effect of vitamin D supplementation on insulin sensitivity in non- western immigrants in the Netherlands”. Non-western immigrants, with a serum 25(OH)D concentration below 50 nmol/l, an impaired fasting or random glucose and a body mass index (BMI) above 27 kg/m2 were randomly assigned to receive either cholecalciferol 1200 IU and calcium 500 mg once daily or placebo combined with calcium 500 mg once daily during 16 weeks. Before and after the intervention an oral glucose tolerance test was performed to investigate β-cell function and insulin sensitivity. This study is described in Chapter 3. The secondary outcomes regarding physical activity and physical performance in this study are described in Chapter 4.

In Chapter 5 the relation between vitamin D and testosterone was explored to gain insight in possible effects of vitamin D on male fertility.

Chapter 6 describes the association between the bone marker osteocalcin and the metabolic syndrome in the LASA study.

In Chapter 7 the results are summarized and discussed and placed in context of the existing literature.

Figure 2. Interactions between bone and adipocytes, pancreas and muscle mediated by undercarboxylated osteocalcin (adapted from (74))

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Reference List

1. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M. Nation- al, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011 July 2;378(9785):31-40.

2. Baan CA, van Baal PH, Jacobs-van der Bruggen MA, Verkley H, Poos MJ, Hoogenveen RT, Schoemaker CG. [Diabetes mellitus in the Netherlands: estimate of the current disease burden and prognosis for 2025]. Ned Tijdschr Geneeskd 2009;153:A580.

3. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999 September;104(6):787-94.

4. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of he- moglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004 September 21;141(6):413-20.

5. Glucose tolerance and mortality: comparison of WHO and American Diabetes Asso- ciation diagnostic criteria. The DECODE study group. European Diabetes Epidemiol- ogy Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet 1999 August 21;354(9179):617-21.

6. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin AA, Birbeck G et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012 December 15;380(9859):2095-128.

7. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Dia- betes 1988 December;37(12):1595-607.

8. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002 December 17;106(25):3143-421.

9. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition.

Lancet 2005 September 24;366(9491):1059-62.

(13)

1

10. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Jr., Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005 October 25;112(17):2735-52.

11. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC, Jr. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epide- miology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society;

and International Association for the Study of Obesity. Circulation 2009 October 20;120(16):1640-5.

12. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010 January;33 Suppl 1:S62-S69.

13. Misra A, Ganda OP. Migration and its impact on adiposity and type 2 diabetes. Nu- trition 2007 September;23(9):696-708.

14. Cappuccio FP, Cook DG, Atkinson RW, Strazzullo P. Prevalence, detection, and management of cardiovascular risk factors in different ethnic groups in south London.

Heart 1997 December;78(6):555-63.

15. LaRosa JC, Brown CD. Cardiovascular risk factors in minorities. Am J Med 2005 De- cember;118(12):1314-22.

16. CBS. www.statline.cbs.nl. 2013.

17. Ujcic-Voortman JK, Schram MT, Jacobs-van der Bruggen MA, Verhoeff AP, Baan CA.

Diabetes prevalence and risk factors among ethnic minorities. Eur J Public Health 2009 October;19(5):511-5.

18. Uitewaal PJ, Manna DR, Bruijnzeels MA, Hoes AW, Thomas S. Prevalence of type 2 diabetes mellitus, other cardiovascular risk factors, and cardiovascular disease in Turkish and Moroccan immigrants in North West Europe: a systematic review. Prev Med 2004 December;39(6):1068-76.

19. van der Meer IM, Boeke AJ, Lips P, Grootjans-Geerts I, Wuister JD, Deville WL, Wielders JP, Bouter LM, Middelkoop BJ. Fatty fish and supplements are the greatest modifiable contributors to the serum 25-hydroxyvitamin D concentration in a mul- tiethnic population. Clin Endocrinol (Oxf) 2008 March;68(3):466-72.

20. Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr 2008 June;87(6):1738-42.

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21. Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev 1998 October;78(4):1193-231.

22. Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006 September;92(1):4-8.

23. Peterlik M, Cross HS. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 2005 May;35(5):290-304.

24. Lips P. Vitamin D status and nutrition in Europe and Asia. J Steroid Biochem Mol Biol 2007 March;103(3-5):620-5.

25. Das G, Crocombe S, McGrath M, Berry JL, Mughal MZ. Hypovitaminosis D among healthy adolescent girls attending an inner city school. Arch Dis Child 2006 July;91(7):569-72.

26. Lips P, Hosking D, Lippuner K, Norquist JM, Wehren L, Maalouf G, Ragi-Eis S, Chan- dler J. The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med 2006 Septem- ber;260(3):245-54.

27. Lips P, Bouillon R, van Schoor NM, Vanderschueren D, Verschueren S, Kuchuk N, Milisen K, Boonen S. Reducing fracture risk with calcium and vitamin D. Clin Endo- crinol (Oxf) 2010 September;73(3):277-85.

28. Snijder MB, van Schoor NM, Pluijm SM, van Dam RM, Visser M, Lips P. Vitamin D status in relation to one-year risk of recurrent falling in older men and women. J Clin Endocrinol Metab 2006 August;91(8):2980-5.

29. van Schoor NM, Visser M, Pluijm SM, Kuchuk N, Smit JH, Lips P. Vitamin D deficiency as a risk factor for osteoporotic fractures. Bone 2008 February;42(2):260-6.

30. Health Council of the Netherlands. Towards an adequate intake of vitamin D. The Hague: Health Council of the Netherlands. 2008.

31. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA.

The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011 January;96(1):53-8.

32. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Mu- rad MH, Weaver CM. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011 July;96(7):1911-30.

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1

33. Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Manson JE, Mayne ST, Ross AC, Shapses SA, Taylor CL. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab 2012 April;97(4):1146-52.

34. Bischoff-Ferrari HA. Which vitamin D oral supplement is best for postmenopausal women? Curr Osteoporos Rep 2012 December;10(4):251-7.

35. Gallagher JC, Sai A, Templin T, Smith L. Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med 2012 March 20;156(6):425-37.

36. Bouillon R, Carmeliet G, Verlinden L, van EE, Verstuyf A, Luderer HF, Lieben L, Ma- thieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 2008 October;29(6):726-76.

37. Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG. Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J 2003 March;17(3):509-11.

38. Bourlon PM, Billaudel B, Faure-Dussert A. Influence of vitamin D3 deficiency and 1,25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat endocrine pancreas. J Endocrinol 1999 January;160(1):87-95.

39. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004 May;79(5):820-5.

40. Baynes KC, Boucher BJ, Feskens EJ, Kromhout D. Vitamin D, glucose tolerance and insulinaemia in elderly men. Diabetologia 1997 March;40(3):344-7.

41. Liu S, Song Y, Ford ES, Manson JE, Buring JE, Ridker PM. Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women.

Diabetes Care 2005 December;28(12):2926-32.

42. Reis JP, von MD, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. Vitamin D, parathyroid hormone levels, and the prevalence of metabolic syndrome in community- dwelling older adults. Diabetes Care 2007 June;30(6):1549-55.

43. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 2004 December;27(12):2813-8.

44. Pittas AG, Dawson-Hughes B, Li T, Van Dam RM, Willett WC, Manson JE, Hu FB. Vi- tamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care 2006 March;29(3):650-6.

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45. Knekt P, Laaksonen M, Mattila C, Harkanen T, Marniemi J, Heliovaara M, Rissanen H, Montonen J, Reunanen A. Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology 2008 September;19(5):666-71.

46. Pittas AG, Sun Q, Manson JE, Dawson-Hughes B, Hu FB. Plasma 25-hydroxyvitamin D concentration and risk of incident type 2 diabetes in women. Diabetes Care 2010 September;33(9):2021-3.

47. Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review.

Eur J Clin Nutr 2011 September;65(9):1005-15.

48. Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as de- terminants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 2003 December;88(12):5766-72.

49. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, Zhang Y, Karlson EW, Dawson-Hughes B. Higher 25-hydroxyvitamin D concentrations are associated with better lower-ex- tremity function in both active and inactive persons aged > or =60 y. Am J Clin Nutr 2004 September;80(3):752-8.

50. Wicherts IS, van Schoor NM, Boeke AJ, Visser M, Deeg DJ, Smit J, Knol DL, Lips P.

Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007 June;92(6):2058-65.

51. Snijder MB, van Schoor NM, Pluijm SM, van Dam RM, Visser M, Lips P. Vitamin D status in relation to one-year risk of recurrent falling in older men and women. J Clin Endocrinol Metab 2006 August;91(8):2980-5.

52. Bunout D, Barrera G, Leiva L, Gattas V, de la Maza MP, Avendano M, Hirsch S. Effects of vitamin D supplementation and exercise training on physical performance in Chil- ean vitamin D deficient elderly subjects. Exp Gerontol 2006 August;41(8):746-52.

53. Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher dose of vitamin d reduces the risk of falls in nursing home residents: a randomized, multiple-dose study. J Am Geriatr Soc 2007 February;55(2):234-9.

54. Faulkner KA, Cauley JA, Zmuda JM, Landsittel DP, Newman AB, Studenski SA, Red- fern MS, Ensrud KE, Fink HA, Lane NE, Nevitt MC. Higher 1,25-dihydroxyvitamin D3 concentrations associated with lower fall rates in older community-dwelling women. Osteoporos Int 2006;17(9):1318-28.

55. Brunner RL, Cochrane B, Jackson RD, Larson J, Lewis C, Limacher M, Rosal M, Shu- maker S, Wallace R. Calcium, vitamin D supplementation, and physical function in the Women’s Health Initiative. J Am Diet Assoc 2008 September;108(9):1472-9.

(17)

1

56. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nichol- son GC. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010 May 12;303(18):1815-22.

57. Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R, Stahelin HB, Dick W. In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J 2001 January;33(1):19-24.

58. Ceglia L, Harris SS. Vitamin D and its role in skeletal muscle. Calcif Tissue Int 2013 February;92(2):151-62.

59. Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE. The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev 2013 Febru- ary;34(1):33-83.

60. Blomberg JM, Nielsen JE, Jorgensen A, Rajpert-De ME, Kristensen DM, Jorgensen N, Skakkebaek NE, Juul A, Leffers H. Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract. Hum Reprod 2010 May;25(5):1303-11.

61. Johnson JA, Grande JP, Roche PC, Kumar R. Immunohistochemical detection and distribution of the 1,25-dihydroxyvitamin D3 receptor in rat reproductive tissues.

Histochem Cell Biol 1996 January;105(1):7-15.

62. Kinuta K, Tanaka H, Moriwake T, Aya K, Kato S, Seino Y. Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads. Endocrinology 2000 April;141(4):1317-24.

63. Nimptsch K, Platz EA, Willett WC, Giovannucci E. Association between plasma 25-OH vitamin D and testosterone levels in men. Clin Endocrinol (Oxf) 2012 July;77(1):106-12.

64. Wehr E, Pilz S, Boehm BO, Marz W, Obermayer-Pietsch B. Association of vitamin D status with serum androgen levels in men. Clin Endocrinol (Oxf) 2010 Au- gust;73(2):243-8.

65. Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, Wehr E, Zittermann A. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res 2011 March;43(3):223-5.

66. Jorde R, Grimnes G, Hutchinson MS, Kjaergaard M, Kamycheva E, Svartberg J.

Supplementation with Vitamin D Does not Increase Serum Testosterone Levels in Healthy Males. Horm Metab Res 2013 May 17.

67. Lee AJ, Hodges S, Eastell R. Measurement of osteocalcin. Ann Clin Biochem 2000 July;37 ( Pt 4):432-46.

(18)

68. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell 2007 August 10;130(3):456-69.

69. Clemens TL, Karsenty G. The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res 2011 April;26(4):677-80.

70. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellstrom D. Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 2009 May;24(5):785-91.

71. Hwang YC, Jeong IK, Ahn KJ, Chung HY. The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced beta-cell function in middle-aged male subjects. Diabetes Metab Res Rev 2009 November;25(8):768-72.

72. Shea MK, Gundberg CM, Meigs JB, Dallal GE, Saltzman E, Yoshida M, Jacques PF, Booth SL. Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr 2009 November;90(5):1230-5.

73. Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A 2008 April 1;105(13):5266-70.

74. Amelio PD, Panico A, Spertino E, Isaia GC. Energy metabolism and the skeleton:

Reciprocal interplay. World J Orthop 2012 November 18;3(11):190-8.