Abstract
Background:
Vitamin D deficiency is prevalent in diabetes type 2 and this vitamin may be related to insulin action. This randomized controlled trial study was done to evaluate the effect of vitamin D supplementation on glucose control and insulin resistance in patients with diabetes type 2.
Methods:
Participants of this randomized clinical trial study consisted of 28 patients with type 2 diabetes who received 100 microgram (4000 IU) vitamin D and 30 diabetic patients who received placebo for 2 months between September 2012 and February 2013. The effect of vitamin D on glucose control was assessed by measuring HbA1c and insulin resistance as HOMA-IR at the baseline and the end of the intervention.
Results:
The results showed a significant decrease in HbA1c (from 7.29 ± 0.22 % to 6.76 ± 0.18 %, P<0.001) and insulin concentration (from 8.24 ± 0.97 μIU/mL to 6.55 ± 0.28 μIU/mL, P=0.048), but a non-significant decrease in HOMA-IR in vitamin D group. Also, HDL-C level increased significantly in both of vitamin D (P=0.046) and placebo groups (P=0.028).
Conclusion:
It seems that vitamin D supplementation has beneficial effects on glucose homeostasis and can increases insulin sensitivity in diabetic 2 patients.
Keywords: Vitamin D, Diabetes type 2, HbA1c, Insulin resistance
Introduction
Diabetes type 2 is a worldwide disease and it is estimated that at the end of 2030 more than 550 million people suffer from this disease (1). There are several studies showing that vitamin D deficiency may resulted in developing diabetes type 2 (2–4). Vitamin D may facilitate insulin function by regulating its receptor expression, so it may be increases insulin sensitivity (5). Vitamin D may also regulate glucose homeostasis by stimulating insulin release from pancreatic B-cells (6, 7). Therefore, the correction of vitamin D deficiency may result in improved glucose control and has beneficial effects on complications of diabetes type 2 (8). Lower circulating level of calcidiol was associated with the increased risk of coronary artery disease in diabetic patients (9). Vitamin D supplementation increases significantly insulin sensitivity in IGT patients (10). Recently, Malekshah et al. reported high prevalence of vitamin D deficiency in several cities of Iran (11).
Because of the role of vitamin D in insulin function and the prevalence of vitamin D deficiency in Iran, the aim of this study was to examine the effects of vitamin D supplementation on glucose control and insulin sensitivity and lipid profile in patients with type 2 diabetes.
Methods
The participants of this randomized double-blind placebo-controlled clinical trial study consist of 65 diabetic type 2 patients at the age range of 30–60 years old who agreed to take place in our study between September 2012 and February 2013. An informed consent was obtained from all of the participants. Seven patients discontinued the supplements consumption, three from placebo group and four from vitamin D group. The study completed with 58 patients (36 women and 12 men). Patient selected from Iranian Diabetes Association (IDA). This study was approved by the Tehran University of Medical Sciences (TUMS) ethical committee (ID: 17112) and registered on www.clinicaltrial.org as NC 01876563.
The exclusion criteria were consuming vitamin D supplements within 3 months before beginning of the study and having complications of diabetes, thyroid disorders, and using insulin, thiazolidindiones or anti- obesity drugs. None of the women patients were pregnant or breastfeeding. All patients used metformin and/or glibenclamide as anti-diabetic drugs and agreed to maintain their usual dietary and physical activity habits at the time of intervention.
Participants of this study divided into two randomly allocated groups (vitamin D and placebo) by random permuted blocks within the strata (BMI) method. The vitamin D group received 100 microgram or 4000 IU (one tablet of vitamin D) daily and placebo group received one placebo tablet per day for 2 months. Minoo Pharmaceutical, Cosmetic and Hygienic Company made both vitamin D supplements and placebo. Height, hip and waist circumference was measured to the nearest centimeter and weight to the nearest kilogram. BMI was calculated as the weight divided by the square of height. In the beginning of the study and after 2 months, blood samples were taken after 12–14 hours fasting overnight. After centrifuging, serums were separated and stored at −80 C until measuring the concentration of serum calcidiol, lipid profile and insulin. In addition, HbA1c was measured with HPLC columns as long-time control of glucose.
Biochemical measurements: Serum calcidiol was measured using chemiluminecense method with ELECSYS system 2010 with Roche kit (code number: 05894973). Serum insulin was measured by human insulin ELISA kit (Diametra, Italy) with the sensitivity of 0.25 mcIU/ml and an intraassay and interassay of ≤5% and ≤10% respectively. HOMA-IR was calculated using the formula of fasting glucose (mmol/L) × fasting insulin (μIU/mL) / 22.5 (12).
Statistical analysis: Statistical analysis was performed by using SPSS version 18. All data were shown as mean ± SE. The Kolmogorov smirnoff test was used for determining normality of the parameters and Wilcoxon test and mann-whitnes test were used to analysis of non-normal distribution variables within and between groups. Independent sample t-test and paired t-test were used for comparison between groups before and after supplementation and within groups for analysis of normal distribution variables. In all analysis, P-value <0.05 was considered statistically significant.
Results
Vitamin D group consisted of 28 patients (15 men and 13 women) and placebo group consisted of 30 patients (21 men and 9 women) and there was not significant differences in the sex distribution between 2 groups (P=0.154). In addition, there was no significant differences in times at sun exposure between two groups (P=0.580).
Table 1 illustrates the baseline characteristics of 2 groups participated in this study. As it demonstrated, there are no significant differences between anthropometric parameters and duration of disease between 2 groups.
Table 1:
Baseline characteristics of anthropometric parameters in vitamin D and placebo groups before the intervention
| Variable | Vitamin D group (n=28) | Placebo group (n=30) | P-value |
|---|---|---|---|
| Age (yr) | 50.03 | 49.90 | 0.924 |
| Weight (kg) | 75.73 ± 3.09 | 82.32 ± 2.90 | 0.125 |
| BMI (kg/m2) | 27.94 ± 0.92 | 28.75 ± 0.95 | 0.541 |
| Waist circumference (cm) | 92.56 ± 2.33 | 96.53 ± 2.23 | 0.223 |
| Hip circumference (cm) | 104.19 ± 1.88 | 106.40 ± 1.47 | 0.356 |
| WHR | 0.89 ± 0.014 | 0.90 ± 0.012 | 0.348 |
| Duration (year) | 5.89 ±0.84 | 6.07±0.73 | 0.877 |
Data are expressed as mean ± SE, t-test was used to detect differences between the groups
Table 2 illustrates Fasting biochemical characteristics of two groups at baseline and Post intervention. The results show that supplementation with vitamin D caused a significant decrease in HbA1c (P<0.001) and it was still significant after removing the baseline effect (P<0.001, ANCOVA). Serum insulin concentration decreased significantly in vitamin D group (P=0.048), it was not significant between two groups at the end of the study but after adjusting for the baseline values the difference got statistically significant (P<0.001, ANCOVA). There was not any significant difference in HOMA-IR between two groups at the end of intervention, but it got statistically significant (P=0.036, ANCOVA) after adjusting for the baseline values. HDL-C concentration increased significantly in both vitamin D (P=0.046) and placebo receiving groups (P=0.028). In addition, mean concentration of FBS and TC increased significantly in placebo group. For TC concentration, the difference between two groups was statistically significant after removing the effect of baseline values (P=0.021, ANCOVA). Serum calcidiol was still significantly different between two groups after removing baseline amounts (P<0.001, ANCOVA).
Table 2:
Fasting biochemical characteristics of vitamin D and placebo groups at baseline and Post intervention
| Treatment group | Vitamin D group (n=28) | Placebo group (n=30) | P.value* | |
|---|---|---|---|---|
| FBS (mg/dl) | baseline | 147.07 ± 10.11 | 151.23 ± 7.48 | 0.740 |
| Post-intervention | 147.74 ± 10.16 | 161.27 ± 7.69 | 0.288 | |
| difference | 2.70 ± 9.66 | 10.03 ± 4.61 | 0.483 | |
| P.value# | 0.782 | 0.038 | ||
| TG (mg/dl) | baseline | 158.25 ± 12.41 | 167.43 ± 16.10 | 0.656 |
| Post-intervention | 145.33 ± 10.28 | 178.20 ± 14.80 | 0.080 | |
| difference | −13.07 ± 13.15 | 10.76 ± 14.45 | 0.231 | |
| P.value# | 0.329 | 0.462 | ||
| TC (mg/dl) | baseline | 201.82 ± 7.91 | 184.53 ± 6.73 | 0.100 |
| Post-intervention | 189 ± 7.04 | 200.87 ± 8.70 | 0.301 | |
| difference | −12.88 ± 7.25 | 16.33 ± 6.93 | 0.005 | |
| P.value# | 0.087 | 0.025 | ||
| HDL-C (mg/dl) | baseline | 42.29 ± 1.84 | 41.17 ± 2.15 | 0.697 |
| Post-intervention | 49.63 ± 3.28 | 49 ± 3.03 | 0.888 | |
| difference | 6.81 ± 3.25 | 7.83 ± 3.39 | 0.830 | |
| P.value# | 0.046 | 0.028 | ||
| LDL-C (mg/dl) | baseline | 88.93 ± 7.23 | 97.37 ± 7.64 | 0.427 |
| Post-intervention | 88.37 ± 6.94 | 98.67 ± 7.22 | 0.311 | |
| difference | 0.89 ± 7.19 | 1.30 ± 8.65 | 0.971 | |
| P.value# | 0.903 | 0.882 | ||
| HbA1c (%) | baseline | 7.29 ± 0.22 | 7.84 ± 0.28 | 0.132 |
| Post-intervention | 6.76± 0.18 | 7.73 ± 0.23 | 0.002 | |
| difference | −0.53 ± 0.08 | −0.11 ± 0.08 | 0.001 | |
| P.value# | <0.001 | 0.176 | ||
| Insulin (μIU/mL) | baseline | 8.24 ± 0.97 | 7.49 ± 0.58 | 0.505 |
| Post-intervention | 6.55 ± 0.28 | 7.96 ± 0.94 | 0.171 | |
| difference | −1.68 ± 0.81 | 0.47 ± 0.51 | 0.027 | |
| P.value# | 0.048 | 0.367 | ||
| MOMA-IR | baseline | 2.50 ± 0.19 | 2.55 ± 0.16 | 0.841 |
| Post-intervention | 2.38 ± 0.18 | 2.78 ± 0.19 | 0.134 | |
| difference | −0.14 ± 0.14 | 0.22 ± 0.13 | 0.056 | |
| P.value# | 0.307 | 0.092 | ||
| Calcidiol (ng/ml) | baseline | 15.55 ± 1.91 | 14.64 ± 2.22 | 0.759 |
| Post-intervention | 27.50 ± 2.04 | 15.95 ± 2.20 | <0.001 | |
| difference | 11.95 ± 1.44 | 1.92 ± 0.89 | <0.001 | |
| P.value# | <0.001 | 0.040 | ||
Data are expressed as mean ± SE,
Independent samples t-test,
Paired t-test
Discussion
The results of this study showed that vitamin D supplementation decreased serum insulin concentration and had beneficial effects in decreasing HbA1c in diabetic type 2 patients. There are several studies with similar results supporting this idea that vitamin D is an important nutrient in control of glucose homeostasis (13, 14). Vitamin D intake decreased prevalence of diabetes type 2 in long-time (15).
One mechanism that plausible for relating vitamin D to diabetes may be its action on insulin receptor in beta cells. Vitamin D can stimulate gene expression of insulin receptor and increases glucose transport from the intestine (5). Another mechanism is that 1,25 (OH)2D3 involves in calcium absorption from the gut and calcium is necessary for insulin release from beta-cells (16, 17). Recently, it has been cleared that beta-cells have receptors for 1,25 (OH)2D3, the active form of vitamin D and this cells can convert calcidiol to this form of vitamin (17).
One study showed that whether calcium is used or not, vitamin D supplementation improves glucose control in adults at high risk of diabetes type 2 (18).
Supplementation with vitamin D was only related to improved glucose control in diabetic patients with vitamin D deficiency and this nutrient had not any beneficial effect in patients with normal range of serum calcidiol (19). Supplementation of 1000 IU vitamin D combined with or without calcium in the form of fortified yogurt resulted in decreased HbA1c (20). However, vitamin D supplementation although can normalize the calcidiol concentration in diabetic patients; it has no long-term effect on glycemic control in this people (21).
In our study, vitamin D supplementation did not changed serum lipid profile in diabetic patients significantly except for HDL-C. However, the concentration of LDL-C and FBS increased significantly in placebo receiving group. One previous study showed that supplementation with vitamin D did not result in significant reduction in plasma glucose, TC, LDL-C and TG (19). Moreover, vitamin D supplementation had not significant effect in reducing serum FBS or insulin resistance in one systematic review (22).
Unlike our results, in the study of Al-Daghri et al. supplementation with vitamin D had decreased significantly serum TC and LDL-C concentration (23).
One of limitations of our study is the number of patients participated in the study. Maybe, if we used more patients, we could achieve better results such as reduction in some fractions of lipid profile.
Conclusion
Supplementation with UL dose of vitamin D could improve glucose control in diabetic type 2 patients, but did not exhibit any beneficial change in lipid profile except for HDL-C concentration. Therefore, it seems that vitamin D supplementation might be used as a strategy for control of glucose control in these people.
Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.
Acknowledgments
This study was supported by Health Services grants from the School of Nutritional Science and Dietetics of Tehran University of Medical Sciences (ID: 17112). This study was registered in accordance with the clinical trial registration system. (NC 01876563). The authors declare that there is no conflict of interests.
References
- 1. Whiting DR, Guariguata L, Weil C, Shaw J. ( 2011). IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract, 94: 311– 21. [DOI] [PubMed] [Google Scholar]
- 2. Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langenberg C, Wareham NJ. ( 2012). Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia, 55: 2173– 82. [DOI] [PubMed] [Google Scholar]
- 3. Mitri J, Muraru MD, Pittas AG. ( 2011). Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr, 65: 1005– 15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM. ( 2010). Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med, 152: 307– 14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Maestro B, Campion J, Davila N, Calle C. ( 2000). Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J, 47: 383– 91. [DOI] [PubMed] [Google Scholar]
- 6. Pitocco D, Crino A, Di Stasio E, Manfrini S, Guglielmi C, Spera S, Anguissola GB, Visalli N, Suraci C, Matteoli MC, Patera IP, Cavallo MG, Bizzarri C, Pozzilli P. ( 2006). The effects of calcitriol and nicotinamide on residual pancreatic beta-cell function in patients with recent-onset Type 1 diabetes (IMDIAB XI). Diabet Med, 23: 920– 3. [DOI] [PubMed] [Google Scholar]
- 7. Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R. ( 2003). The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract, 57: 258– 61. [PubMed] [Google Scholar]
- 8. Baz-Hecht M, Goldfine AB. ( 2010). The impact of vitamin D deficiency on diabetes and cardiovascular risk. Curr Opin Endocrinol Diabetes Obes, 17: 113– 9. [DOI] [PubMed] [Google Scholar]
- 9. Joergensen C, Reinhard H, Schmedes A, Hansen PR, Wiinberg N, Petersen CL, Winther K, Parving HH, Jacobsen PK, Rossing P. ( 2012). Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate. Diabetes Care, 35: 168– 72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, Shulman GI. ( 1998). Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med, 338: 867– 72. [DOI] [PubMed] [Google Scholar]
- 11. Malekshah AF, Kimiagar M, Pourshams A, Yazdani J, Kaiedi Majd S, Goglani G, Jaafari E, Semnani S, Malekzadeh R. ( 2012). Vitamin deficiency in Golestan Province, northern Iran: a high-risk area for esophageal cancer. Arch Iran Med, 13: 391– 4. [PubMed] [Google Scholar]
- 12. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. ( 1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28: 412– 9. [DOI] [PubMed] [Google Scholar]
- 13. Lim S, Kim MJ, Choi SH, Shin CS, Park KS, Jang HC, Billings LK, Meigs JB. ( 2013). Association of vitamin D deficiency with incidence of type 2 diabetes in high-risk Asian subjects. Am J Clin Nutr, 97: 524– 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. ( 2011). Effects of vitamin D and calcium supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr, 94: 486– 94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Ozfirat Z, Chowdhury TA. ( 2010). Vitamin D deficiency and type 2 diabetes. Postgrad Med J, 86: 18– 25; quiz 24. [DOI] [PubMed] [Google Scholar]
- 16. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. ( 2007). The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab, 92: 2017– 29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, Hewison M. ( 2004). Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol, 89–90: 121– 5. [DOI] [PubMed] [Google Scholar]
- 18. Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. ( 2007). The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care, 30: 980– 6. [DOI] [PubMed] [Google Scholar]
- 19. Jorde R, Figenschau Y. ( 2009). Supplementation with cholecalciferol does not improve glycaemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels. Eur J Nutr, 48: 349– 54. [DOI] [PubMed] [Google Scholar]
- 20. Nikooyeh B, Neyestani TR, Farvid M, Alavi-Majd H, Houshiarrad A, Kalayi A, Shariatzadeh N, Gharavi A, Heravifard S, Tayebinejad N, Salekzamani S, Zahedirad M. ( 2011). 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. Am J Clin Nutr, 93: 764– 71. [DOI] [PubMed] [Google Scholar]
- 21. Ryu OH, Lee S, Yu J, Choi MG, Yoo HJ, Mantero F. ( 2013). A prospective randomized controlled trial of the effects of vitamin D supplementation on long-term glycemic control in type 2 diabetes mellitus of Korea. Endocr J, 61: 167– 76. [DOI] [PubMed] [Google Scholar]
- 22. George PS, Pearson ER, Witham MD. ( 2012). Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med, 29: e142– 50. [DOI] [PubMed] [Google Scholar]
- 23. Al-Daghri NM, Alkharfy KM, Al-Othman A, El-Kholie E, Moharram O, Alokail MS, Al-Saleh Y, Sabico S, Kumar S, Chrousos GP. ( 2012). Vitamin D supplementation as an adjuvant therapy for patients with T2DM: an 18-month prospective interventional study. Cardiovasc Diabetol, 11: 85. [DOI] [PMC free article] [PubMed] [Google Scholar]