Study: Vitamin D reduces inflammation in patients with type 2 diabetes

reference

Johny E, Jala A, Nath B, et al. Vitamin D supplementation modulates platelet-mediated inflammation in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.Frontimmunol. 2022;13:869591.

Study objective

To determine whether vitamin D₃Nutritional supplementation affects platelet activation and platelet-mediated systemic inflammation in patients with vitamin D deficiency and uncontrolled HbA_1c ≥7%) non-insulin-dependent diabetes mellitus (type 2 diabetes)

Key to take away

Vitamin D supplementation₃Compared to placebo, platelet aggregation, platelet activation, and platelet-mediated inflammatory cytokines/chemokines decreased significantly.

design

Single-center, randomized, double-blind, placebo-controlled study

Participant

Participants were 59 patients with uncontrolled type 2 diabetes (HbA)._1c≥7%) and serum 25-hydroxy (OH) vitamin D ≤20 ng/ml. Of the people included in the study, 42 were men and 17 were women. The mean age of the placebo group (n=29) was 55.06 ± 9.57 years and was 53.6±9.6 years in vitamin D₃group (n=30).

Excluded from the study were patients who had previously taken vitamin D, those who had signs of liver or kidney failure, type 1 diabetes, cancer or thyroid disease, and those who were pregnant.

intervention

Vitamin D₃60,000 IU per week for 3 months, followed by vitamin D₃60,000 IU per month for another 3 months; or placebo.

Evaluated study parameters

-Total 25-OH vitamin D content in serum

-Serum vitamin D binding protein (VDBP)

-Fasting blood sugar (FBS)

-Hemoglobin A_1c(HbA_1c)

-Platelet activation markers:

• PAC-1-Ausdruck
• P-Selectin-Ausdruck
• Serumplättchenfaktor 4 (PF-4)
• 11-Dehydrothromboxan B2 im Urin

-Inflammatory markers in serum:

• Interleukin (IL) 1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13 und IL-18
• Tumornekrosefaktor Alpha (TNFα)
• Interferon-Gamma (IFN-γ)
• Granulozyten-Makrophagen-Kolonie-stimulierender Faktor (GM-CSF)
• Chemokine CXCL-1, CXCL-10, CXCL-12, CCL-2, CCL-3, CCL-4, CCL-5 und CCL-11

-Platelet immune cell aggregation (%):

• Thrombozyten-Monozyten-Aggregate,
• Thrombozyten-klassische (CD14++ CD16-) Monozytenaggregate
• Plättchen-intermediäre (CD14++ CD16+) Monozytenaggregate
• Thrombozyten-nichtklassische Monozytenaggregate (CD14+ CD16++).
• Thrombozyten-Neutrophile-Aggregate
• Thrombozyten-T-Zellen CD4 (CD3+ CD4+) und CD8 (CD3+ CD8+) Aggregate
• Aggregate aus Blutplättchen und NK-Zellen (CD3-CD56+).
• Thrombozyten-NKT-Zellaggregate (CD3+ CD56+).
• Blutplättchen-plasmozytoide dendritische (HLA DR+ CD123+) Zellaggregate
• Plättchen-myeloische dendritische (HLA DR+ CD11C+) Aggregate

-Oxidative stress markers:

• Serumsuperoxiddismutase (SOD)
• Glutathion (GSH)
• Gesamtstickstoffmonoxid (TNO)

Primary outcome

The effect of vitamin D₃Supplementation of Platelet Activation and Platelet-Mediated Systemic Inflammatory Markers in Patients With Type 2 Diabetes and Vitamin D Deficiency.

Key findings

Total 25-OH vitamin D increased significantly after 6 months of treatment (14,15).±5.8 ng/ml to 51.99±16.56 ng/ml,P<0.0001).

25-OH vitamin D increased significantly after 6 months of treatment (14.02 ± 5.76 ng/ml to 53.12 ± 16.44 ng/ml).P<0.0001).

VDBP increased significantly from 170.6 ± 60.24 µg/ml to 205.4 ± 88.30 µg/ml after 6 months of treatment(P=0.0425).

No significant changes in FBS or HbA_1cwere observed after 6 months of treatment with vitamin D₃.

Vitamin D supplementation₃For 6 months, percent PAC-1 and percent P-selectin expression decreased significantly compared to baseline. Results are expressed as median value (25).^Th–75^Thpercentile).

PAC-1 expression (%) was 0.20 (0.07–0.57) at baseline and 0.10 (0.09–0.18) at 6 months (P=0.03), while the percent P-selectin expression (%) decreased from 53.83 (42.51–59.76) to 34.10 (25.76–47.96) during the same period (P<0.001).

Serum PF-4 levels decreased significantly with vitamin D3 from baseline to 6 months. Values ​​not reported (P=0.0049).

Urine levels of 11-dehydrothromboxane B2 (ng/ml creatinine) also decreased significantly in volunteers taking vitamin D₃after 6 months compared to baseline. Values ​​not reported (P=0.0390).

Six months of vitamin D₃Supplementation significantly reduced platelet aggregation in the following innate immune cells:

• Thrombozyten-Monozyten-Aggregate (%): 80,0 (95 %-KI: 71,75–87,337) bis 49,80 (95 %-KI: 36,80–67,88), P<0,001
• Thrombozyten-klassische Monozyten-Aggregate (%): 84,33 (95 %-KI, 74,67–89,75) bis 45,14 (95 %-KI, 33,11–65,03), P<0,001
• Thrombozyten-intermediäre Monozytenaggregate (%): 94,80 (88,09–98,12) bis 72,41 (42,69–87,38), P<0,001
• Thrombozyten-nichtklassische Monozytenaggregate (%): 91,39 (85,44–100) bis 64,40 (52,73–81,04), P<0,001
• Thrombozyten-Neutrophile-Aggregate (%): 62,96 (54,53–69,92) bis 54,10 (39,78–65,40), P=0,004
• Thrombozyten-T-Zell-Aggregate (%): 28,55 (20,91–34,83) bis 23,25 (19,96–28,66), P=0,001
• Thrombozyten-NK-Zellaggregate (%): 26,80 (13,54–33,21) bis 17,58 (13,24–25,56), P=0,03.
• Aggregate aus Blutplättchen und dendritischen Zellen (%): 44,11 (34,0–55,89) bis 31,49 (17,33–48,69), P=0,04

The following cytokines/chemokines significantly (P<0.05) decreased after 6 months of vitamin D intake₃Supplementation compared to baseline: IL-18, TNF-α, IFN-γ, CXCL-10, CXCL-12, CCL-2, CCL-5 and CCL-11. The researchers did not provide any information about the baseline and follow-up values ​​for the individual analytes.

SOD activity expressed as a percentage inhibition rate, serum GSH and TNO (an inhibitor of platelet aggregation) all increased significantly in the treatment group after 6 months of vitamin D supplementation₃compared to the initial value (P<0.05).

The placebo group did not show significant changes in any of the variables measured during the study.

transparency

The authors declared that they had no commercial or financial relationships that could give rise to a conflict of interest.

Implications and limitations for practice

Chronic inflammation is a central mechanism in endothelial damage and end-organ failure in patients with diabetes, including progression to diabetic retinopathy, diabetic kidney disease (DKD), and diabetic peripheral neuropathy.^1-3Patients with type 2 diabetes also have a higher incidence of coagulopathies than people without diabetes, which is caused by increased inflammatory cytokines and platelet activation.⁴Therefore, understanding ways to reduce inflammatory cytokines and platelet activation may be beneficial for these patients.

In the current study, vitamin D supplementation was performed₃significantly attenuated platelet activation, reduced inflammatory cytokines/chemokines and improved markers of oxidative stress in patients with uncontrolled type 2 diabetes (HbA)._1c>7%) and vitamin D deficiency (25-OH-vitamin D <20 ng/ml).

Previous studies have also shown benefits, although they measured different – ​​and fewer – markers of oxidative stress. A 2019 randomized clinical trial examined the ability of vitamin D to reduce oxidative DNA damage in patients with vitamin D deficiency (<20 ng/ml) and type 2 diabetes. Initial HbA_1cwas not reported. Supplement with 2,000 IU vitamin D₃Daily for 3 months, serum 25-OH vitamin D levels increased to a mean of 31.8 ng/ml and oxidative DNA damage was significantly reduced (P<0.05).⁵

“Chronic inflammation is a central mechanism in endothelial damage and end-organ failure in patients with diabetes, including progression to diabetic retinopathy, diabetic kidney disease (DKD), and diabetic peripheral neuropathy.”

Similarly, a 2019 study examined the effects of 4,000 IU of vitamin D per day₃over 8 weeks on oxidative stress and DNA damage in 75 patients (47 women, average age 60.71 years; 28 men, average age 65.24 years) with insulin-dependent type 2 diabetes and an HbA_1c<9.5%. Eight weeks of treatment significantly increased serum 25-OH vitamin D levels and significantly reduced DNA damage caused by oxidative stress (P<0.05 for both). In addition, ALT, AST and GGT also decreased (P<0.05 for all 3).⁶

In the current study, vitamin D₃The dose they used - 60,000 IU per week for 3 months, followed by 60,000 IU per month for another 3 months - increased total serum 25-OH vitamin D to a median of 51.99 ng/ml. Clinically, it would be helpful to know whether a lower dose of vitamin D should be used₃and lower serum 25-OH vitamin D levels also improve the same inflammatory markers. A future dose-response study could answer this question.

Several studies have concluded that serum vitamin D levels increase by approximately 1 ng/ml for every 2.5 mcg (100 IU) of vitamin D₃.^7.8Therefore, taking 125 mcg (5,000 IU) of vitamin D per day may be as effective at raising serum vitamin D levels above 50 ng/mL as the higher, less frequent dose used in the current study.

Finally, because the researchers only prescribed one dose of vitamin D and tested patients only at baseline and after 6 months, we do not know whether lower serum vitamin D levels would produce similar results and whether the results are visible sooner than 6 months.