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Association Between Vitamin D Supplementation and Glycemic Control in Patients with Type 2 Diabetes

HUN 3231

April 9, 2017
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Introduction:

The purpose of this paper is to determine if supplementation of vitamin D can help to improve

glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus. Many studies have

shown that there is a correlation between vitamin D deficiency and diabetes, and how vitamin D levels

can either negatively or positively impact the glycemic status of a patient. Vitamin D has been shown in

many areas to be linked to many other chronic diseases such as cardiovascular disease and cancer.1 Type

2 diabetes is a chronic metabolic disorder that is defined as patients who experience insulin insensitivity

as a result of insulin resistance. This leads to a decrease of glucose being transported into the liver,

muscle, and fat cells to decrease blood glucose levels.2 In patients with type 2 diabetes it has been

associated that low vitamin D levels can be seen with decreased insulin sensitivity.3

The two main forms of vitamin D are ergocalciferol (vitamin D2) and cholecalciferol (vitamin

D3). Vitamin D2 is synthesized in plants, unlike vitamin D3 which is synthesized in the skin when exposed

to ultraviolet B rays from the sun. There are a few other foods that contain dietary vitamin D3 which

include fatty fish like salmon or tuna. The dietary reference intake for vitamin D for ages 9-70 is 600

IU/day, and 800 IU/day for those older than 70 years of age.1 It is very hard to eat enough vitamin D

containing foods to receive the adequate intake of vitamin D2 and D3 from food. For this reason, they are

both synthetically made and used to fortify foods. Milk products, margarine, and soymilk are a few of the

products fortified with both D2 and D3. When foods containing D2 are consumed they are absorbed in the

small intestine with other fat-soluble vitamins. However, vitamin D3 enters the circulation after being

synthesized in the skin. The metabolism of both forms of vitamin D requires the conversion in the

kidneys and liver to its active forms.1 Calciferol in the blood is converted in the liver to 25(OH)D also

known as calcidiol, and is the main circulating form that they use to test vitamin D levels in patients.

Calcidiol can then be converted by the kidneys to 1,25-dihy-droxyvitamin D (calcitriol), which can then

bind to vitamin D receptors.1 This explains why diabetic patients with kidney and liver problems are at a

higher risk for developing vitamin D deficiency. Calcitriol has been shown in animal studies to stimulate

the pancreatic B-cells to secrete insulin.4 This could explain why vitamin D could play a significant role
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in managing blood glucose in patients with type 2 diabetics. When a diabetic patient has a deficiency in

vitamin D their insulin secretion is reduced, therefore increasing blood glucose levels.1 The purpose of

this paper is to determine if there is sufficient evidence to suggest that supplementation of vitamin D can

improve glycemic control and insulin sensitivity in patients with type 2 diabetes.

Methods:

The research for this paper was received from multiple databases including CINHAL plus,

Google scholar, Science Direct, and Pub Med. Search terms that were used to find the articles presented

in this paper include, Mechanism of action of vitamin D in type 2 Diabetes patients, Diabetes and

glycemic control in patients with type 2 diabetes, Type 2 diabetes, Vitamin D and diabetes,

Supplementation of vitamin D and glycemic control, Supplementation of Vitamin D and Diabetes type

2, Role of Vitamin D in diabetes, Vitamin D and Metabolism. The main findings in this paper are

original research articles, with different study designs. The types of studies that are presented in this

article include a randomized clinical trial study, randomized placebo controlled study, and clinical trial.

Main Findings:

An article published by the Iranian Journal of Public Health, conducted a study on the effects of

vitamin D supplementation on glucose control and insulin resistance in patients with type 2 diabetes. The

study suggests that vitamin D may facilitate insulin function by regulating the receptors expression and

increasing insulin sensitivity. In addition, it may also regulate glucose homeostasis by stimulating insulin

release from pancreatic B-cells. As a result, when vitamin D deficiency is corrected in type 2 diabetes

patients it could possibly result in increased glucose control and lessen complications that arise with

diabetes. This study took place between September 2012 and February 2013, and included 65 diabetic

type 2 patients from the age of 30-60. The study completed with 58 patients, and to be included in the

study you must have consumed vitamin D supplements within 3 months before the beginning of the

study. The patients also must have had previous complications with diabetes, thyroid disorders, insulin

use, thiazolidindiones, and anti-obesity drugs. The participants of this study were randomly divided into

two groups, the vitamin D group and placebo group. The vitamin D group received 100 micrograms daily
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and the placebo group received a placebo pill tablet every day for two months. At the beginning of the

study blood samples were taken, as well as after two months. Serum calcidiol, lipid profile, and insulin

were all measured from each participant each time. After two months the vitamin D group included 28

patients, and the placebo group contained 30 patients. In addition, there was no significant difference in

times of sun exposure for each patient. The results for this experiment show that supplementation with

vitamin D resulted in a significant decrease in HbA1C, in addition to serum insulin concentrations. Mean

concentrations of fasting blood sugar and TC increased significantly in the placebo group. To conclude,

the results of this study have shown that supplementing vitamin D decreased serum insulin concentrations

and HbA1c levels in type 2 diabetics. Supplementing patients with vitamin D was only beneficial to type

2 diabetic patients with a vitamin D deficiency. There are two mechanisms of action that explain these

results. Vitamin D stimulates gene expression of insulin receptors in beta cells. Beta-cells which are

located in the pancreas, have receptors for 1,25 (OH)2 D3 (calcidiol), and these cells can convert calcidiol

to the active form. Secondly, calcitriol is involved in calcium absorption from the gut and calcium is

necessary for insulin to be released by beta cells.5

The second study published by the Journal of the American College of Nutrition completed a

study on the effect of vitamin D supplementation on glycemic control and lipid profile in patients with

type 2 diabetes mellitus. This study states that the association between vitamin D and diabetes mellitus

can be explained because of the enzyme 1A hydroxylase which is expressed in pancreatic B-cells and

activates vitamin D. Vitamin D also controls nuclear peroxisome proliferative activated receptor, which is

an important factor in insulin sensitivity. In this study, 100 patients with type 2-diabetes were eligible to

partake in this study. Any patients with liver or renal malignancy, bone disease, gallbladder disease,

gastrointestinal disease, history of anticonvulsants, or calcium or vitamin D intake for the last 3 months

before the study were not allowed to partake in the study. The subjects were administered 4500 IU in oral

vitamin D drops for 2 months. The patients were told to continue on their normal antidiabetic drugs and

diet. Lab measures were taken at the initial visit and at the 2-month mark. Fasting blood glucose (FBG),

HbA1c, 25(OH)D, LDL, HDL, and TG was measured at each visit. In this study vitamin D deficiency
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was defined as serum 25 (OH)D levels less than 20ng/ml in adults. Out of all the patients 96% of them

were on oral hypoglycemic treatment or diet or both, 4% were on insulin therapy, 12% were on

antilipidemic therapy, and the range for diabetes was between 1-15 years. 75% of the patients had

25(OH)D levels below 20ng/ml, which is classified as a deficiency in vitamin D. There was a significant

increase in 25 (OH)D levels after the patients were supplemented with vitamin D. FBG and HbA1c levels

were significantly decreased after supplementation as well. They found that there is an inverse

relationship between 25 (OH)D levels and FBG and HbA1c levels. Before the study 32% of the patients

had controlled HbA1c levels, compared to 48% after supplementation. The study concluded that vitamin

D supplementation could help to improve glycemic control in patients who have type 2 diabetes.6

A study published by Diabetes Care, explored the effect of vitamin D supplementation on

glycemic control in patients with type 2 diabetes. Along with the other mechanisms of action previously

stated, the article suggests that vitamin D is known to have an immunomodulatory and anti-inflammatory

effect and may reduce the peripheral insulin resistance by altering low grade inflammation. This study

was a double-blind, randomized, placebo-controlled clinical trial where they studied the effect of vitamin

D supplementation on glycemic control. Adult patients with type 2 diabetes who were treated with

lifestyle advice, metformin, or sulfonylurea derivatives were allowed to participate in the study. Exclusion

criteria from the study includes impaired renal function, any granuloma forming disorder, hypercalcemia,

or serum 25(OH)D <15 or >150 nmol/L. All participants were randomized and given either an oral dose

of 50,000 IU of cholecalciferol or placebo 50,000 IU for 6 months. There was no stratification used and

the participants and the researchers remained blinded until the end of the study. Out of the 423 patients

invited to participate, 275 showed to their first appointment and were randomized into the placebo or

vitamin D group. There was a total of 261 who completed the 3 month study. Vitamin D deficiency was

present in 98 out of 261 patients, and no differences were reported in their dietary intake. At the end of

the study serum 25 (OH)D levels increased significantly in patients who received the vitamin D

supplementation, however no change was seen in the placebo. A significant inverse association was found

between baseline serum 25(OH)D levels at 6 months in both groups. HbA1c levels from baseline to 6
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months in both groups did not see a significant difference. No other significant differences between both

groups were seen in other indicators of glycemic control. Overall the researchers did not find a significant

effect of vitamin D supplementation on glycemic controls. Researchers only saw a significant effect of

supplementation on patients who had severe vitamin D deficiencies. This study concludes that vitamin D

supplementation does not improve glycemic levels in patients who have sufficient levels of vitamin D.7

Lastly, a study was conducted on the effect of vitamin D on insulin resistance in patients with

type 2 diabetes. This study was a single blind study that included 100 patients between the ages of 30-70

with type 2 diabetes. The patients participated in the study for 8 weeks, and vitamin D3 was added to their

medication. During the trial the subjects were asked not to change their diabetes drugs or diet. Fasting

plasma glucose, insulin, and HbA1c were measured among others. The examiners also assessed liver

function by measuring AST and ALT to rule out liver disease and major non-alcoholic fatty diseases of

the liver, which could affect vitamin D status of the patient. Patients were given 50,000 units of vitamin

D3 for two months. After two months of treatment measurements were repeated. The results for this

experiment suggest that vitamin D supplementation in type two diabetic patients significantly decreased

serum FPG, insulin, and HOMA-IR in these subjects. The study also found an inverse relationship

between final FPG and 25(OH)D concentrations. If the patient had a higher serum 25(OH)D that led to

lower FPG. They also reported that the effects of vitamin D on insulin resistance were significant when

vitamin D concentrations were between 40-60ng/ml. These studies findings are consistent with other

studies that have been published, where insulin resistance seems to decrease as a result of

supplementation of vitamin D. The study explains that the mechanisms of action for the effects of vitamin

D include vitamin D activation of 1 alpha hydroxylase that is expressed in pancreatic Beta cells, the

presence of vitamin D response element in the insulin gene, presence of vitamin D receptors in skeletal

muscle and how the presence of 1,25(OH)D increases transcription of insulin receptor genes. Vitamin D

also suppresses the renin gene reducing hyperglycemic induced increases in renin levels in beta cells.8
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Conclusion:

The information and articles included in this paper were combined and summarized to understand

the association between vitamin D supplementation and glycemic control in patients with type 2 diabetes.

Type 2 diabetes is a chronic metabolic disorder that is becoming an epidemic in some countries in the

world; this problem is adding to the burden for many health care providers.2 Even though vitamin D can

be found in some foods like fatty fish, and ultraviolet B rays from the sun, it is very hard for a person to

get the adequate amount each day.1 Vitamin D may play an important role in patients with type 2

diabetes, especially those who are deficient. Vitamin D could possibly help diabetic patients to have

better insulin sensitivity and glycemic control. There are many mechanisms of action by which vitamin D

supplementation can be beneficial to diabetics, which include that it may facilitate insulin function by

regulating the receptors expression, which would increase insulin sensitivity. In addition, it could help

regulate glucose homeostasis by stimulating insulin release from pancreatic B-cells.5 Lastly, because of

the enzyme 1A hydroxylase in pancreatic B-cells, which activates Vitamin D. Vitamin D, also regulates

nuclear peroxisome proliferative activated receptor, which is an important factor in insulin sensitivity. 6

Three of the studies that are summarized all had data that supported that vitamin D supplementation in

type 2 diabetics showed positive correlations. The results from those studies include seeing better levels

of fasting blood glucose, HbA1c, 25(OH)D, and serum insulin concentrations, which all helped improve

glycemic control. The fourth study concluded overall that they did not see a significant effect of

supplementation on glycemic control. However, it was beneficial to those diabetics who had severe

vitamin D deficiencies.8 To conclude, overall it is apparent that from these studies vitamin D deficiency

is beneficial to type 2 diabetics who are deficient in vitamin D. Two of the studies found an inverse

relationship with FBG and 25 (OH)D, which supports the data that those with normal/ high levels of

25(OH)D had good glycemic control, and those with low 25(OH)D had poor glycemic control. This

explains why vitamin supplementation in diabetics was beneficial to those with a deficiency. The purpose

of this paper was to determine if vitamin D supplementation could increase glycemic control in patients

with type 2 diabetes.

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References

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doi:10.2337/diaspect.24.2.113.

2. Olokoba AB, Obateru OA, Olokoba LB. Type 2 Diabetes Mellitus: A Review of Current Trends. Oman

Medical Journal. 2012;27(4):269-273. doi:10.5001/omj.2012.68.

3. Al-Timimi DJ. Serum 25(OH) D in Diabetes Mellitus Type 2: Relation to Glycaemic Control. Journal

Of Clinical And Diagnostic Research. 2013. doi:10.7860/jcdr/2013/6712.3733.

4. Lips P, Eekhoff M, Schoor NV, et al. Vitamin D and type 2 diabetes. The Journal of Steroid

Biochemistry and Molecular Biology. 2016. doi:10.1016/j.jsbmb.2016.11.021.

5. YOUSEFI RAD E, DJALALI M, KOOHDANI F, et al. The Effects of Vitamin D Supplementation on

Glucose Control and Insulin Resistance in Patients with Diabetes Type 2: A Ran- domized

Clinical Trial Study. Iranian Journal of Public Health . 2014;43(12):1651-1656.

6. Mohamad MI, El-Sherbeny EE, Bekhet MM. The Effect of Vitamin D Supplementation on Glycemic

Control and Lipid Profile in Patients with Type 2 Diabetes Mellitus. Journal of the American

College of Nutrition. 2015;35(5):399-404. doi:10.1080/07315724.2015.1026427.

7. Krul-Poel YH, Westra S, Boekel ET, et al. Effect of Vitamin D Supplementation on Glycemic Control

in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled

Trial. Diabetes Care. 2015;38(8):1420-1426. doi:10.2337/dc15-0323.

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8. Talaei A, Mohamadi M, Adgi Z. The Effect of Vitamin D on Insulin Resistance in Patients with type 2

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