STUDY OF VITAMIN D LEVELSIN DIABETICS

AND ITS CORRELATION WITH DIABETIC RETINOPATHY

PRESENTED BY

VINEET MISHRA

GUIDESChief guide:

Prof Sarita BajajMD DM (Endocrinology)DIRECTOR PROFESSOR

& HEADPG DEPARTMENT OF

MEDICINEM.L.N. MEDICAL

COLLEGEALLAHABAD

Co-guides:

DR KAMALJEET SINGH MS (OPHTHALMOLOGY)PROFESSORP.G. Department of OPHTHALMOLOGYM.L.N. Medical CollegeAllahabad DR MANOJ MATHUR MD(MEDICINE)P.G. Dept. of MEDICINEM.L.N. Medical CollegeAllahabad

DR RAKESH YADAV MD(MEDICINE)P.G. Dept. of MEDICINEM.L.N. Medical CollegeAllahabad

INTRODUCTIONDiabetes mellitus is a major medical problem prevalence of which is increasing and appears to be greater in developing countriesLonger a person has diabetes, the higher his or her chances of developing diabetic retinopathyStudies 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 retinopathyPrevalence of diabetic retinopathy was 18% in an urban population with diabetes mellitus in India

PATHOPHYSIOLOGY AND TYPESMechanism 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 NeovascularizationNonproliferative 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 quadrantProliferative 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

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.

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

METHODPresent 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-/macro-vascular 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

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 maximumAnother 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;100:526-529Because of the long half-life of 25-OH vitamin D, its level is used to assess vitamin D deficiencyThe 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 presentNormal 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/mLWith 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

REVIEW OF LITERATURE

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

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 cellsSuggested 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

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 –52005 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

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

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

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, cross-sectional study Ophthalmol/Vol 129 (No. 4), Apr 2011

Kaur et al on Jan 2011 :In a mouse model of ischemic retinopathy, 1,25-dihydroxyvitamin 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

Sep 2011 Payne JF et al :Diabetic subjects, especially those with proliferative diabetic retinopathy (PDR), have lower 25(OH)D levels than those without diabetesSubjects underwent dilated examination between December 2009 and March 2010It 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

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

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