Journal of Delhi Diabe c Forum

OFFICIAL PUBLICATION OF DELHI DIABETIC FORUM

Jul-Sep 2016

DDF Board of Management 2016‐2017

Dr. Anupam Prakash‐ President Dr. Pikee Saxena‐ Gen. Secretary Dr. Piyush Jain‐ Finance Secretary Dr. Ashok Kumar‐ Joint Secretary Members Dr. Rajiv Gupta, Past President Dr. S.P. Kalra, Past President Dr. Anil Kulshreshtha Dr. Sudesh Ratan Dr. Aruna Nigam Dr. P. Venkata Krishnan Dr. J.K. Sharma Dr. Gunjan Agarwal Mittal Dr. Aakriti Shukla Dr. Narendra Kumar Dr. Shikha Sharma Mr. Rajesh Sharma Ms. Somyaa Ms. Kanchan Khanka

President’s Pen / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

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From the President's pen Esteemed members of the Delhi Diabetic Forum, It is a great privilege to communicate with you all after assuming the post of President of Delhi Diabetic Forum, but I am deeply aware that it has brought with it great responsibilities. Like all organizations, as I always say, a time comes when the relatively younger people have to take charge and more importantly, they have to come up to expectations. The new Board of Management is a relatively younger lot, and it were to happen in the Silver Jubilee year of DDF is no chance. After completing a quarter of century, as the nation witnesses a change with a more active government, it is time to take charge in DDF also, and give this transition an impetus, which will make a mark. I thank the DDF members who turned up in unprecedented large numbers to elect the present Board of Management. I welcome the new D D F Board of Management members. However, there is a serious loss that DDF has incurred since the new Board of Management took over. Mr. DC Keswani, who was one of the most spirited and untiring DDF workers, and had been continuously with the Board of Management since its inception left for his heavenly abode. Loss of a family member is always cruel, but Mr. Keswani was not only a family member to the DDF, but he was a rock solid pillar who would work relentlessly for the DDF and contributed immensely in achieving its goals. I pray God to give courage to the bereaved family members and May his soul rest in peace. It is an irreparable loss to the DDF as well, and he would be sorely missed in the meetings and the DDF camps. On a personal front, I met him so many times at the gates of Bal Bharati Public School, where he used to come in the afternoon to pick up his grandson. He was always very affectionate and his work ethics and commitment to DDF, belied his age. He would himself volunteer for activities and any responsibility entrusted to him would be done efficiently. We are left with fond memories of Mr. Keswani at this juncture. Dr. Pikee Saxena, presently the General Secretary of DDF has been consistently working to improvise the activities of the D D F and works with great professionalism and perfection. She is ably supported by Dr. Ashok Kumar, Associate Professor of Medicine at Santosh Medical College, Ghaziabad and Dr. Piyush

Jain, Associate Professor of Medicine at PGIMER & Dr. RML Hospital, New Delhi. The Board of Management of DDF is honoured to have Dr. SP Kalra and Dr. Rajiv Gupta as its Members, though both have been Past‐ Presidents of DDF and have consistently worked for the success of DDF. Dr. Yash Pal Munjal, past‐President API and former Dean, ICP, and presently Director of the Physician's Research Foundation (API) along with Dr. Sachin K Jain, DM Endocrinology and presently Director Professor & Head of the Department of Medicine at Lady Hardinge Medical College; and Dr. Satish K. Agarwal, former Director Professor & Head of the Department of Medicine at Maulana Azad Medical College and presently Medical Advisor at Indraprastha Apollo Hospital, Delhi are the trinity to which the DDF Board of Management looks forward for guidance in the scientific activities of DDF in the coming years. We are in the 25th year of DDF and we are working on a Vision Document for DDF for the year 2025, so that we work cohesively to take DDF to greater heights in the next decade. We would be glad to receive constructive suggestions from the DDF members in this regard. A number of things are being revamped including the constitution. There is a shift from conducting diabetes screening camps to conducting Diabetes Awareness camps. A purely scientific journal is being started from this year itself (for the doctors). The articles for the patients and specially written in Hindi, would be ensured in every issue of the DDF newsletter (which shall go to all members). A number of communications are being returned back to the DDF office, and so please fill up the attached postcard and post it to the DDF Office. Research grants are also being started by the DDF to promote research in Diabetes. Like every year, the World Diabetes Day activities for 2016 are all lined up and mentioned in the General Secretary's column. With the Festival season ongoing, I on behalf of the DDF Board of Management wish all readers a very Happy Navrataras, Happy Dussehra and a joyous festival of lights. Enjoy the festivities, but do remember, enjoyment is in the mind and enjoy with the heart, not with your tongue. Restrict sweets and simple sugars, walk more, when you go to meet relatives so that you can burn some calories. Be healthy, remain healthy! Best wishes, Dr. Anupam Prakash Professor of Medicine, Lady Hardinge Medical College, New Delhi

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Secretary’s Desk / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

From the General Secretary's Desk Dear members of the DDF, Warm greetings to all of you and my heartfelt gratitude for giving me this opportunity to serve you as the General Secretary for another term. It is a great privilege to be the General Secretary of such an esteemed organisation that ceaselessly works for the people in the community. I am hopeful that with the support of the new and dynamic executive we will be able to take the Society to greater heights. India has 69.2 million people living with diabetes (8.7%) as per the 2015 data. Of these, it remained undiagnosed in more than 36 million people. This year theme of the World Health Day 2016 is “Diabetes”. We all need to join hands to increase awareness regarding diabetes, its prevention, early diagnosis and appropriate treatment to avoid complications. The theme of the World Diabetes Day 2016 is “Eye on Diabetes”. Screening for type 2 diabetes and its complications is necessary to reduce the morbidity burden associated with diabetes and to improve the overall quality of life in diabetes patients. Diabetes can lead to eye disease which can cause blindness if not detected early. Therefore, the theme depicts that we should keep an eye on diabetes, and simultaneously care about eyes in diabetes too, because complications of diabetes can involve the eye. Eye changes can be a reflection of the vascular system of the body. Therefore, we have included two articles pertaining to the 'Eye and Diabetes' in this issue. The bimonthly CME of DDF was organised on 27th August, 2016 at Hotel The Royal Plaza, New Delhi. It was a very well appreciated CME with a lot of interaction. On the occasion of Wold Diabetes Day, DDF plans to hold month long activities with the aim of sensitising the lay public about the disease, modifying the lifestyle to prevent the disease and initiate early treatment for preventing complications. DDF is organising a mega‐Diabetes camp that will be held at Gurudwara Sri Guru Singh Sabha, GK II, New Delhi on November 27 (Sunday), 2016 . An early morning Camp will be organised at Lodhi Garden on Nov. 13 (Sunday) to screen and create awareness among people coming for a walk to the Lodhi gardens.DDF shall be holding an educative programme for staff th working for the Delhi Metro on the 15 of November,

2016. Public forum will also be organised in the antenatal outpatient department of different hospitals to educate pregnant women and their relatives about healthy diet, exercise and prevention of diabetes. If the lady of the house decides to take control of the diet, eating habits of all members can be improved. We also propose to hold training and educative programmes for nursing personnel/students and general physicians. It has been observed that a huge number of DDF journals are being returned as the addresses of the members have not been updated. The new executive has decided to update the address of all members. We have decided to take out a “DDF Newsletter” for the DDF members to increase awareness about important issues related to diabetes. It will also contain Hindi articles which will provide useful and practical tips for the readers. The current issue of DDF Newsletter carries brief report of the Annual General Body Meeting and the list of the newly elected Board of Management which was attended by more than a 100 members this time. It has been decided that the DDF Journal will be circulated to the doctor members to update the medical professionals with the latest/recent advances to update their knowledge. For this all members are requested to send their Name, address, mobile number, e‐ mail and educational qualifications on the attached self addressed postcards by 31st October so that the journal and the Newsletter can reach the members without wastage of money paper and time. D D F is pleased to announce that 2 research scholarships worth Rs. 50,000 have also been introduced for encouraging research in the field of diabetes. You are requested to send your research proposals to the DDF office with details of your name, brief biodata along with details of publications, designation, affiliations by 31st December 2016 for consideration of these scholarships. I request the readers to provide their inputs for strengthening the forum and also provide their feedback about various activities that are being carried out by the DDF. With the festival season approaching, I wish the DDF members a Happy Vijayadashmi and a Prosperous and Shubh Deepawali. I wish you all an enjoyable and safe celebration. Dr. (Prof.) Pikee Saxena General Secretary, DDF

Diabetic Retinopathy : Essentials a physician must know / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016 Review Artical

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Diabetic Retinopathy : Essentials a physician must know Vinod Kumar MS DNB MNAMS FRCS (Glasg), Assistant Professor, Vitreoretina

Akshay Tayade MD Senior resident, Vitreoretina Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi

Introduction: Diabetic retinopathy (DR) is a micro‐ vasculopathy seen in the patients with Diabetes Mellitus (DM). Various studies report the prevalence of 1‐4 DR in Indian population with DM to be 12‐26.8 %. When considering the Indian scenario, the number of people affected by DM are expected to rise to 79.4 million by the year 2030 making India at the top position in terms of the diabetic population. Currently India hosts about 65.1 million patients of DM, highest in the world earning 5 the nickname "Diabetes capital of world" . The ICMR INDIAB study found that the prevalence of DM is between 10.4‐13.6% and the prevalence of DR among patients with DM is 18% in urban and 10.4% in rural th th population. This means every 5 and 10 person with 6 DM in urban and rural areas has DR respectively . Visual impairment due to DR accounts for 0.2% of blindness7. It th th has moved up from the 17 position to 6 position as a cause of blindness in India8. There are estimated 6 million DM patients with sight threatening retinopathy (proliferative diabetic retinopathy or diabetic macular edema), which is expected to increase to 10 million by 2035 if the current trend continues9. Clinical features: Diabetic retinopathy is classified as non‐proliferative diabetic retinopathy (NPDR) when there are intraretinal vascular changes without neovascularization and proliferative diabetic retinopathy (PDR) when it is associated with retinal neovascularization (due to ischemia). Clinically NPDR is characterized by microaneurysms (Figure 1), dot blot haemorrhages, flame shaped haemorrhages (Figure 2), hard and soft exudates (Figure 3) and intraretinal microvascular abnormalities ( I R M A ). P D R is characterised by neovascularization (Figure 4) at optic disc (NVD) and neovascularization elsewhere (NVE). These new vessels being fragile lead to recurrent vitreous haemorrhages, which are the most common cause of severe vision loss in patients with DR. Tractional retinal detachment ( T R D ), neovascularization of the iris (NVI) and neovascular glaucoma may eventually occur if DR is not treated10. The third component of DR is macular oedema, which could be seen at any stage of DR and is the most

common cause of moderate vision loss in patients with DR (Figure 5). Risk factors for DR: There are several factors that affect incidence and severity of DR. These are as below 

Duration of DM is the most important risk factor for DR and the prevalence of any type DR increases as the duration of DM increases. (21.1% vs. 76.3% for DM of duration less than 10 years and more than 20 years respectively).



Hyperglycaemia‐ Poor glycaemic control in the form of HbA1c levels is associated with higher risk of DR (18% vs. 51.2% with HbA1c levels of <7% and >9% respectively).



Hypertension‐ Higher blood pressure is associated with increased risk of DR (30.8% vs 39.6% with B P of <140/90 and >140/90 respectively).

• Dyslipidaemia‐ Higher levels of serum cholesterol are associated with increased risk of visually threatening DR and also of DME. • Type of DM‐ Type 1 diabetics have higher risk of DR compared to Type 2 diabetics (77.3% vs. 25.2%). Patients with type 1 DM after adjusting known risk factors are 2.7 times more prone for any type of DR, 5 times more likely to have DME and 15 times more prone to have PDR when 11 compared to type 2 diabetes . • Age at diagnosis‐ The Wisconsin epidemiologic study of diabetic retinopathy (WESDR) study noted that when the age at diagnosis of DM was ≥30 years then the severity of DR was related to younger age at diagnosis and when the age at diagnosis was less than 30 years and duration of diabetes ≤10 years then the risk and severity of the DR increases with increasing severity was related to the higher age examination12,13. • Diabetic Nephropathy‐ Diabetic nephropathy is associated with severe macular oedema and DR is more severe in patients with diabetic

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Diabetic Retinopathy : Essentials a physician must know / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

nephropathy and patients with advanced diabetic nephropathy have far more severe lesion of DR14. • Pregnancy‐ is associated with more rapid progression of diabetic retinopathy15. • Anaemia‐ Patients with anaemia are more prone to develop DR than those without anaemia16. • Ethnicity‐ Severe DR was found to be more frequent in Hispanics and African americans17. • Obesity‐ Increased risk of DR was associated with high BMI18, 19, but the study from South India noted that the high BMI has a protective role for any type diabetic retinopathy20. • Smoking‐ is a risk factor and detrimental for DR21

pregnancy should have an eye examination soon after conception or early in the first trimester. The follow up should be closer in patients with DM and pregnancy. However patients with gestational diabetes do not appear to be at increased for development of DR and 23 do not require an eye examination during pregnancy . Apart from regular screening, any diabetic patient with visual complaints would warrant an eye examination. Table 2 describes the recommended schedule of patients with various stages of DR. Ophthalmic examination should consist of: 1. Visual acuity examination 2. Intraocular pressure 3. Slit lamp examination 4. Gonioscopy 5. Dilated Fundus examination is must.

When and how to screen:

Ancillary tests:

Screening Guidelines (Table 1): According to American

1. Fundus fluorescein angiography (FFA) ‐ It is an invasive investigation to assess the status of the retinal vasculature. Sodium fluorescein dye is injected intravenously and then a series of fundus pictures are taken with the help of fundus camera (Figure 6). FFA can help to detect subtle changes of DR, differentiate NPDR from PDR and detect DME. It is a must at baseline before any treatment for DR is initiated and is also a useful tool for documentation for medico‐legal purposes. FFA is useful for diagnosis, management as well as follow‐up of patients with DR.

Table1. Screening of DR Type of diabetes Type 1 Type2 Type 1 or 2 with pregnancy

Initial examination

Follow up

After 5 years of diagnosis At the time of diagnosis Soon after conception and early in the first trimester

Yearly Yearly Every 3‐12 months if no retinopathy to mild or mod NPDR Every 1‐3 months if severe NPDR or worse

Table2. Follow up schedule No apparent retinopathy

Yearly

Mild NPDR

Yearly

Moderate NPDR

6 months

Severe NPDR

1‐3 months

DME

2‐4 months

preferred practice pattern, dilated fundus examination by an ophthalmologist is recommended for a patient of type1 DM after 5 years of initial diagnosis of DM and then yearly thereafter. For a patient of type 2 DM, dilated fundus examination by an ophthalmologist is recommended at the time of diagnosis and yearly thereafter. Patients with either type 1 or type 2 DM with

2. Optical Coherence Tomography (OCT) ‐ It is a non‐ invasive imaging modality which provides the real time cross sections of the retinal layers (Figure 7). It gives qualitative and quantitative assessment of macular oedema and is an indispensable tool for the management of all patients with DME. It is extremely useful in the follow‐up of patients with DME. Treatment: Good metabolic control is paramount in delaying the onset of DR and slowing the progression of already present D R. Good metabolic control includes appropriate control of hyperglycaemia, dyslipidaemia, hypertension, associated diabetic nephropathy and anaemia. Table 3 summarises the appropriate control of various systemic parameters. Discontinuation of smoking is encouraged. No treatment is usually required for NPDR itself except for the appropriate systemic control. The DME, especially if involving the centre of the fovea requires treatment, irrespective of the stage of DR. This could be

Diabetic Retinopathy : Essentials a physician must know / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

Table3. Recommended systemic parameters HbA1c*

<7%

Blood Pressure*

<140/90

LDL‐C*

<100 mg%

Triglycerides**

<1.7 mmol/L

HDL Cholesterol**

>1.1mmol/L

Total cholesterol**

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*24, **25 in the form of intra‐vitreal injections of anti‐VEGF drugs (Bevacizumab / Ranibizumab / Aflibercept), intra‐vitreal steroids injections (Triamcinolone Acetonide/Dexamethasone implant) or laser photocoagulation (focal/grid laser). Pan retinal photocoagulation (PRP) is the treatment of choice for the treatment of PDR. Surgery in the form of pars plana vitrectomy (PPV) is reserved for late complications like non‐resolving vitreous haemorrhage and retinal detachment. To summarise, diabetic retinopathy is rapidly emerging as a cause of blindness in India. The disease course is long term with a latent phase, making it possible for early detection with screening techniques. With the availability of timely treatment, it is possible to prevent the vision loss and blindness of DR. References : 1. Ramachandran A, Snehalatha C, Vijay V et al. Impact of poverty on the prevalence of diabetes and its complications in urban southern India. Diabet Med 2002;19:130 –5. 2. Dandona L, Dandona R, Naduvilath TJ, et al. Population based assessment of diabetic retinopathy in an urban population in southern India. Br J Ophthalmol 1999;83:937– 40. 3. Rajiv R, Rani P K, Sudhir R et al. Prevalence of Diabetic Retinopathy in India. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study Report 2. Ophthalmology 2009;116:311–318. 4. Narendran V, John RK, Raghuram A, et al. Diabetic retinopathy among self reported diabetics in southern India: a population based assessment. Br J Ophthalmol 2002;86:1014 – 8. 5. Sarah Wild, MB BCHIR, Global Prevalence of Diabetes. Diabetes Care 2004 ; 27: 1047‐1053. 6. Anjana RM, Pradeepa R, Deepa M, Mohan V et al ICMR–INDIAB Collaborative Study Group. Prevalence of diabetes and pre‐diabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I

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results of the Indian Council of Medical Research‐India Diabetes (ICMR‐INDIAB) study. Diabetologia. 2011; 54:3022‐ 7. Neena J, Rachel J, Praveen V, Murthy GVS, for the RAAB India Study Group. Rapid Assessment of Avoidable Blindness in India. Myer L, ed. PLoS ONE. 2008;3:e2867. 8. Vashist P, Singh S, Gupta N, Saxena R. Role of Early Screening for Diabetic Retinopathy in Patients with Diabetes Mellitus: An Overview. Indian Journal of Community Medicine : Official Publication of Indian Association of Preventive & Social Medicine. 2011;36:247‐252. 9. The Emerging Epidemic of Diabetic Retinopathy in India. Report of a Situation Analysis and Evaluation of Existing Programmes for Screening and Treatment for Diabetic Retinopathy. The Queen Elizabeth Diamond Jubilee Trust. Indian Institute of Public Health, 2014. 10. VISION 2020: The Right to Sight ‐ INDIA Programme, Guidelines for Diabetic Eye Care. 11. Joanne W.Y, Sophie L. R. Global Prevalence and Major Risk Factors of Diabetic Retinopathy. Diabetes Care 35:556–564, 2012. 12. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102:527–32. 13. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984;91:1464–74. 14. Nedal H. A, Barry I. F, Heritability of the Severity of Diabetic Retinopathy: The F I N D‐Eye Study, Invest Ophthalmol Vis Sci. 2008 September; 49: 3839–3845. 15. Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care.1990;13:34–40. 16. Rani P K, Rajiv R, Sudhir R R, Swakshyar S, Vaitheeswaran K, Praveena L, Uthra S, Govindasamy K, Tarun S. Anemia and Diabetic Retinopathy in Type 2 Diabetes Mellitus. JAPI, Feb 2010, Vol. 58. 17. Emanuele N, Sacks J, Klein R, Reda D, Anderson R, Duckworth W, et al. Veterans Affairs Diabetes Trial Group. Ethnicity, race, and baseline retinopathy correlates in the veterans affairs diabetes trial. Diabetes Care. 2005;28:1954–8. 18. Snježana Kaštelan, Martina Tomić, Antonela Gverović Antunica, Spomenka Ljubić, Jasminka Salopek Rabatić, and Mirela Karabatić, “Body Mass Index: A Risk Factor for Retinopathy in Type 2 Diabetic Patients,” Mediators of Inflammation, vol. 2013, Article ID 436329, 8 pages, 2013. doi:10.1155/2013/436329 19. Katušić, Damir, et al. "Obesity–a risk factor for diabetic retinopathy in type 2 diabetes?." Collegium antropologicum 29.1 (2005): 47‐50. 20. Rajiv R, Rani P K, Perumal G, Sudhir R R, Govindasamy K,

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Diabetic Retinopathy : Essentials a physician must know / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

Tarun S. Association of obesity with diabetic retinopathy: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN‐DREAMS Report no. 8) Acta Diabetol. DOI 10.1007/s00592‐009‐0113‐8.

22. American academy of ophthalmology Retina/ Vitreous panel. Preferred practice pattern guidelines. Diabetic retinopathy. San Francisco, CA: American academy of ophthalmology, 2016.

21. Hammes HP, Welp R, Kempe HP, Wagner C, Siegel E, et al. Risk Factors for Retinopathy and D M E in Type 2 Diabetes—Results from the German/Austrian DPV Database. (2015) Risk Factors for Retinopathy and DME in Type 2 Diabetes—Results from the German/Austrian DPV Database. PLoS ONE 10(7): e0132492.

23. Edward J. Shahady, Goals and guidelines for HbA1C, LDLC, and blood pressure in patients with diabetes: Sorting out the confusion. Consultant. 2016;56:582585.

Figure legends: Figure 1: Colour fundus photograph of left eye of a patient with diabetic retinopathy showing multiple microaneurysms (arrows). Figure 2: Colour fundus photograph of right eye of a patient with diabetic retinopathy showing dot blot (arrows) and flame shaped haemorrhages (arrowheads). Figure 3: Colour fundus photographs of diabetic retinopathy showing hard exudates (left) and soft exudates (right). Figure 4: Colour fundus photographs of diabetic retinopathy showing neovascularisation at the disc (left) and neovascularisation elsewhere (right). Figure 5: Colour fundus photograph of left eye of a patient with diabetic retinopathy showing diabetic macular edema. Figure 6: The left photograph depicts a normal fluorescein angiogram. The right picture is a fluorescein angiogram of diabetic retinopathy showing multiple small hyper‐fluorescent dots corresponding to microaneurysms. Figure 7: The picture at top shows an OCT scan of normal eye with normal (dipping) foveal contour. The OCT scan at the bottom is of a patient with diabetic macular oedema and shows loss of foveal contour, intraretinal hyper‐reflective echoes (corresponding to hard exudates) and hypo‐reflective spaces (retinal oedema).

24. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study.Lancet. 1999 Feb 20;353(9153):617‐22.

The Diabetic Eye: Beyond retinopathy / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016 Review Artical

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The Diabetic Eye: Beyond retinopathy Sagnik Sen MBBS, Junior Resident

Mukesh Patil MBBS, MD, Senior Resident

Rohit Saxena MBBD, MD, Ph D Additional Professor Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi‐110029

In 2000, India had the world's highest number of people living with diabetes mellitus (1) and has now become a very important cause of permanent vision loss. Though diabetic retinopathy resulting in visual loss is the most plausible reason , many other manifestations of diabetes can plague the patient unknowingly and may be a cause of chronic morbidity or vision loss too. Routine eye checkup should be carried out to detect any of the following conditions and treated if possible. Cataract Diabetes has been shown to be associated with increased risk of development of posterior subcapsular and cortical cataracts (Blue Mountains Eye Study, Beaver Dam Study) and that uncontrolled fasting blood sugar may also be associated with the same risk. The risk increases as the duration of the disease increases. Young type 1 diabetics with uncontrolled disease are also prone to a different type of cataract named as "snowflake cataract", which progresses rapidly and may actually be the presenting feature for diabetes (Figure 1).With metabolic control, the diabetic cataracts in young population can be reversible. Treatment of cataracts in modern day is via phacoemulsification. Diabetic cataracts progress rapidly and need to be operated early both in type 1 and 2 diabetics. Post surgical inflammation rates are higher in diabetics and vision gain may be poorer than healthy patients. Moreover, patients may have an underlying retinopathy affecting the vision. Risks of post cataract surgery endophthalmitis risk is also higher in this subgroup of patients and hence pre‐ operative antibiotic prophylaxis and post‐ operative antibiotic drop treatment becomes very crucial in them. Figure 1: Early snowflake cataract

• Glaucoma Glaucoma is a multifactorial condition affecting the eye under the control of multiple risk factors. The relation between glaucoma and diabetes have been elusive with several studies proving and refuting evidence for such an association. • Open angle glaucoma Patients will be mostly asymptomatic. Microvascular changes in diabetes may affect the posterior ciliary circulation thereby damaging the optic nerve head(2) (Figure 2). Alternately, the optic nerve of individuals with diabetes are also said to be more sensitive to early compression with prolonged intraocular pressure elevation. At the end stages there will be extreme constriction of central vision and only a tubular vision remains. Patients with diabetes are more likely to be under closer ophthalmic observation and patients under closer observation are more likely to have glaucoma detected. Figure 2: Optic nerve cupping in open angle glaucoma • Closed angle glaucoma This condition is caused by an intumescent cataract with a shallow anterior chamber. Other reason may be an autonomic dysfunction (3). • Neovascular glaucoma Proliferative diabetic retinopathy which has been undiagnosed in a patient may come to notice with development of neovascular glaucoma with new vessels on iris (Figure 3) and the anterior chamber angle, causing raised intraocular pressure. Retinal laser will cause this condition to regress slowly. Figure 3: Neovascularization of iris

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The Diabetic Eye: Beyond retinopathy / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

Neurodegenerative diseases research has come up with a novel concept of glaucoma being "diabetes of the brain." There are striking similarities in genetic, biochemical, and molecular changes in both the diseases (4).

differentials such as intracranial aneurysms or space occupying lesions. Spontaneous recovery is expected to be within 6 weeks to three months of the attack. During this time, patients are advised patching of the

Meibomian gland dysfunction MGD MGD is an inflammatory condition of the ocular surface which involves dry eye disease and poor quality and consistency of the meibomian gland secretions (Figure 4). There was a significant increase in the frequency of MGD in diabetics as compared to the non‐ diabetics.Depending on the severity of the condition, it needs to be treated adequately with frequent lubricant drops and ointments, antibiotics along with lid hygiene and cleaning with soap/ shampoo. Figure 4: Obstructed meibomian gland openings in MGD and associated dry eye Anterior ischemic optic neuropathy Both non‐arteritic anterior and posterior ischemic neuropathies have a higher prevalence in diabetics. These conditions are acute vascular conditions of the optic nerve presenting as hyperemic disk initially (Figure 5) which later on will lead to disk pallor. AION occurs in optic disks with small cups, also called "disk at risk" (5). 25% of patients with A I O N have a history of diabetes (6).There are currently no proven treatments for AION, however several neuroprotective antioxidant treatments are being tried in animal models. Figure 5: Optic disc in an "Non‐arteritic AION" patient Extraocular muscle movement disorders Eye movements are controlled by the 3rd, 4th and 6th cranial nerves. Diabetic neuropathy can affect any one or a combination of these nerves and affect the control of eye movements, causing double vision. Diabetes is the underlying cause in 25–30% of patients aged 45 years and older who develop acute extraocular muscle palsy(7).Third nerve palsy in diabetics is characteristically pupil sparing as the fine vessels supplying the external part of the nerve is only affected and this is a distinguishing factor from other

normal eye to avoid unacceptable diplopia and face turn, and also for strict control of metabolism. Figure 6: Right 6th nerve palsy Diabetic papillopathy Diabetic papillopathy, a masquerader of AION, is another manifestation of ocular diabetes. It is a self‐ limiting, bilateral disease that may affect both type 1 and type 2 diabetics. Signs involve optic disc swelling and mild vision loss, occasionally accompanied by intra‐ retinal hemorrhages and hard exudates. This condition spontaneously improves and the prognosis is generally good. Recent studies are showing positive results after local injections of corticosteroids as well as Bevacizumab (Avastin) (8) Primary optic atrophy Studies have reported optic nerve involvement in diabetes due to toxic metabolic changes in patients with chronic uncontrolled diabetes. Toxic amblyopia may be due to increased sensitivity of the nerve to inflammatory changes. All such optic atrophies seen in diabetics are a form of chronic retrobulbar neuritis. Diabetes mellitus patients with a Diabetes insipidus component and presenting with bilateral asymmetric primary optic atrophy are said to have what is now called the Wolfram syndrome (DIDMOAD). Retinal artery occlusion (RAO) RAO presents as an acute onset painless unilateral vision loss with a visual field defect. Retina may show pallid fundus with a cherry red spot on the macula. Prevalence of diabetes in RAO has been reported to be 21% (9). In the acute phase, several modalities of treatment like digital massage, carbogen inhalation, intravenous acetazolamide, etc have been tried. Prognosis is generally quite poor. Retinal vein occlusion (RVO) Vein occlusion in the retina may occur in the central vein or the branch veins leading to retinal edema, hemorrhages, exudates, ischemia and finally neovascularization of retina and the anterior chamber angle. Patient presents with sudden onset painless vision loss which may be unilateral or bilateral.

The Diabetic Eye: Beyond retinopathy / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

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Although diabetes has been thought to be a risk factor for RVO, conflicting data is present in literature (10) (11). RVO can occur concurrently in a patient having retinopathy and the signs like exudates and hemorrhages can mimic retinopathy changes. Hence when any diabetic retinopathy patient complains of acute onset asymmetric vision loss, RVO should always be under suspicion. RVO can be treated according to the stage of the disease with laser photocoagulation and/or Bevacizumab (Avastin) injections for macular edema and surgery for vitreous hemorrhage.

6 Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol 114:1366–1374, 1996

Figure 7: Retinal pallor due to CRAO

7 Rush JA: Extraocular muscle palsies in diabetes mellitus. Int Ophthalmol Clin 24:155–159, 1984 Giuliari GP

Therefore there are numerous conditions besides diabetic retinopathy that are required to be evaluated in a patient with diabetes and regular screening for these is essential for early detection and to prevent irreversible visual loss.

8 1, Sadaka A, Chang PY, Cortez RT. Diabetic papillopathy: current and new treatment options. Curr Diabetes Rev. 2011 May;7(3):171‐5.

Figure 8: Tomato splashed appearance in CRVO

References 1

Australas Med J. 2014; 7(1): 45–48

2 Grunwald JE, et al: Retinal autoregulation in open‐angle glaucoma. Ophthalmology. 91:1690–1694, 1984 3 Mapstone R, Clark CV: The prevalence of autonomic neuropathy in glaucoma. Trans Ophthalmol Soc UK 104:265–109, 1985 4 –Glaucoma Diabetes of the brain: A radical hypothesis about its nature and pathogenesis [i.e., the mechanisms that cause it] May 2014 Medical Hypotheses. 5 Sohan Singh Hayreh. Management of ischemic optic neuropathies. Indian J Ophthalmol. 2011 Mar‐Apr; 59(2): 123–136.

9 Recchia FM, Brown GC: Systemic disorders associated with retinal vascular occlusion. Curr Opin Ophthalmol 11:462–467, 2000 10 Shahsuvaryan ML, Melkonyan AK: Central retinal vein occlusion risk profile: a case‐control study. Eur J Ophthalmol 13:445–452, 2003 11 The Eye Disease Case‐Control Study Group: Risk factors for central retinal vein occlusion. Arch Ophthalmol 114:

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Dermatological Manifestations of Diabetes Mellitus / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016 Review Artical

Dermatological Manifestations of Diabetes Mellitus Dr. Taru Garg Professor, Dept. of Dermatology, LHMC & SSKH Dr. Soumya Agarwal Senior Reasdent, Dept. of Dermatology, LHMC & SSKH

ABSTRACT Skin is commonly involved in diabetes, with approximately 30% of patients experiencing some dermatological problem during the disease course. Skin manifestations generally appear during the course of the disease in patients known to have diabetes, but may be the first presenting sign of diabetes or even precede the diagnosis. Dermatological disorders can result from vascular damage (leg ulcers, diabetic dermopathy), neurological damage (diabetic foot), formation of advanced glycation end products (cheiroarthropathy, scleredema), and infections like erythrasma, necrotizing fasciitis, and mucormycosis. Pharmacologic treatment of diabetes, in addition, can also result in skin changes, such as lipodystrophy at the site of injection of insulin, and oral antidiabetic agents can cause multiple allergic skin reactions as adverse effects. The management of these skin disorders is modified depending upon the underlying etiopathogenesis, but a strict control of blood sugar is a prerequisite in all treatment approaches. REVIEW ARTICLE The health burden of diabetes mellitus(DM) is fast increasing to a potential epidemic level, with more than 62 million diabetic individuals currently diagnosed with the disease. [1] Four types of DM are recognised: a) Type I DM(insulin dependent; usually juvenile onset, and prone to ketoacidosis); b) Type 2 DM (non‐insulin dependent; usually adult onset, and associated with obesity; c) Secondary diabetes (iatrogenic or associated with pancreatic, hormonal and genetic disease); and d) Gestational diabetes (associated with pregnancy). A considerable number of specific and non‐specific cutaneous disorders accompany DM. [2,3] These can be classified on pathophysiological basis as described in Table 1. VASCULAR DAMAGE Hyperglycaemia leads to nonenzymatic glycosylation of various proteins, including collagen which results in the formation of advanced glycation end products (AGE), which are believed to play a pivotal role in vascular damage. A cascade of metabolic events leads

Vascular damage

1. Leg ulceration 2. Diabetic dermopathy 3. Erysipelas‐like erythema 4. Rubeosis 5. Wet gangrene of the foot

Neurology damage

1. Diabetic foot 2. Diabetic foot ulcer 1. Bacterial Impetigo Folliculitis Furuncle Erysipelas Cellulitis Necrotizing Fasciitis Maliganant ititis externa 2. Fungal Candidiasis Dermatophytosis Rhinocerebral mucormycosis

Infections

Obesity & Hyperlipidaemia related skin disorders

1. Acanthosis nigricans 2. Skin tags 3. Eruptive xanthoma of skin

Granulomatous disorders

1. Necrobiosis lipoidica diabeticorum 2. Granuloma annulare

Stiff skin & joints

1. Cheirothropathy 2. Finger pebbles 3. Sceleredema diabeticorum

Pruitus Diabetic bullae Treatment related skin disorders

1. Insulin lipodystrophy 2. Allergic reactions to insullin 3. Allergis reactions to oral hypoglycaemic drugs

Disease associations

1. Reactive perforating collagenosis 2. Autoimmune diseases Vitiligo Dermatitis herptiformis pertibial myxedema 3. Genetic disease Werner syndrome Lipoid proteinosis Autoimmune polyendocrine disease 1. Psoriasis 2. Yellow skin & nails (carotenemia) 3. Calciphylaxis 4. Nephrogenic fibrosing dermopathy

Others

Table 1. Classification of skin disorders linked to DM to endothelial proliferation, thickening of basement membrane with deposits of periodic acid–Schiff stain (PAS) positive material, and narrowing of arterioles, capillaries and venules [4]. Microangiopathy is responsible for the retinopathy, nephropathy, neuropathy and diabetic dermopathy. 1. Diabetic dermopathy (shin spots, pigmented pretibial papules) It is considered as the most common cutaneous manifestation of DM, affecting 7‐70% of all diabetics [5,6]. It presents as asymptomatic, oval, dull‐red papules around 0.5–1 cm in diameter covered with a superficial scale, which evolve slowly on the shins, forearms, thighs and over bony prominences. It heals

Dermatological Manifestations of Diabetes Mellitus / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

leaving behind atrophic brown scars. Histologically, there is hyperpigmentation of epidermal basal layer, thickened vessels in the papillary dermis, mild perivascular lymphohistiocytic infiltrate, and dermal deposition of hemosiderin and melanin. 2. Leg ulceration Foot ulcerations account for significant morbidity and mortality in diabetic population. It is caused by vascular and/or neurological damage. There is both structural and functional impairment of cutaneous blood flow due to vascular damage and autonomic neuropathy respectively [7]. Elevated tissue glucose levels further complicates situation by impairing healing [8]. The development of ulcer starts with callus formation that is followed by necrosis and breakdown of tissue over bony prominences of feet on great toe and sole, usually over first and second metatarsophalangeal joints. Daily foot care is of utmost importance to prevent leg ulcerations (Table 2) Table 2. Foot care guidelines for diabetic patients Daily self‐examination of feet, especially areas between toes Regular washing and proper drying of feet, especially areas between toes Water temperature should be less than 37 degree C, and should be checked with hand Avoidance of walking barefoot and wearing shoes without socks Nails should be cut straight across Daily inspection and palpation of inside of the shoes for any irregular surfaces or foreign objects Emollients should be used for dry skin but not for areas between toes Corns and calluses should be cut by health care provider, and not patient Regular check‐ups with health care provider Early health care should be seeked for any cut, scratch, sore, boil, ingrown toenail, or dermatitis 3. Wet gangrene of the foot Wet necrotic area results from sudden loss of perfusion to the already compromised cutaneous microcirculation (e.g. due tolocal infection or heart failure).It requires intravenous antibacterials and surgical debridement, and vascular reconstruction. [9] 4. Erysipelas‐like erythema It manifests as well‐defined erythema on the legs and feet of elderly diabetic patients. The onset of Charcot

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arthropathy may be preceded by similarchanges on the feet. 5. Rubeosis Diabetic rubeosis is characterised by a peculiar rosy reddening of the face, or hands and feet, which occurs due to microangiopathy or decreased vascular tone. A prevalence of less than 10% has been suggested by recent surveys [10]. NEUROLOGICAL DAMAGE Nearly 50% of those with diabetes develop a chronic, sy m m et r i ca l , l e n gt h ‐ d e p e n d e nt s e n s o r i m o to r polyneuropathy [11],possibly due to damaged endoneurial microvessels. It leads to autonomic dysfunction (impaired sweating of legs) andneuropathic pain (numbness,tingling, aching and burning of the legs, more at night). 1. Diabetic foot Diabetic charcot arthropathy [12] classically presents as a warm,swollen and erythematous foot and ankle. The foot is deformed with distally displaced plantar fat pads, depressed metatarsalheads, hammer toes and pes cavus. 2. Diabetic foot ulcer The lifetime risk for a diabetic patient of eveloping a footulcer is around 15% [13]. The ulcer is painless, circular and punched out in shape, slowly penetrating, and occurs in the middle of a callosity. Surrounding skin may be discoloured due to an initial subepidermal haemorrhagic bulla. Local treatment includes debridement, treatment of infection, and dressings. Multidisciplinar y management is required to assess the need for revascularization, offloading pressure by proper footwear,crutches and occasionally surgery. INFECTIONS Population‐based studies have demonstrated an increased risk of skin and soft tissue bacterial and fungal infections in diabetic patients [14,15]. Candidal infection of the mucous membranes, nail folds, flexures, and balanitis, are more common predominantly in poorly controlled diabetes [16]. OBESITY AND HYPERLIPIDAEMIA RELATED SKIN DISORDERS 1. Acanthosis nigricans It is seen most commonly in obese type 2 diabetic patients. It presents as smooth, velvety, hyperkeratotic and hyperpigmented skin predominantly affecting the flexures. Stimulation of insulin‐like growth factor 1 receptor present on fibroblasts and keratinocytes leads to hyperkeratosis of skin.

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Dermatological Manifestations of Diabetes Mellitus / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

2. Skin tags Skin tags or acrochordons are small, soft, pedunculated lesions occurring on the eyelids,neck and axillae, often associated with obesity and acanthosis nigricans. These appear to be a marker for d i a b ete s , i n d e p e n d e nt o f obesity and acanthosis nigricans[17,18]. 3. Eruptive xanthomas of the skin Eruptive xanthomas manifest as sudden appearance of crops of small, discrete, yellow and erythematous papules over the buttocks, elbows, and knees. Multiple xanthomas may coalesce to form tuberous xanthomas. Histology reveals accumulation of foamy, lipid‐laden histiocytes with a mixed lymphocytic and neutrophilic infiltrate in the dermis. The lesions slowly resolve with adequate management of diabetes and hyperlipidaemia. GRANULOMATOUS DISORDERS 1. Necrobiosis lipoidica diabeticorum (NLD) NLD is one of the most widely recognized diabetic skin disorder. It is uncommon in the diabetic population as a whole (0.3–1.2%), although it may be seen in 2–3% of type 1 diabetes [19].NLD starts as erythematous and irregular, single or multiple coalescing plaques with an elevated border over bilateral pretibial or medial malleolar areas, which later become brownish yellow, telangiectatic, porcelain‐like, and depressed. The lesions may ulcerate but heal spontaneously to leave behind atrophic scars. Histologically, the dermis shows degenerated collagen surrounded by a horizontal palisade of histiocytes with minimal mucin and interspersed lymphocytes, plasma cells, and foreign body giant cells. 2. Granuloma annulare Granuloma annulare may or may not be associated with diabetes [3], although there is conflicting literature.Disseminated form of granuloma annulare is characterised by flesh‐colored or erythematous papules, which progress to form annular rings. Histology shows focal degeneration of collagen in the dermis, palisaded histiocytes around collagen bundles, and abundant dermal mucin. STIFF SKIN AND JOINTS Skin thickening and stiff joints are attributed to irreversible cross‐linking of collagen and other proteins in the skin and accretion of AG Es such as carboxymethyllysine and pentosidane [3].

Physiotherapy, aspirin, and glycaemic control provide some relief to the patients. 1. Cheiroarthropathy This is characterized by waxy tight skin on the back of the hands and limited joint mobility ('prayer sign'). It is a manifestation of underlying microvascular change [20],neuropathy, and retinopathy. 2. Finger pebbles This occurs more commonly in diabetics. These are grouped,multiple, tiny papules on the extensor surface of the fingers near the knuckle‐pads or periungual region. 3. Scleredema diabeticorum It is uncertain whether scleredema associated with diabetes is a separate form of condition 21]. scleredema diabeticorum is characterized by ill‐defined induration of the skin of neck and upper back, which is essentially permanent, painless and usually causes little morbidity. PRURITUS A recent study has reported an increased prevalence of truncal pruritus in DM as compared to healthy controls (11.3% versus 2.9%) due to associated autonomic neuropathy [22]. Generalised pruritus could be due to chronic renal insufficiency (high blood urea levels) or neuropathy (caused by irritation of nerve endings). Secondaryinfection with candidiasis or haemolytic streptococci may cause anogenital pruritus. DIABETIC BULLAE These are non‐scarring subepidermal bullae on a non‐ inflamed base which may affect lower legs, feet, and occasionally hands and fingers [23]. Although uncommon, they are believed to be a distinct marker for diabetes. TREATMENT RELATED SKIN CONDITIONS 1. Insulin lipodystrophy Lipohypertrophy was seen in almost two‐thirds of the patients in few studies [24]. It is more common in patients who do not rotate the site of injection of insulin thereby can lead to impaired insulin absorption. Lipoatrophy appears to be an immunological reaction [25], and is much less common with synthetic insulins. However, even newer synthetic insulins and analogues have potential to cause atrophy and hypertrophy 2. Allergic reactions to insulin Localized allergic reactions to insulin and analogues include: urticaria, painful nodules and granulomas [26]. The use of an insulin pump may benefit, but contact dermatitis to acrylates, epoxy resin, glue components and nickel needles have been reported [27].

Dermatological Manifestations of Diabetes Mellitus / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

3. Allergic reactions to oral hypoglycaemic drugs Sulphonylureas are the most common offending agents, particularly causing a disulfiram‐like reaction to chlorpropamide. Photosensitivity,pruritus, erythema nodosum,urticaria, lichenoid eruptions, morbilliform eruptions and erythema multiforme have been repotred [2,28]. CONCLUSION Dermatological manifestations of diabetes are quite common and should be addressed aggressively. The skin and diabetes may be interrelated by association (eg, necrobiosis lipoidica), infection, diabetic complication (eg, neuropathic ulcer), or treatment related adverse event. Tight glycaemic control in diabetic patients can definitively prevent and minimize most of the infectious skin diseases, however its role in preventing non infectious skin disorders is still disputed. REFERENCES 1. Kumar A, Goel MK, Jain RB, Khanna P, Chaudhary V. India towards diabetes control: Key issues. Australas Med J. 2013;6: 524‐31. 2. Huntley AC . The cutaneous manifestations of diabetes. J Am Acad Dermatol1982;7: 427‐55 3. Cox N H . Diabetes and the skin: an update for dermatologists. Expert Rev Dermatol2007;2: 305‐16 4. Ajam Z, Barton SP, Marks R. Characterization of abnormalities in the cutaneous microvasculature of diabetic subjects. Br J Dermatol 1982; 107 (Suppl. 22): 22‐3. 5. S i b b a l d R G , L a n d o l t S J , To t h D . S k i n a n d diabetes.Endocrinol Metab Clin North Am 1996;25: 463‐72. 6. Shemer A, Bergman R, Linn S, et al. Diabetic dermopathyand internal complications in diabetes mellitus. Int J Dermatol 1998;37: 113‐ 5. 7. Chao CYL, Cheing GLY. Microvascular dysfunction in diabetic foot disease and ulceration. Diabetes Metab Res Rev 2009;24: 604‐14. 8. Christman AL, Selvin E, Margolis DJ, et al. Hemoglobin A1c predicts healing rate in diabetic wounds. J Invest Dermatol 2011;131: 2121‐7. 9. Edmonds M. Diabetic foot ulcers: practical treatment recommendations. Drugs 2006; 66: 913–29. 10. Morgan AJ, Schwartz RA. Diabetic dermopathy: a subtle sign with grave implications. J Am Acad Dermatol 2008;58: 447‐51. 11. Tesfaye S, Boulton AJM, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33(10): 2285‐93.

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12. Wukich DK, Sung W. Charcot arthropathy of the foot and ankle: modern concepts and management review. J Diabetes Complicat 2009;23(6): 409–26. 13. Reiber GE. The epidemiology of diabetic foot problems. Diabetic Med 1996;13(Suppl. 1):S6–11. 14. Ray GT, Suaya JA, Baxter R. Incidence, microbiology, and patient characteristics of skin and soft‐tissue infections in a US population: a retrospective population‐based study. BMC Infect Dis 2013;13(1):252. 15. Muller LM, Gorter KJ, Hak E, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis 2005;41(3):281–8. 16. Belazi M, Velegraki A, Fleva A, et al. Candidal overgrowth in diabetic patients: potential predisposing factors. Mycoses 2005;48(3):192–6. 17. Sari R, Akman A, Alpsoy E, Balci MK. The metabolic profile in patients with skin tags. ClinExp Med 2010;10(3):193‐7. 18. Rasi A, Soltani‐Arabshahi R, Shahbazi N. Skin tag as a cutaneous marker for impaired carbohydrate metabolism: a case‐control study. Int J Dermatol2007;46(11):1155–9. 19. Pavlovic MD, Milenkovic T, Dinic M, et al. The prevalence of cutaneous manifestations in young patients with type 1 diabetes. Diabetes Care 2007;30(8):1964–7. 20. Rosenbloom AL, Silverstein JM, Lezotte DC, et al. Limited joint mobility in childhood diabetes mellitus indicates increased risk of microvascular disease. N Engl J Med 1981;305:191–4. 21. Venencie PY, Powell FC, Su WP, Perry HO. Scleroedema: a review of 33 cases. J Am Acad Dermatol 1984; 11:128–34. 22. Yamaoka H, Sasaki H, Yamasaki H, et al. Truncal pruritus of unknown origin may be a symptom of diabetic polyneuropathy. Diabetes Care 2010;33:150–5. 23. Basarab T, Munn SE, McGrath J, Jones RR. Bullosisdiabeticum. A case report and literature review. ClinExp Dermatol 1995;20:218–20. 24. Blanco M, Hernández MT, Strauss KW, Amaya M. Prevalence and risk factors of lipohypertrophy in insulin‐injecting patients with diabetes. Diabetes Metab 2013;39(5):445–53. Cross Ref link Pubmed link 25. Holstein A, Stege H, Kovacs P. Lipoatrophy associated with the use of insulin analogues: a new case associated with the use of insulin glargine and review of the literature. Expert Opin Drug Saf 2010;9:225–31. 26. Radermecker RP, Scheen AJ. Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues. Diabetes Metab Res Rev2007;23:348–55. 27. Saccabusi S, Boatto G, Asproni B, Pau A. Sensitization to methyl methacrylate in the plastic catheter of an insulin pump infusion set. Contact Dermatitis 2001;45(1):47–8. 28. Litt JZ. Litt's Drug Eruptions and Reactions Manual, 19th edn. Boca Raton, FL: CRC Press.

14 Medical Nutrition therapy in management of diabetes in pregnancy /Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016 Review Artical

Medical Nutrition therapy in management of diabetes in pregnancy Archana Mishra1, Akanksha Mangala2, Pragati Dwivedi3, Pikee Saxena4 1 Assistant Professor, Department of Obstetrics and Gynaecolgy, V.M.M.C. & Safdarjung Hospital ,New Delhi 2 Senior Resident, Department of Obstetrics and Gynaecolgy, V.M.M.C. & Safdarjung Hospital ,New Delhi 3 Assistant Professor, Department of Obstetrics and Gynaecolgy, RIMSNR , Saifai, Etawa, UP 4 Professor, Department of Obstetrics and Gynaecolgy, L.H.M.C.& S.S.K. Hospital ,New Delhi

Direct correlation between diet and diabetes is a well known fact. Management of diabetes in pregnancy needs multipronged approach which includes diet , exercise, insulin or hypoglycaemic agents, self monitoring of blood glucose levels and education. Aim of this approach is to ensure enough nutrition for normal development of foetus and overall health for mother. According to ADA Nutrition Practice guidelines for GDM 2007 Medical nutrition therapy aims at “Carbohydrate controlled meal plan, which promoters adequate nutrition, appropriate weight gain, normoglycemia and absence of ketosis”[1]. Practical goals for medical nutrition therapy are : ‐ Blood glucose levels in the normal range or close to normal. ‐ Normalised lipid and lipoprotein profile to reduce the cardiovascular complications. ‐ Blood pressure in normal range. ‐ Reasonable body weight. ‐ Promotion of overall health and delay in chronic disease. Role of Dietician: Registered Dietician is the key person for success in medical nutrition therapy. Dietician has to team up with physician and gynaecologist providing care to the pregnant women. Pregnant women suffering with diabetes need to be educated about the disease and self care. Medical nutrition therapy [M N T] and Diabetes self management Training [ DSMT] should be carried out simultaneously. DSMT is provided by physician, gynaecologist, trained nurse and physiotherapist. MNT should be provided by registered Dietician. Nutritional therapy for every pregnant diabetic woman needs to be individualised. It needs a motivated & committed patient and one to one sessions with dietician. The counselling needs to involve not only the patient but also the spouse and family. It ensures compliance and family support in implementing diet plan. Patient should be independent enough for self management of her diet. Dietician needs to assess the medical history, psycho ‐social status of patient and present nutrition status to decide the goals before planning a meal

pattern. Counselling is liable to change according to cultural and financial background of the pregnant woman. Importance of timely meals and balanced diet should be emphasized to the patient and family. Sessions of MNT follow a step wise approach Nutritional Referral Nutritional Assessment Nutritional diagnosis Nutritional intervention Monitoring and evaluation Documentation Assessment of outcome & revision of diagnosis and intervention if needed. Weight gain in pregnancy: Recommendation of weight gain in pregnancy for a normal BMI women [ BMI 19.8 ‐ 26 ] is 11.4‐15.9 kg. An overweight women [BMI 26.1‐29] should gain from 6.8‐11.4 kg and weight gain for an obese women [ BMI >29] should be less than 6.8 kg. Till now recommendations regarding weight gain are not clear about diabetic women. Infant birth weight is affected by prepregnancy maternal weight along with weight gain in pregnancy. Medical Nutrition Therapy: Care givers should avoid use of confusing terms like “avoid concentrated sweets” or “use liberal diabetic diet”. Advice needs to be objective, practical and sustainable. Daily total intake of carbohydrate needs to be consistent, although its distribution throughout the meals may vary. Glycemic index of different foods need to be educated to patient but it should be emphasized that mixed diet has different escalation in blood glucose levels. Due to myths, diabetic women avoid many healthy foods too. Fruits and vegetables containing sucrose should not be restricted. Fructose too has low and delayed post prandial response. Alcohols are never sugar free and not recommended for pregnant women at all. Four sugar substitutes are safe and approved by FDA. These are aspartame, saccharin, acesulfame K and sucralose. Sample diet should contain 50‐60% of carbohydrate, 15‐20% of proteins and 20‐30% of fat [2]. Proteins should be from both vegetarian and animal sources. Vegetarian sources are less nephrotoxic. Monounsaturated fat should be increased to 20 %. Polyunsaturated fat should be less than 10% of total calorie intake. Cholesterol should be less than 300 mg /day. Fibre intake should be 20 to 35 gm a day.

Medical Nutrition therapy in management of diabetes in pregnancy / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

Management of Type 1 Diabetes Mellitus: In pregnant women of Type 1 Diabetes Mellitus, constant and consistent energy is required for growth of foetus and demands of pregnancy. Diet and insulin both are required to control blood sugars. Key to success lies in equal distribution of carbohydrate throughout the meals for insulin activity. Consistent daily intake of carbohydrate is important for proper control of blood sugar. Insulin regimen can be fixed and specific amount of carbohydrate intake could be modulated according to insulin. Other regimen is the flexible regimen in which insulin is administered according to carbohydrate content of diet.1 unit of insulin can be increased for every 10‐15 gm increase in carbohydrate. Patient is advised to eat carbohydrate if blood glucose is less than 100mg/dl. Dietician must analyse the eating pattern of person's usual food intake and physician needs to integrate insulin therapy with usual food intake. Patient needs to be educated in self monitoring of blood glucose and modulating insulin dose accordingly. If patient is exercising then additional food is needed to meet the demands of activity. Exercise to be avoided if blood glucose levels are more than 250mg/dl in presence of urinary ketone. If blood sugars are more than 300mg/dl in absence of ketones then also exercise should be abandoned . Carbohydrates need to be consumed before, during and after exercise to prevent hypoglycaemia. Snacks are advisable in between the meals. Management of Type 2 Diabetes Mellitus: In pregnant women with gestational diabetes or pre existing Type 2 diabetes management goals are different. Dietician needs to concentrate on reduction of energy intake and moderation of weight gain. In type 2 diabetes it is possible to control blood sugars on diet only. Consistency in daily intake is essential to control weight gain. Equal distribution of carbohydrates throughout the meals is desirable but not essential. Low fat diet is advisable. Timing of meals is not as strict as in type 1

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diabetes. Snacks are not advisable. Exercise is recommended but additional food for exercise is advisable only if woman is on insulin or oral hypoglycaemic drugs. Rest of the dietary advice is similar to patients of Type 1 diabetes Mellitus. Evidence in favour of MNT: Several RCT's have been performed on effectiveness of MNT. If applied appropriately, benefits of MNT are apparent after 3‐6 months. MNT is found to be effective in decreasing HbA1C by 1% in type 1 diabetes mellitus and by 1‐2% in type 2 diabetes mellitus [3,4]. MNT not only decreases blood sugars but also helps in treating hypertension and hyperlipidemia in both diabetic and non diabetic subjects [5]. Conclusion: Medical Nutrition therapy is most fundamental in management of all aspects of prevention of diabetes and its complications in pregnancy. It helps in prevention and delaying development of Diabetes in women with gestational diabetes. It manages the pregnancy with overt diabetes and prevent its complications in pregnancy and postpartum.Obstetricians should understand the importance of MNT and should refer the patient to a Registered Dietician. References: (1) ADA Nutrition Practice Guideline for GDM 2007. (2) Yates et al, Jour Am Diet Assoc. 1998:98:699‐706. (3) Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K: The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care 25:608–613, 2002 (4) Pastors JG, Franz MJ, Warshaw H, Daly A, Arnold MS: How effective is medical nutrition therapy in diabetes care? J Am Diet Assoc 103:827–831, 2003 (5) Yu‐Poth S, Zhao G, Etherton T, Naglak M, Jonnalagadda S, Kris‐Etherton PM: Effects of the National Cholesterol Education Program's Step I and Step II dietary intervention programs on cardiovascular disease risk factors: a metaanalysis. Am J Clin Nutr 69:632– 646, 1999

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Dulaglutide Pens / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016 Drug Corner

Dulaglutide Pens Vikrant Anjna1, Dr. Anupam Prakash2, Dr. S.K Gupta3 1. Research scholar, Deptt. Of clinical research, Delhi Institute of Pharmaceutical Sciences and Research, Pushp Vihar, New Delhi‐110 017 2. Professor of Medicine, Lady Hardinge Medical College, New Delhi‐110 001 3. Head of Department, Clinical Research, Delhi Institute of Pharmaceutical Sciences and Research, Pushp Vihar, New Delhi‐110 017

Mechanism of action Dulaglutide is one of the latest anti‐diabetes drug that has been launched in India.It is an innovative once a week non‐insulin injectable medication.Dulaglutide is a long‐acting glucagon‐like peptide 1 (GLP‐1) receptor agonist. It exhibits several antihyperglycaemic actions of G L P‐1. In the presence of elevated glucose concentrations, dulaglutide increases intracellular cyclic AMP (cAMP) in pancreatic beta cells leading to insulin release. Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. Dulaglutide also slows gastric emptying. Dulaglutide improves glycaemic control through the sustained effects of lowering fasting, pre‐meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval. Pharmacokinetic properties: Absorption: Following subcutaneous administration to patients with type 2 diabetes, dulaglutide reaches peak plasma concentrations in 48 hours. The mean peak (Cmax) and total (AUC) exposures were approximately 114 ng/ml and 14,000 ngh/ml, respectively. The mean absolute bioavailability of dulaglutide following single‐ dose subcutaneous administration of single 1.5 mg and 0.75 mg doses was 47 % and 65%, respectively. Distribution: The mean volume of distribution after subcutaneous administration of dulaglutide 0.75 mg and 1.5 mg at steady state in patients with T2DM is approximately 19.2 L and 17.4 L. Biotransformation: Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways. Elimination: The mean apparent clearance of dulaglutide 0.75 mg and 1.5 mg at steady state was 0.111 L/h and 0.107 L/h with an elimination half‐life of 4.5 and 4.7 days, respectively.

Preparations available: 0.75mg / 1.5mg solution for injection. Therapeutic indications: It is indicated in adults with type 2 diabetes mellitus to improve glycaemic control as: Monotherapy: When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications. The recommended dose is 0.75 mg once weekly. Add‐on therapy: In combination with other glucose‐ lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. Method of administration: Dulaglutide is to be injected subcutaneously in the abdomen, thigh or upper arm. It should not be administered intravenously or intramuscularly. The dose can be administered at any time of day, with or without meals. If a dose is missed, it should be administered as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If less than 3 days (72 hours) remain before the next scheduled dose, the missed dose should be skipped and

Dulaglutide Pens / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

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the next dose should be administered on the regularly scheduled day.

Common: Hypoglycaemia (when used as monotherapy or in combination with metformin + pioglitazone)

Special warnings and precautions for use:

Gastrointestinal disorder: Very common: Nausea, diarrhoea, vomiting, abdominal pain.

Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Use of GLP‐1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when treating patients with impaired renal function since these events, i.e. nausea, vomiting, and/or diarrhoea , may cause dehydration which could cause a deterioration of renal function. Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients. Acute pancreatitis: Use of GLP‐1 receptor agonists has been associated with a risk of developing acute pancreatitis. In clinical trials, acute pancreatitis has been reported in association with dulaglutide. Hypoglycaemia: Patients receiving dulaglutide in combination with sulphonylurea or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea or insulin. It should not to be used during pregnancy and lactation. Dulaglutide has no or negligible influence on the ability to drive or use machines. When it is used in combination with a sulphonylurea or prandial insulin, patients should be advised to take precautions to avoid hypoglycaemia while diving and using machines. Frequency of adverse effects: The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies and are listed as MedDRA preferred term by system organ class and in order of decreasing incidence (very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000).The frequency of adverse reactions of dulaglutide: Metabolic and nutritional disorder: Very common: Hypogycaemia(when used in combination with prandial insulin, metformin or metformin + glimepride)

Common: Decreased appetite, dyspepsia, constipation, flatulence, gastroesophageal reflux disease. Rare:Acute pancreatitis General disorders and administration site conditions: Common: Fatigue. Uncommon: injection site reactions. Shelf life and storage: Shelf life is 2 years. Store in a refrigerator (2 °C – 8 °C).Do not freeze. Store in original package in order to protect from light. In use: Dulaglutide may be stored unrefrigerated for up to 14 days at a temperature not above 30 °C. Tr a d e n a m e a n d M a n u f a c t u r e r : T h e d r u g ismanufactured by Eli lilly under the trade nametrulicity. Price of each pen: Rs 2499 Recent studies conducted are showing promising results. Umpierrez G, Tofe Povedano S, Perez Manghi F, et al conducted a study to access the efficacy and safety of dulaglutide 1.5mg or 0.75mg versus metformin on glycemic control in adults with type 2 diabetes in a 52‐ week , randomized, open label study. At the 26‐week primary endpoint, mean HbA1C reductions were dulaglutide1.5mg: 0.8%; dulaglutide0.75mg: 0.7%; metformin: 0.6%. NauckM, Weinstock RS, Umpierrez GE, et al conducted a study to access the efficacy and safety of dulaglutide 1.5mg or 0.75mg versus sitagliptin on glycemic control in adults with type 2 diabetes in a 104‐week, placebo‐ controlled, randomized, double‐blind study. At the 52‐ week primary endpoint, mean HbA1C reductions were dulaglutide1.5mg: 1.1%; dulaglutide0.75mg: 0.9%; sitagliptin: 0.4%. Conclusion: Dulaglutide has been studied as monotherapy or in combination with metformin, glimepride, pioglitazone, and insulin lispro. It has demonstrated superior reductions in HbA1C, fasting glucose levels and body weight from baseline compared with placebo, metformin, insulin glargine, sitagliptin, and twice daily exenatide. Dulaglutide

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Ongoing Research Selected Abstracts / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

Ongoing Research : Selected Abstracts Effect of Vildagliptin Versus Sulfonylurea in Muslim Patients with Type 2 Diabetes Fasting During Ramadan in Egypt: Results from VIRTUE Study. Khattab M, Mahmoud K, Shaltout I. DiabetesTher. 2016 Aug 22. [Epub ahead of print] Abstract INTRODUCTION: Fasting in patients with type 2 diabetes mellitus (T2DM) is associated with high risk of hypoglycemia. The aim of this study was to compare the effectiveness and safety of vildagliptin in T2DM patients fasting during Ramadan in a real‐life setting in Egypt. METHODS: In this 16‐week prospective and noninterventional study, data were collected up to 6 weeks before and after Ramadan fasting. Patients who had received vildagliptin or sulfonylurea (SU) either as dual therapy with metformin or as monotherapy were enrolled into the study. RESULTS: Two hundred fifty four patients were enrolled in the study, out of which 246 [121 (97.6%) treated with vildagliptin and 125 (99.2%) with SU] were included in the safety analysis set. A significantly lower proportion of patients experienced ≥1 hypoglycemic event (HE) with vildagliptin as compared to those receiving SUs (1.7% vs. 19.2%, respectively; p < 0.001). No patient in either group reported a grade 2 HE. At week 16, mean change in HbA1c from baseline for vildagliptin and SU were ‐0.1% and +0.3%, respectively, with a between‐ treatment difference of ‐0.4% (p < 0.001). Mean change in body weight from baseline for vildagliptin and SU were ‐0.8 and ‐0.1 kg, with a between‐treatment difference of ‐0.7 kg (p = 0.011). A higher proportion of SU‐treated patients experienced adverse events compared to those treated with vildagliptin (23.2% vs. 5.8%, respectively), the primary reason being the high incidence of hypoglycemia in the SU group (n = 24, 19.2%). CONCLUSIONS: Treatment with vildagliptin was associated with lower incidence of hypoglycemia compared with SU and showed good glycemic and weight control in patients with T2DM fasting during Ramadan in a real‐life setting in Egypt.

Why not to use the handgrip test in the assessment of cardiovascular autonomic neuropathy among patients with diabetes mellitus? Körei AE, Kempler M, Istenes I, Vági OE, Putz Z, Horváth VJ, Keresztes K, Lengyel C, Tabák ÁG, Spallone V, Kempler P. Curr Vasc Pharmacol. 2016 Aug 22. [Epub ahead of print] Abstract OBJECTIVE: Historically, a set of 5 cardiovascular autonomic reflex tests (CARTs) was considered to be the gold standard in the assessment of cardiovascular autonomic neuropathy (CAN). However, measuring diastolic blood pressure (BP) response to sustained handgrip is omitted in recent guidelines. We aimed to assess the association between the handgrip and the other 4 tests as well as to identify determinants of the handgrip test results in diabetic patients. PATIENTS AND METHODS: 353 patients with diabetes (DM) were recruited (age: 60.2±7.4 years; female: 57.2%; BMI: 29.3±2.1 kg/m2; DM duration: 15.6±9.9 years; HbA1c: 7.8±1.4% (66 mmol/mol); with type 1 DM: 18.1%). CAN was assessed by 5 CARTs: the deep breathing test, Valsalva ratio, 30/15 ratio, handgrip and orthostatic hypotension test. RESULTS: Sensitivity and specificity of the handgrip test in the diagnosis of definite CAN were 24.6% (95%CI 17.7‐33.1%) and 79.4% (95%CI 73.3‐84.4%), respectively. Results of the handgrip test did not show any association with those of the deep‐breathing test (γ=0.004, p=0.563), 30/15 ratio (γ=0.282, p=0.357), Valsalva ratio (γ=‐0.058, p=0.436) and orthostatic hypotension (γ=‐0.026, p=0.833). Handgrip test abnormality showed an independent association with higher initial diastolic BP (OR 1.05, p=0.0009) and an independent inverse association with the presence of hypertension (OR=0.42, p=0.006). CONCLUSIONS: Our data confirm that the handgrip test should no longer be part of the cardiovascular autonomic testing being highly dependent on hypertensive status and baseline diastolic BP. Exaggerated exercise pressor response is proposed as putative mechanism for the inverse association between abnormal results of the

Ongoing Research Selected Abstracts / Journal of Delhi Diabetic Forum Vol. 24 (3):July‐Sep. 2016

handgrip test and hypertension. Adequate CARTs important to allow their use in clinical trials and for the prevention of DM‐associated complications by initiating early treatment.

Wine consumption and prevention of coronary artery disease. 1

2

3

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Flesch M , Morbach S , Erdmann E , Bulut D . Herz. 2016 Aug 19. [Epub ahead of print] Abstract There is a J‐shaped correlation between the amount of alcohol consumed per day and overall mortality risk and an inverse correlation between the amount of alcohol consumed per day and cardiovascular mortality. The evidence is stronger for men than for women. The correlations are independent of the type of alcoholic beverage predominantly consumed. Possible mechanisms explaining the cardioprotective, antiatherosclerotic effects of moderate alcohol consumption are inhibition of platelet aggregation, increase in serum high density lipoprotein (HDL) levels and prevention of diabetes mellitus. The two latter mechanisms can also explain a delayed progression of atherosclerosis due to alcohol consumption. The beneficial effects are counteracted by detrimental effects of alcohol on the incidence of cancer diseases, liver cirrhosis, violence and accidents; therefore, alcohol consumption in general cannot be recommended for prevention of cardiovascular diseases. Metabolic Surgery for Diabetes Treatment: Sleeve Gastrectomy or Gastric Bypass? Lee WJ, Chong K, Aung L, Chen SC, Ser KH, Lee YC. World J Surg. 2016 Aug 22. [Epub ahead of print] Abstract BACKGROUND: Bariatric surgery has gained reputation for its metabolic effect and is increasingly being performed to treat type

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2 diabetes mellitus (T2DM). However, there is still a gray area regarding the choice of surgical procedure according to patient characteristics due to inadequate evidences, so far. We aim to compare the efficacy of two most commonly performed bariatric/metabolic surgeries, sleeve gastrectomy (SG) and gastric bypass (GB) with regard to remission of T2DM after surgery. METHODS: Outcomes of 579 (349 female and 230 male) patients who had undergone SG (109) or GB (470) for the treatment of T2DM with 1‐year follow‐up were assessed. The remission of T2DM after SG or GB surgery was evaluated in matched groups using the ABCD scoring system. The ABCD score is composed of the age, BMI, C‐peptide levels and duration of T2DM (years). RESULTS: The weight loss of the SG patient at 1 year after surgery was similar to the GB patients [26.3 (1.1) vs. 32.6 (1.2) %; p = 0.258]. The mean BMI decreased from 35.7 (7.2) to 2 28.3 (3.7) Kg/m in SG patients at 1 year after surgery and decreased from 36.9 (7.2) to 26.7 (4.5) Kg/m2in the GB patients. The mean HbA1c decreased from 8.8 to 6.1 % of the SG group and from 8.6 to 5.9 % of the GB group. Sixty‐one (56.0 %) patients of the SG group and 300 (63.8 %) of the GB group achieved complete remission of T2DM (HbA1c < 6.0 %) at 1 year after surgery without statistical difference. However, G B exhibited significantly better glycemic control than the SG surgery in groups stratified by different ABCD score. At 5 year after surgery, GB had a better remission of T2DM than SG (53.1 vs. 35.3 %; p = 0.055). CONCLUSIONS: In conclusion, although both SG and GB are effective metabolic surgery, GB carries a higher power on T2DM remission than SG. ABCD score is useful in T2DM patient classification and selection for different procedures

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DELHI DIABETIC FORUM 25th Annual Conference on Diabetes

DIABCON 2017 April 22 & 23, 2017 Hotel Le Meriden, Windsor Place, New Delhi‐110001 Theme ‐ Diabetes New Horizon, Widening prespactives

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