1. STUDY OF VITAMIN D LEVELS
IN DIABETICS
AND ITS CORRELATION WITH
DIABETIC RETINOPATHY
PRESENTED BY
VINEET MISHRA
2. GUIDES
Chief guide:
Co-guides:
Prof Sarita Bajaj
MD DM (Endocrinology)
DIRECTOR PROFESSOR & HEAD
PG DEPARTMENT OF MEDICINE
M.L.N. MEDICAL COLLEGE
ALLAHABAD
DR KAMALJEET SINGH MS (OPHTHALMOLOGY)
PROFESSOR
P.G. Department of OPHTHALMOLOGY
M.L.N. Medical College
Allahabad
DR MANOJ MATHUR MD(MEDICINE)
P.G. Dept. of MEDICINE
M.L.N. Medical College
Allahabad
DR RAKESH YADAV MD(MEDICINE)
P.G. Dept. of MEDICINE
M.L.N. Medical College
Allahabad
3. INTRODUCTION
Diabetes mellitus is a major medical problem prevalence of which is
increasing and appears to be greater in developing countries
Longer a person has diabetes, the higher his or her chances of
developing diabetic retinopathy
Studies that link vitamin D levels with the diabetic nephropathy and
retinopathy coexisting but direct link between the vitamin D levels and
diabetic retinopathy is still the matter of interest
EPIDEMIOLOGY OF DIABETIC RETINOPATHY IN INDIA
Age and gender adjusted prevalence rate of diabetes in an urban
Chennai population was 28.2% (95% confidence interval [CI], 27.0-29.3),
and the prevalence of diabetic retinopathy in general population was 3.5%
(95% CI, 3.49-3.54)
Prevalence of diabetic retinopathy in the population with diabetes
mellitus was 18.0% (95% CI, 16.0-20.1)
Differences in the socioeconomic status did not influence the occurrence
of diabetic retinopathy
Prevalence of diabetic retinopathy was 18% in an urban population with
diabetes mellitus in India
4. PATHOPHYSIOLOGY AND TYPES
Mechanism by which diabetes causes retinopathy remains unclear BUT important roles are
played by Growth hormone, Platelets and blood viscosity, Aldose reductase and
vasoproliferative factors, Macular edema,Hypoxia and Neovascularization
Nonproliferative diabetic retinopathy
Microaneurysms: small bulges in blood vessels
Retinal hemorrhages: tiny spots of blood
Hard exudates: deposits of cholesterol
Macular edema: swelling or thickening of the macula
Macular ischemia: small blood vessels (capillaries) close
Mild nonproliferative diabetic retinopathy (NPDR) presence of at least 1 microaneurysm
Moderate nonproliferative diabetic retinopathy presence of hemorrhages,
microaneurysms, and hard exudates
Severe NPDR (4-2-1) hemorrhages and microaneurysms in 4 quadrants, with venous
beading in at least 2 quadrants and IRMA in at least 1 quadrant
Proliferative diabetic retinopathy
Neovascularization is the hallmark and often occurs near the optic
disc(neovascularization of the disc [NVD]) or within 3 disc diameters of the major retinal
vessels (neovascularization elsewhere [NVE])
Any amount of NVD with vitreous or preretinal hemorrhage; and NVE is one-half or
greater of the DA, with preretinal or vitreous hemorrhage
5. AIMS AND OBJECTIVES:
• To study the association of vitamin D levels with diabetic retinopathy.
• To study association of vitamin D levels with grade and severity of
diabetic retinopathy.
• To study whether vitamin D sufficient patients are having decreased
prevalence of diabetic retinopathy
MATERIALS AND METHODS:
A.CASE SELECTION
• Cases 18 years and above will be selected from the patients who are
attending Medicine OPD or are admitted in Dept of
medicine/ophthalmology in our hospital as a case Diabetic retinopathy.
• Patients who are diagnosed as a case of Diabetes as per American
Diabetes Association, 2007 Guidelines.
• Patient should not be previously diagnosed as Vitamin D deficient and
should not be on treatment.
B. CONTROL SELECTION
• The control group comprised of age and sex matched normal healthy
volunteers.
6. C.INCLUSION CRITERIA
• Age 18 years onwards with Diabetic Retinopathy
D. EXCLUSION CRITERIA
• patients with type 1 diabetes
• vitamin D intake greater than 1000 IU/day
• disorders that change the metabolism of vitamin D
• Significant cardiac, hepatic, renal and cranial/extracranial oncologic
disease
• Use of medications known to affect serum phosphate levels including
phosphate-binding antacids, sodium etidronate, calcitonin, excessive
doses of vitamin D (> 1000 units per day), excessive doses of vitamin A (>
20,000 units/day), calcitriol, growth hormone, or anti-convulsants
• TSH < 0.1 or > 7 uU/mL
• Serum calcium < 8 or > 11 mg/dL, creatinine > 1.5 mg/dL
• WBC < 2,000 or > 15,000/cmm
• Platelet count < 100,000 or > 500,000/cum
• Hormone replacement therapy , steroids or testosterone use
7. METHOD
Present study is mainly centered on Diabetic patients.The detail
history and thorough clinical examination will be done in each patient
to assess disease severity and its complications micro-/macrovascular and others and giving main emphasis on Vitamin D level and
their proper and detailed ocular, fundoscopy and other appropriate
investigation. All of them will be divided into 4 groups:
• no diabetes or retinopathy
• type 2 diabetes but no retinopathy
• type 2 diabetes with nonproliferative diabetic retinopathy
• and type 2 diabetes with proliferative retinopathy
8. Vitamin D Deficiency epidemiology and Defciency in India
One study from North India18 reported requirement of 60,000-120,000
IU per month to achieve Vit D level > 30 ng/ml. This is the level at which
calcium absorption from the gut is maximum
Another study by Goswami et al have reported correction of Vit D level
to normal after 8 weeks of supplementation with weekly dose of 60,000
IU
Br J Nutr 2008;100:526-529
Because of the long half-life of 25-OH vitamin D, its level is used to
assess vitamin D deficiency
The active form of vitamin D, 1-25-OH vitamin D, will if renal function is
normal, almost always be in the normal range even when severe vitamin
D deficiency is present
Normal 25-OH vitamin D levels are between 42 and 65 ng/mL have
been documented
An abnormal 25-OH-vitamin D level is below 10 ng/mL
With aging the ability of skin to manufacture vitamin D declines, so that
by age 65 the capacity to produce vitamin D3 is reduced by 75%
JAPI • november 2011 • VOL. 59
10. Vitamin D Deficiency and its correlation with diabetic retinopathy-at a glance
1988, Pietschmann et al :Serum osteocalcin and 25 hydroxy vitamin D
levels were significantly decreased in Type 2 diabetic patients when
compared with corresponding control subjects.
Serum osteocalcin levels were significantly lower in Type 1 diabetic patients
with retinopathy and/or proteinuria than in Type 1 diabetic patients without
microangiopathy.
Serum parathyroid hormone levels in Type 2 diabetic patients with
retinopathy and/or proteinuria were significantly increased, 25 hydroxy
vitamin D levels were decreased when compared with Type 2 diabetic
patients without microangiopathy.
Diabetologia,Volume 31,no.12:892-895
October 1997, Koya et al :Hyperglycemia and diabetes may also affect
other signal transduction pathways besides DAG-PKC.
Progress has been made to identify some of these potential secondary
parameters of vascular pathologies, such as the levels of VEGF
Diabetes, Vol. 47, June 1998
11. 2000, Hu¨ Lya Aksoy et al :Inverse relationship between the severity of
the retinopathy and serum 1,25(OH)2D3 concentrations, being the lowest
in PDR and the highest in diabetic patients without retinopathy (NDR)
patients.
Difference in serum 1,25(OH)2D3 concentrations between patients with
retinopathy (especially with PDR groups) and control group, suggests that
neovascularization in the retina may involve a decrease in serum
1,25(OH)2D3 concentrations in patients with DR.
Clinical Biochemistry, Volume 33, February 2000
April 2000, Mantell et al :Highlighted the potential use of 1,25(OH)2D3 in
both the prevention and regression of conditions characterized by
pathological angiogenesis.
Shown that 1,25(OH)2D3 has no effect on the expression of VEGF receptor
genes by endothelial cells
Suggested that 1,25(OH)2D3 (or analogues of this hormone) may be of
use in the prevention of conditions involving pathological angiogenesis and
may also be of use in the therapeutic regression of such conditions
characterized by aberrant angiogenesis
American Heart Association,2000
12. August 2001, Isaia et al:Found no difference in 25(OH)D levels between type 1
diabetic patients and control subjects, whereas 25(OH)D levels were significantly
decreased in type 2 diabetic patients.
Diabetes Care, Volume 24, Number 8, August 2001
2001 and 2005, Taverna et al :The plasma concentration of 1,25 Di-hydroxyvitamin D3
has been inversely correlated with the severity of diabetic retinopathy (DR), which
raises the possibility that VD, through its anti-inflammatory , antioxidant,
antiproliferative , and antiangiogenic properties, may protect diabetic retina.
Calcium homeostasis and calcium-dependent signaling pathways have an important
role in the development of retinal hypoxia , a major process in severe DR.
Diabetologia(2002) 45:436-442
The Journal of Clinical Endocrinology & Metabolism 90(8):4803–4808
2004 Chiu et al:Showed in his study that a positive correlation of 25(OH)D
concentration with insulin sensitivity and a negative effect of hypovitaminosis D on cell
function.
Am J Clin Nutr 2004;79:820 –5
2005 Ford et al :An inverse association between serum concentrations of vitamin D
and the prevalence of the metabolic syndrome(including high blood pressure and
hyperglycemia)
Diabetes Care, Volume 28, Number 5, May 2005
13. March, 2006 Cigolini et al :Showed low 25-hydroxyvitamin D3 [25(OH)D]
concentrations may be inversely associated with type 2 diabetes , metabolic
syndrome , insulin resistance , and cardiovascular disease (CVD)
Diabetes Care, Volume 29, Number 3, March 2006
Albert et al in October 2006:Calcitriol-treated animals demonstrated a significant
decrease in retinal neovascularization compared with control animals.
•Effect was dose dependent, and retinal neovascularization was significantly
inhibited in calcitriol-treated mice.
•Ocular level of VEGF was similar in control and calcitriol treated animals
Investigative Ophthalmology & Visual Science, May 2007, Vol. 48, No. 5
2006 Suzuki et al :Microvascular complications and insulin treatment in type 2
diabetes patients are associated with the co-existence of hypovitaminosis D.
Subjects with proliferative diabetic retinopathy had lower serum 25-OHD
concentrations than those without retinopathy and those with simple diabetic
retinopathy
Endocrine Journal 2006, 53 (4), 503–510
14. Sugden et al,in October 2007 :Single large dose of oral vitamin D2 improves
endothelial function in patients with Type 2 diabetes and vitamin D insufficiency.
Low levels of 25- hydroxyvitamin D are associated with many markers of cardiovascular
disease; for example, hypertension , increased vascular resistance and increased left
ventricular mass index.
Journal Compilation Diabetes Uk.Diabetic Medicine,25,2008:320–325
2008 Penckofer et al :Evidence to indicate that it may help to reduce some of the
complications associated with diabetes (cardiovascular disease, renal insufficiency, and
peripheral neuropathies).
Vitamin D deficiency correlation with diabetic retinopathy was not the part of this
study.
Diabetes Educ. 2008 ; 34(6): 939-950
March 2010, Millen et al :Relationship between serum 25- hydroxyvitamin D
(25[OH]D) concentrations and the prevalence of early age-related macular
degeneration (AMD).
Arch Ophthalmol/Vol 129 (No. 4), Apr 2011
October 2010 Nguyen et al :Demonstrated that among patients with diabetes, those
with DR had a reduction in the skin microvascular responses to iontophoresis of both
SNP (endothelium independent response) and ACh (endothelium- dependent
response)
Diabetes Care:2011
15. Oct 2010 Joergensen et al :Associations between severe vitamin D
deficiency and increased risk of all-cause and cardiovascular mortality in
type 2 diabetic patients complement recent data from studies suggesting
similar associations in the general population and among patients with
nondiabetic CKD or ESRD
Diabetes Care, Volume 33, Number 10, October 2010
Jan 2011 Joergensen et al :Patients with type 1 diabetes, severe vitamin D
deficiency independently predicts all-cause mortality but not development
of microvascular complications in the eye and kidney.
Whether vitamin D substitution in type 1 diabetic patients can improve the
prognosis remains to be investigated
Diabetes Care, Volume 34, May 2011
April 2011, Millen et al:Association between vitamin D status, as reflected
by low serum concentrations of 25-hydroxyvitamin D (25[OH]D), and the
prevalence of early AMD was reported in a nationally representative, crosssectional study
Ophthalmol/Vol 129 (No. 4), Apr 2011
16. Kaur et al on Jan 2011 :In a mouse model of ischemic retinopathy, 1,25dihydroxyvitamin D3 [1,25(OH)2D3] inhibited retinal neovascularization.
The severity of diabetic retinopathy was inversely related to serum
1,25(OH)2D3 levels in adults with type 2 diabetes.
VDD is associated with an increased prevalence of retinopathy in young
people with type 1 diabetes. The inflammatory and angiogenic effects of
VDD may contribute to early retinal vascular damage.
Retinopathy was more common in young people with VDD compared with
their sufficient counterparts , but there were no between-group differences
for elevated AER/ACR, microalbuminuria, or peripheral nerve function
Diabetes Care, Volume 34, June 2011
2011, Devaraj et al:T1DM is associated with an increased risk of vascular
complications, and patients with T1DM with proteinuria and/or retinopathy
have a significantly increased risk of fatal coronary artery disease.
Am J Clin Pathol 2011;135:429-433
17. Sep 2011 Payne JF et al :Diabetic subjects, especially those with
proliferative diabetic retinopathy (PDR), have lower 25(OH)D levels than
those without diabetes
Subjects underwent dilated examination between December 2009 and
March 2010
It has been found that patients with diabetic retinopathy, especially the
proliferative type, are more likely to have insufficient serum vitamin D
levels than people without diabetes.
More than 75% of patients with diabetic retinopathy were deficient in
vitamin D.
An inverse relationship between the severity of the retinopathy, i.e.,
neovascularization, and serum 1,25(OH)2D3 concentrations, being the
lowest in PDR and the highest in diabetic patients without retinopathy
(NDR) patients
Abstract PO223. Presented October 17, 2010
18. Jan 2012 Yan C. Li et al:Studies consistently demonstrated an association of
low serum 25(OH)D levels with high blood pressure, increased prevalence of
cardiovascular disease and cardiovascular risk factors including
hypertension, diabetes, obesity and hyperlipidemia.
Monotreatment with paricalcitol or doxercalciferol or combination therapy
with these analogs and RAS inhibitors (losartan or enalapril) prevented
cardiac hypertrophy.
Curr Opin Nephrol Hypertens 2012, 21:72–79
Rangasamy et al in Jan 2012:Indicated ‘retinal inflammation’ as an
important player in the pathogenesis of diabetic retinopathy.
Elevated serum concentrations of IL-1beta, TNF-alpha, and VEGF, correlate
with the presence and severity of diabetic retinopathy
Middle East Afr J Ophthalmol. 2012 Jan-Mar; 19(1): 52–59
