25(OH)D, Fetuin A levels in patients of IFG/IGT, Type 2

diabetes mellitus and Type 2 diabetes mellitus with

cardiovascular disease

Presented by – Dr. Rishika Gaur Jr2 Internal medicine , KGMU

Principal Guide• Dr. Madhukar Mittal

Co-Guides• Prof Ravi Misra• Prof Arvind Mishra• Dr. Vivek Kumar• Prof A.A.Mahdi

Known since years: The adverse association between low serum vitamin D levels and bone and calcium metabolism

Recently researched:Inverse relation between serum vitamin D levels and metabolic syndrome, diabetes mellitus , hypertension and cardiovascular disease

Background

Insulin secretion Research shows that severe vitamin D deficiency may inhibit insulin

secretion

Insulin Resistance Vitamin D deficiency also associated with insulin resistance in humans

Vitamin D supplementation Conflicting data on whether supplementation improves glycemic control

in T2D Inconsistent results regarding supplementation and prevention of

progression of prediabetes to diabetes

Role of Vitamin D

IL-6 levels correlate negatively with insulin sensitivity TNF α levels increase with insulin resistance hsCRP-directly associated with insulin resistance Fetuin A

Fetuin APeptide moleculeSecreted from hepatocytesBinds to Insulin receptor present on adipose cells and

musclesHigher serum Fetuin A levels are associated with

insulin resistance

Molecular markers in T2D

Comparison of 25(OH)D and Fetuin A levels• Impaired Fasting Glucose/Impaired Glucose

Tolerance(IFG/IGT)• Type 2 Diabetes mellitus(T2D), No CAD• Type2 Diabetes Mellitus with Coronary artery disease

Effect of Vitamin D supplementation on glycemic parameters

Aim & Objectives

Study Design-• Observational Cross sectional study • Prospective open label study

Duration of study-one year

Study population- 3 groups• IFG/IGT• T2D, No CAD • T2D with CAD

Material & Methods

Age : >18 and <70 years

Blood sugar

CAD: Coronary artery disease- previous h/o myocardial infarction, cardiomyopathy, stable angina, unstable angina

Inclusion Criteria

IFG: FBS -100-125

IGT: PPBS-140-199

T2D 1.FBS: ≥ 126 2.PPBS: ≥200 3.RBS: ≥200 with symptoms

25(OH)D deficiency: Classification

Holick’s Classification Lip’s Classification

1.Sufficiency :≥ 30 ng/ml

2.Insufficiency: 20-29 ng/ml

3.Deficiency :<20 ng/ml

1. Mild- 25-50 ng/ml

2. Moderate- 12.5-25 ng/ml

3. Severe- <12.5ng/ml

• Chronic kidney disease• Vitamin D Supplementation in last 3 month• Vitamin D Fortified food• Malabsorption• Primary hyperparathyroidism• Pregnancy• Breast feeding• Antiepileptics, Steroids, Antifungal, ATT, ART

Exclusion Criteria

• Complete Blood Count • Liver function test• Kidney function test• HbA1c• 25(OH) D : Chemiluminescence (CLIA)• Fetuin A: Human Fetuin A ELISA kit(Booster

Immunoleader)• ECG and USG

Laboratory Investigations

Sno. Publication Study design Intervention

Effect Remarks

1. Mittal M et al. (Journal of diabetes &metabolic disorder)

Systematic review

- - No improvement with vitamin D supplementationon glycemic parameters

2. George PS, Pearson ER,Witham Md et al(2012)

Systematic review and meta analysis

- - Further studies need to establish relation between 25(OH) D and T2D

Review of Literature: Systematic review & Metaanalysis

S No. Publication Study design Intervention Change in glycemic parameters

REMARKS

1. Jehle et al, 2014, Switzerland

RCT, N=55 300,000 IU IM once in 3 month x 6mo

HOMA-IR - ↓ by 12.8% ± 5.6% in the D3 group and ↑ by 10% ± 5.4% in placebo group(p = 0.032) 0

Improved HOMA-IR

2. Al-Daghri et al, 2012, Saudi

Prospectivelongitudinal,N=92

Vitamin D3 oral 2000 IU daily for 18 months

HOMA-B: 52 ± 9 vs. 97 ± 15 (p=0.002)

Individuals studies

S No. Publication Study design Intervention Change in glycemic parameters

Remarks

3. Talaei et al, 2013, Iran

Longitudinal study, N=100

50,000 U vitaminD3 orally/weekly for 8 weeks

HOMA-IR: 3.57±3.18 and 2.89±3.28 (P=0.008)

4. Nikooyeh et al , 2011, Iran

RCT,N = 90 500 IU vitamin D+ calciumtwice daily for12 weeks

HbA1c(8.7±1.4 v/s 7.3±1.3(p<0.001) and HOMA-IR (5.5±3.7 v/s 3.0±1.5)(p<0.001)

Significant improvement inHbA1c and HOMA-IR

S No. Publication Study design

Intervention Change in glycemic parameters

Remarks

5. Tabesh et al , 2014, Iran

RCT, N = 70

Cholecalciferol for 8 weeks

changes from baseline, HbA1c (-0.70 ± 0.19%, (p = 0.02), HOMA-IR (-0.46 ± 0.20, p = 0.001)QUICKI (0.025 ± 0.01,( p = 0.004)

improvedHbA1c, HOMA-IR

6. Shab-bidar et al, 2011, Iran

RCT, N = 100

1,000 IU vitaminD3 orally daily for12 weeks

QUICKI- 0.27±0.02 V/S 0.30±0.02,HBA1c-8.7±1.8 v/s 7.8±1.3(p=0.015)

QUICKI only showed improvement, rest no significant change.

S No. Publication Study design

Intervention

Change in glycemic parameters

Remarks

7. Chan et al , 2013, Hong Kong

RCT, N = 100

5000 IU Vitamin D3 daily for 12 weeks

HbA1c -7.35 vs. 7.20,p = 0.08

No change in HBA1C and other glycemic parameters

8. Hassan et al, 2011, Iran

RCT, N = 70

Calcitriol 0.25 μg daily orally for 12 weeks

HbA1c -7.1 ± 1.6vs. 7.9 ± 2.1, p=0.004,QUICKI-0.33±0.03 v/s0.31±0.02 (p=0.002)

Attenuated the increasein glycemic, and QUICKI

Results: IFG/IGT1. N, % 14 (87.5)

2.BMI 27.21±4.37 27.57(23.84-30.36)

3.25(OH)D, ng/ml

15.29±14.69 9.03(4.45-24.44)

4.HBA1c, % 6.31±0.86 6.30(5.62-6.87)

5.Fasting insulin, mU/L

11.04±7.43 9.92(5.79-13.20)

6.HOMAIR2.893±1.914 2.642(1.68-3.29)

7.QUICKI 0.341±0.040 0.330(0.320-0.352)

Values are means ± SD or median (inter-quartile range)

1. N,% 43(63.2)

2.BMI 27.24±6.50 25.77(22.56-31.00)

3.25(OH)D, ng/ml

14.62±9.67 12.67(7.277-19.91)

4.HBA1c,% 9.16±2.63 8.65(6.70-11.28)

5.Fasting insulin, mU/L

13.12±18.65 8.17(4.60-14.70)

6.HOMAIR4.201±6.561 2.57(1.28-4.00)

7.QUICKI 0.339±0.0488 0.331(0.311-0.368)

Results: T2D No CAD

Values are means ± SD or median (inter-quartile range)

1. N,% 5(31.2)

2.BMI 27.55±7.27 25.96(25.00-27.63)

3.25(OH)D, ng/ml 16.12±13.25 12.56(5.89-24.47)

4.HBA1c,% 9.54±2.25 9.50(8.80-10.60)

5.Fasting insulin, mU/L

7.16±4.17 5.46(4.60-10.76)

6.HOMAIR2.297±1.566 1.600(1.30-3.68)

7.QUICKI 0.354±0.047 0.355(0.315-0.368)

Results: T2D WITH CAD

Values are means ± SD or median (inter-quartile range)

Comparison of Vitamin D Deficient vs. Non DeficientCharacteristic Deficient

(N=92)Non deficient(N=8)

P value

1. N,% 57(91.93) 5(8.06) 0.976

2.BMI 27.48±6.42 25.96(23.68-30.08)

25.20±4.65 25.61(21.22-27.18)

0.332

3.25(OH)D, ng/ml 12.57±7.30 10.97(5.8-18.77)

42.55±10.01 40.91 0.00

4.HBA1c,% 8.89±2.64 8.60(6.6-10.7)

7.30±1.60 6.70(6.07-8.35) 0.097

5.Fasting insulin, mU/L

10.933±9.425 8.38(4.81-13.5)

22.422±47.213

5.56(4.18-10.75) 0.049

6.HOMAIR3.262±2.933 2.57(1.38-

3.80)6.822±15.016 1.60(0.94-2.77) 0.074

7.QUICKI 0.340±0.043 0.331(0.313-0.36)

0.359±0.074 0.355(0.328-0.387)

0.272

Values are means ± S D or median (inter-quartile range)

Characteristic Female(N=62)

Male(N=38)

P value

1. N, % 62(100) 8(0)

2.BMI 28.54±6.89 26.66(18.00-27.00)

25.22±4.59 25.39(21.98-27.38)

0.012

3.25(OH)D, ng/ml 15.38±11.58 12.76(5.48-21.52)

14.28±10.34 11.68(6.96-19.03)

0.631

4.HBA1c,% 8.72±2.44 8.45(6.47-10.72)

8.83±2.88 8.60(6.50-10.45)

0.844

5.Fasting insulin, mU/L

13.49±19.36 8.80(4.66-15.05)

9.18±6.55 6.94(4.43-12.79)

0.194

6.HOMAIR4.299±6.522 2.72(1.368-

4.454)2.44±1.83 1.925(1027-

3.334)0.134

7.QUICKI 0.336±0.045 0.328(0.307-0.364)

0.352±0.048 0.346(0.319-0.368)

0.123

Comparison of Female vs. Male

Values are means ± SD or median (inter-quartile range)

Characteristic IFG(N=16)

T2D(N=84)

pvalue

1. N , % 14(87.5) 48(57.14) 0.025

2.BMI 27.21±4.37 27.57(23.84-30.36)

27.30±6.60 25.77( 22.91-29.47)

0.961

3.25(OH)D, ng/ml 15.29±14.69 9.03(4.45-24.44)

14.90±10.37 12.76(6.44-19.91)

0.899

4.HBA1c,% 6.31±0.86 6.30(5.62-6.87) 9.23±2.56 8.90(6.70-11.24)

0.00

5.Fasting insulin, mU/L

11.04±7.43 9.92(5.79-13.20)

12.03±17.08 7.42,(4.51-13.46)

0.822

6.HOMAIR2.893±1.914 2.642(1.68-

3.29)3.791±5.895 2.233(1.32-

3.80)0.551

7.QUICKI 0.341±0.0404 0.330(0.320-0.352)

0.3427±0.0485 0.338(0.3138-0.3665)

0.895

Comparison of IFG vs. T2D

Values are means ± SD or median (inter-quartile range)

Sno. Publication Study design Fetuin A levels REMARKS

1. Liang Yin et al, China ,2015

Cross Sectional Study

T2D v/s NGT (368.5±15.6 vs. 152.7±7.1 mg/l (P<0.01)

2. Aiyun Song et al,China,2011

Cross Sectional Study

NGT v/s IFG/IGT v/s T2D 285.3 v/s291.0 v/s 307.7 (p value= 0.0008)

Significant difference among three group.

Individuals studies regarding Fetuin A-