2. Vitamin D and cardiometabolic disorders  Recent data suggests a connection between vitamin D levels and cardiometabolic diseases: o Obesity o Impaired glucose tolerance o Type 2 diabetes mellitus  Vitamin D deficiency is associated with a greater risk of obesity and type 2 diabetes mellitus  An increased body fat and obesity are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels  Obesity is a worldwide epidemic increasing the risk of type 2 diabetes. Glucose homeostasis and insulin release mechanisms could be influenced by vitamin D endocrine system. Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581. ASSOCIATION OF VITAMIN D DEFICIENCY WITH OBESITY AND DIABETES

3. Hypovitaminosis D: Relationship with adiposity and insulin sensitivity  Endocrine disturbances in obesity includes low 25(OH)D resulting in hyperparathyroidism  According to a recent study hypovitaminosis D has been identified in 74% of obese subjects  Serum vitamin D was positively correlated with insulin sensitivity, which was fat mass mediated  Vitamin D level inversely correlated with HbA1c, implying that obese subjects with low vitamin D status may be at an increased risk of developing impaired glucose metabolism Alemzadeh R et al. Metabolism. 2008 Feb;57(2):183-91. PATHOGENIC LINK BETWEEN VITAMIN D DEFICIENCY, OBESITY AND DIABETES

4. Insulin level and vitamin D: The link  In a study between overweight and obese subpopulation, there is a significant correlation between fasting insulin (r=-0.26, p<0.01), 2h OGTT glucose and insulin levels (r=-0.31, p<0.01 and r=-0.29, p<0.01 accordingly) and serum 25(OH)D concentration Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581. PATHOGENIC LINK BETWEEN VITAMIN D DEFICIENCY, OBESITY AND DIABETES

5. Vitamin D deficiency: A risk factor for obesity and T2DM  Numerous studies investigated the relationship between 25(OH)D and insulin levels  When animals who were induced with diabetes mellitus were treated with vitamin D, the progression of diabetes was slowed down  Lack of vitamin D may cause a greater level of glycemia and thus carries a higher risk of type 2 diabetes mellitus  Low plasma 25(OH)D concentrations are seen with increase in visceral adiposity in South Asians  Visceral obesity, hypertriglyceridemia, and metabolic syndrome were found to be associated with vitamin D deficiency in children Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581. PATHOGENIC LINK BETWEEN VITAMIN D DEFICIENCY, OBESITY AND DIABETES

6.  High doses of vitamin D in food consumed by risk-group children are able to reduce the incidence of diabetes  There is a link between 25(OH)D levels and insulin responsiveness of tissues as well as between glucose levels and glycosylated hemoglobin in people without T2DM  The most pronounced effects of vitamin D deficiency are: o Reduced insulin release in people with normal weight o Low tissue insulin sensitivity in overweight or obese people Vinh quốc Lương K et al. Nutrition Journal 2013;12:89. PATHOGENIC LINK BETWEEN VITAMIN D DEFICIENCY, OBESITY AND DIABETES

7. Vitamin D deficiency and metabolic diseases in women  Deficiency of vitamin D in females is an independent risk factor for abdominal obesity  In comparison to normal weight women, obese women transfer less 25(OH)D to offspring, even if the serum levels of vitamin D are same  Obesity in mother is associated with vitamin D insufficiency in cord-blood  In women, even after having a control for age, lifestyle, and PTH, a negative predictor of 25(OH)D levels is total body fat  In a study by Grineva EN et al., the risk of metabolic diseases in women with different vitamin D status was assessed (Table 1) Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581; Vinh quốc Lương K et al. Nutrition Journal 2013;12:89. PATHOGENIC LINK BETWEEN VITAMIN D DEFICIENCY, OBESITY AND DIABETES

8. Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581. PATHOGENIC LINK BETWEEN VITAMIN D DEFICIENCY, OBESITY AND DIABETES

9.  In disease states, immunomodulatory and anti-proliferative effects are exhibited by vitamin D via vitamin D receptors (VDR)  Adipose tissue contains the VDR, which might contribute to the action of vitamin D and its analogs in fat cells  In pre-adipocyte 3T3-L1 cells specific calcitriol-binding is seen, but specific calcitriol-binding in mature adipocytes is not seen  Any influence of vitamin D on adipogenesis would likely be exerted early in the pre-adipocyte to adipocyte transition where more VDR are available Vinh quốc Lương K et al. Nutrition Journal 2013 12:89. GENETIC FACTORS IN VITAMIN D DEFICIENCY AND OBESITY

10.  A recent study was conducted to assess whether obesity alters the cutaneous production of vitamin D 3 (cholecalciferol) or the intestinal absorption of vitamin D 2 (ergocalciferol)  Healthy, white, obese (BMI ≥30 kg/m 2 ) and matched lean control subjects (BMI ≤25 kg/m 2 ) received either whole-body ultraviolet radiation or a pharmacologic dose of vitamin D 2 orally Wortsman J et al. Am J Clin Nutr 2000;72:690–3. DECREASED BIOAVAILABILITY OF VITAMIN D IN OBESITY

11. Results  The response of the obese subjects was attenuated when compared with that of the control group (Figure 2) Wortsman J et al. Am J Clin Nutr 2000;72:690–3. DECREASED BIOAVAILABILITY OF VITAMIN D IN OBESITY

12.  Vitamin D 2 rose rapidly until ≈10 h after intake and then declined slightly thereafter (Figure 3) Wortsman J et al. Am J Clin Nutr 2000;72:690–3. DECREASED BIOAVAILABILITY OF VITAMIN D IN OBESITY

13. Wortsman J et al. Am J Clin Nutr 2000;72:690–3.  The correlation between BMI and peak serum vitamin D 2 concentrations after the oral vitamin D 2 load was highly significant indicating obesity-associated vitamin D insufficiency is likely due to the decreased bioavailability of vitamin D 3 (Figure 4) DECREASED BIOAVAILABILITY OF VITAMIN D IN OBESITY

14. Results  Obese subjects had significantly lower basal 25(OH)D concentrations and higher parathyroid hormone concentrations than did age-matched control subjects  Evaluation of blood vitamin D 3 concentrations 24 h after whole-body irradiation showed that the incremental increase in vitamin D 3 was 57% lower in obese than in non-obese subjects  The obese and non-obese subjects received an oral dose of 50,000 IU (1.25 mg) vitamin D 2. BMI was inversely correlated with serum vitamin D 3 concentrations after irradiation (r=0.55, p=0.003) and with peak serum vitamin D 2 concentrations after vitamin D 2 intake (r=0.56, p=0.007) Wortsman J et al. Am J Clin Nutr 2000;72:690–3. DECREASED BIOAVAILABILITY OF VITAMIN D IN OBESITY

15. Conclusion  Vitamin D insufficiency and secondary hyperparathyroidism are closely associated with obesity  Blood vitamin D 3 concentrations increased in both the obese and non-obese subjects after exposure to an identical amount of UV-B irradiation  However, the increase in blood vitamin D 3 concentrations is 57% less in the obese than in the non-obese subjects 24 h after the exposure  Obesity associated vitamin D deficiency can be corrected by oral vitamin D supplementation  Obesity does not affect the capacity of the skin to produce vitamin D 3, but might alter the release of vitamin D 3 from the skin into the circulation  Obesity-associated vitamin D insufficiency is likely due to the decreased bioavailability of vitamin D 3 from cutaneous and dietary sources because of its deposition in body fat compartments Wortsman J et al. Am J Clin Nutr 2000;72:690–3. DECREASED BIOAVAILABILITY OF VITAMIN D IN OBESITY

16.  Non-skeletal diseases associated with vitamin D deficiency include T2DM  T2DM and vitamin D deficiency have common risk factors like ageing, obesity and poor physical activity  A relationship between vitamin D deficiency and T2DM as well as reduced insulin secretion and sensitivity has been shown  Subjects with T2DM have significantly lower circulating concentration of 25(OH)D Talaei A, et al. Diabetology & Metabolic Syndrome 2013;5:8. VITAMIN D DEFICIENCY: EFFECT ON GLUCOSE HOMEOSTASIS

17. A study on vitamin D deficiency and effect on insulin resistance  A study by Talaei A et al., evaluated the effects of vitamin D supplementation on insulin resistance in T2DM  The study data showed significant improvements in serum FBS, insulin and in HOMA-IR after treatment with vitamin D (Table 2)  The study results suggested that vitamin D supplementation can reduce insulin resistance in T2DM Talaei A, et al. Diabetology & Metabolic Syndrome 2013;5:8. VITAMIN D DEFICIENCY: EFFECT ON GLUCOSE HOMEOSTASIS

18. Talaei A, et al. Diabetology & Metabolic Syndrome 2013;5:8. VITAMIN D DEFICIENCY: EFFECT ON GLUCOSE HOMEOSTASIS

19.  A meaningful reduction is seen after supplementation with vitamin D (Table 3) Talaei A, et al. Diabetology & Metabolic Syndrome 2013;5:8. VITAMIN D DEFICIENCY: EFFECT ON GLUCOSE HOMEOSTASIS

20.  Vitamin D supplementation significantly decreased serum FPG, insulin and HOMA-IR in patients with T2DM  There was an inverse relation between final FPG and basal 25(OH)D concentration.  The effects of vitamin D on insulin resistance were significant when vitamin D concentration was 40–60 ng/mL (100–150 nmol/L)  In lower and upper vitamin D concentration, there was no effect on insulin resistance  Insulin resistance appeared to be decreased in T2DM patients who had received vitamin D  Vitamin D can improve diabetes control and it is recommended that vitamin D supplementation should be included in treatment of type 2 diabetes Talaei A, et al. Diabetology & Metabolic Syndrome 2013;5:8. VITAMIN D DEFICIENCY: EFFECT ON GLUCOSE HOMEOSTASIS

21.  Obesity, a risk factor for type 2 diabetes, has become a global epidemic. The glucose homeostasis and insulin release could get affected by vitamin D endocrine system.  Epidemiological studies suggest that vitamin D deficiency may increase the risk of developing insulin resistance and diabetes  The recent clinical data also points towards the regulatory role of 25(OH)D in the function of pancreatic β-cells and the level of insulin sensitivity  Regulatory role of vitamin D is supported by correlation between o Calcidiol levels and stimulated insulin levels o Insulin resistance o β-cells functional activity o Insulin sensitivity of tissues  The beneficial effect of vitamin D in glucose metabolism cannot be ignored as a potential preventive and even therapeutic measure for obesity and diabetes Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581. CLINICAL EVIDENCE: VITAMIN D DEFICIENCY, OBESITY AND DIABETES

22. Rationale  According to recent data, there may be a connection between vitamin D levels and obesity and diabetes  Though the mechanism is unclear, vitamin D deficiency is associated with a greater risk of these pathological conditions  The vitamin D receptors (VDR) and the 1α-hydroxylase enzyme catalyze the conversion of calcidiol [25-hydroxyvitamin D; 25(OH)D] to calcitriol [1,25-dihydroxyvitamin D; 1,25(OH)2D]  VDRs are found in more than 40 human cell types Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581. CLINICAL EVIDENCE: VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETIC PATIENTS

23.  This indicates vitamin D’s potential role in the regulation of numerous metabolic processes  Furthermore, an increased body fat and obesity is associated with low circulating 25(OH)D level  Vitamin D treatment in diabetes mellitus type 1 slows the progression of diabetes  Food fortified with high dose vitamin D consumed by risk-group population may help decreasing the incidence of diabetes Grineva EN et al. Aging (Albany NY). 2013 Jul; 5(7): 575–581. CLINICAL EVIDENCE: VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETIC PATIENTS

24. Evidence  A study by Talaei et al., showed that vitamin D treatment significantly improves o Serum FPG o Insulin level o HOMA-IR  Vitamin D supplementation has the potential to reduce insulin resistance in T2DM  Obesity may interact with vitamin D to synergistically influence risk of insulin resistance and type 2 diabetes  This is due to decreased bioavailability of vitamin D due to excess storage in body fat compartments  A recent study by Kabadi SM et al., evaluated the association of serum 25(OH)D concentration with insulin sensitivity and found that this association was stronger in overweight individuals than in normal-weight individuals Talaei A, et al. Diabetology & Metabolic Syndrome 2013;5:8; Kabadi SM, et al. Diabetes Care. 2012 Oct;35(10):2048-54. CLINICAL EVIDENCE: VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETIC PATIENTS

25.  National Health and Nutrition Examination Survey (NHANES) 2001–2006 investigated the effect of obesity on the association between 25(OH)D and insulin resistance/type 2 diabetes.  Insulin resistance analysis was limited to participants >20 years of age assigned to the morning session and free of diabetes  A cross-product interaction term in a multiple logistic regression model was used to assess multiplicative interaction.  Calculation of the relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP) was evaluated by the presence of additive interaction between insufficient 25(OH)D and obesity (indicated by BMI or waist circumference) Kabadi SM, et al. Diabetes Care. 2012 Oct;35(10):2048-54. VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETES: THE NHANES STUDY

26. Results  There is strong additive interaction between abdominal obesity and insufficient 25(OH)D (Table 4) Kabadi SM, et al. Diabetes Care. 2012 Oct;35(10):2048-54. VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETES: THE NHANES STUDY

27.  The odds ratio of being insulin resistant in abdominally obese adults who have insufficient 25(OH)D is 6.45 times higher  It was evidenced being overweight or obese modified the associations of 25(OH)D with insulin resistance  Obese individuals with low 25(OH)D had 32.13 times higher risk for insulin resistance  The stronger interaction of 25(OH)D with obesity with regard to insulin resistance may be related to the direct impact of vitamin D deficiency on insulin resistance Kabadi SM, et al. Diabetes Care. 2012 Oct;35(10):2048-54. VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETES: THE NHANES STUDY

28. Conclusion  It has been estimated that 47% of the cases with elevated risk of insulin resistance can be explained by interaction between low 25(OH)D and high BMI  Burden of insulin resistance in obese individuals may be reduced by improving serum 25(OH)D concentration  Given the difficulty in management of overweight or obese status in certain individuals, recommendations to improve vitamin D status may be an inexpensive and practical means of reducing the burden of diabetes Kabadi SM, et al. Diabetes Care. 2012 Oct;35(10):2048-54. VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETES: THE NHANES STUDY

29.  A meta-analysis found that vitamin D supplementation in overweight people: o Reduced the risk of type 2 diabetes o Improved insulin resistance  Future randomized, controlled trials should focus on the impact of vitamin D supplementation among obese individuals  Vitamin D supplementation may be an avenue for obese individuals to improve glucose homeostasis Kabadi SM, et al. Diabetes Care. 2012 Oct;35(10):2048-54. VITAMIN D SUPPLEMENTATION IN OBESITY AND DIABETES: THE NHANES STUDY

30.  Body mass index (BMI) is inversely associated with an increase in the serum 25(OH)D levels in response to vitamin D supplementation  Calcitriol directly regulates adipocyte 11β-HSD-1, generating active cortisol from inactive cortisone, with expression and cortisol production in adipocytes in vitro  This suggests a potential role for calcitriol supplementation in visceral adiposity  In a 12-week double-blind randomized clinical trial, vitamin D 3 supplementation resulted in a statistically significant decrease in body fat mass in healthy and obese women compared with the placebo group  In addition, vitamin D 3 supplementation also improved insulin sensitivity in apparently healthy, middle-aged, centrally obese men Vinh quốc Lương K et al. Nutrition Journal 2013;12:89. VITAMIN D SUPPLEMENTATION IN OBESITY

31.  Obesity is a global epidemic and a risk factor for type 2 diabetes, and vitamin D endocrine system could be involved in glucose homeostasis and insulin release mechanisms  Vitamin D levels negatively correlate with HbA1c and insulin release mechanisms, implying that obese subjects with low vitamin D status may be at increased risk of developing impaired glucose metabolism  Vitamin D deficiency has been associated with obesity, visceral obesity, hypertriglyceridemia and metabolic syndrome  Obesity does not affect the capacity of the skin to produce vitamin D 3, but might alter the release of vitamin D 3 from the skin into the circulation SUMMARY

32.  Vitamin D can improve diabetes control and it is recommended that vitamin D supplementation should be included in treatment of type 2 diabetes  The stronger interaction of 25(OH)D with obesity with regard to insulin resistance may be related to the direct impact of vitamin D deficiency on insulin resistance  Vitamin D supplementation results in a statistically significant decrease in body fat mass in obese diabetics  Vitamin D supplementation in overweight people reduces the risk of type 2 diabetes and improves insulin resistance SUMMARY

33. 1. Grineva E, Karonova T, Micheeva E, Belyaeva O, Nikitina I. Vitamin D deficiency is a risk factor for obesity and diabetes type 2 in women at late reproductive age. Aging (Albany NY). 2013;5(7):575-581. 2. Alemzadeh R, Kichler J, Babar G, Calhoun M. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism. 2008 Feb;57(2):183-91. 3. Vinh quốc Lương K, Nguyễn LTH. The beneficial role of vitamin D in obesity: possible genetic and cell signaling mechanisms. Nutrition Journal. 2013;12:89. 4. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000 Sep;72(3):690-3. 5. Talaei A, Mohamadi M, Adgi Z. The effect of vitamin D on insulin resistance in patients with type 2 diabetes. Diabetol Metab Syndr. 2013 Feb 26;5(1):8. 6. Kabadi SM, Lee BK, Liu L. Joint effects of obesity and vitamin D insufficiency on insulin resistance and type 2 diabetes: results from the NHANES 2001-2006. Diabetes Care. 2012 Oct;35(10):2048-54. REFERENCES