Diabetes is a vasculopathy [autosaved]

Diabetes is a vasculopathy [autosaved]

1. Diabetes is a Vasculopathy : Not a lone Endocrinopathy . Dr.Satchi a.surendran Post graduate , dept of general medicine, Mgmcri . 07.11.2016

2. ‘’ There are in truth, no specialities in medicine since to know fully many of the most important diseases, a man must be familiar with their manifestations in many organs’’ - William Osler Father of Modern Medicine

3. MIC r O VASCULAr complications Diabetic retinopathy Diabetic Nephropathy Diabetic Neu r opathy MACrO VASCULAr complications Cardiovascular Cerebovascula r Pe r ipheal vascular disease

4. The Endocrine “Double Trouble” of Diabetic Vasculopathy

5. Basic Concept: Endotheliopathy The most fundamental Pathogenetic aspect is the phenomena of Endothelial Dysfunction. Principle cause of Micro/Macro Vascular Complications. Main pathophysiology is concerned with EDRF – Endothelium Derived Relaxing Factors Nitric Oxide, Prostacyclin, Endothelium derived Hyperpolarising Factor Endothelium derived vasodilatation.

6. Mechanisms of Unde r lying Impai r ed Endothelium derived Vasodilatation Dec r eased production of EDRF Inc r eased inactivation of EDRF Impai r ed EDRF diffusion to unde r lying smooth muscle cells Dec r eased smooth muscle cell r esponsiveness to EDRF

7. ATHEROGENESIS

8. Illustration

9. Advanced Glycation End Products (AGE) Heterogenous Group of molecules formed by NonEnzymatic Glycation of plasma proteins, causing disruption in their normal functions by altering their molecular conformations/ altered enzyme activity/ interfering with receptor functioning.

10. Oxidative Stress Mitochondrial Superoxide has been identified as main culprit in many experimental models.

11. Oxidative Stress (Contd.,) ROS Mediated cellual r inju r y may be a fo r m of ‘Pathological Memo r y’ that persists even afte r glucose no r malisation

12. Hype r glycemic Low G r ade Inflammation

13. Hallmark Pathology of Diabetic MicroAngiopathy Increased ECM Protein Synthesis Capillary Basement Membrane Thickening Happens even before overt Hype r glycemia

14. NeoVascularisation of VasoVasorum

15. Diabetic Retinopathy - Statistics Statistics ( P r evalance of DR among self reported Diabetic Population in TamilNadu ): 1. CURES (Chennai Urban rural Epidemic Study) (2005) – 17.6% 2.Sanka r a Neth r alaya DR Epidemic& Molecula r Genetic Study (2009) – 18% (U r ban) ; 10% ( RUral ) 3. A r avind Comp r ehensive Eye Study – (2011) – 10.5% US – leading cause of Blindness in 20-74 yea r s of Age group Du r ation of DM and deg r ee of DM control a r e the best predicto r s of r etinopathy

16. Diabetic Retinopathy – Non Proliferative ( Late in the 1 st decade/ ea r ly in the 2 nd decade) Mic r o aneurysms Blot Hemor r hages Cotton Wool Spots Pathophysiology: Loss of r etinal pericytes / inc r eased r etinal vascular permeability/ abnormal r etinal blood flow All leading to r etinal Ischemia. New Concept: Inflammatory processes at the r etinal neurovascula r unit (neu r ons/glia/astrocytes)

17. Diabetic Retinopathy – Proliferative Stage Not all NP – develop into Proliferative Stage ; Seve r e NP p r ogesses in 5 years. Hence Ea r ly detection of DR is important. Pathophysiology: Hallma r k – Neovascularisation in r esponse to Hypoxia Vit r eous Hemor r hage, Fib r osis, r etinal Detachment

18. Diabetic Retinopathy – Macula r Edema Occu r s in the context of Both Non Prolife r ative and Proliferative stages Diagnosed by Fluorescein angiography & Optical Cohe r ence tomography 25% chance of mode r ate visual loss ove r the next 3 yea r s

19. Diabetic Retinopathy - T r eatment Primary: Glycemic Control (Intensive) – delay the prog r ession in both T1/T2 DM. Comprehensive Eye Examinations - yearly Seconda r y Prevention : Proliferative Type – Pan Retinal Photocoagulation Macula r Edema - Focal lase r Photocoagulation / Anti VEGF Therapy (ocular Injection)

20. Diabetic Neph r opathy Statistics United Kingdom P r ospective Diabetes Study (UKPDS) : Involved > 5000 Type 2 Diabetic Patients followed up fo r mo r e than 10 years 2% Inc r ease in the Incidence of Microalbuminu r ia /Yea r It prog r essed to 25% in 10 yea r s post diagnosis. Indian Studies: CURES – 26.9% Mic r o Albuminu r ia / 2 % Ove r t DN prevalence John et al. 1991 – Vellore – 19.7% Mic r o Albuminu r ia /8.9% DN Mohan et al. 2000 – Chennai - Macroproteinu r ia with r etinopathy 6%

21. Diabetic Nephropathy – Risk Facto r s Independent and Modifiable r isk factors: 1. Hype r glycemia 2. Hype r tension 3. LDL/TG Diabetes Cont r ol and Complications Trial (DCCT): (>1500 T1DM; Mean Follow up 6.5 Yea r s) 1. Intensive Glycemic Control – 39% r eduction in Mic r o Albuminu r ia/ 54% r eduction in Clinical Nephropathy. 2. Reduction in Systolic BP by 10 mmHg – 13% r eduction in Mic r ovascular Complications

22. T r eatment Options MicroAlbuminuria : Strict Glycemic Cont r ol; BP ta r get of <140/90 mmHg Use of ACE Inhibitos /ARBs – to be tit r ated to maximum tolerated dose. Concomitant use is detrimental. BP not cont r olled with above measu r es/ use of ARBs/ACE inhibito r s not possible – CCBs, BetaBlocke r s can be used – to r educe intraglomeula r pressu r e and inhibition of angiotensin d r iven scle r osing pathways

23. Treatment Options Ove r t Nephropathy: In Mac r o Albuminuria, whethe r Imp r oved glycemic control is useful is still unclea r Those diabetics with advanced r enal disease requi r ing HD, a r e mo r e p r one to develop Hypotension (due to autonomic neuropathy) Complications of Atheroscle r osis is leading cause of death in this sub g r oup, hence dyslipidiemia to be t r eated aggressively. Combined Pancreas / r enal t r ansplant offe r s the p r omise of Normoglycemia /f r eedom f r om dialysis (T1DM).

24. Diabetic Neuropathy - Pathology

25. Diabetic Neu r opathy Both Myelinated /Demyelinated Fib r es affected. Can be Senso r y/ Moto r (Mono/Poly neu r opathy)/C r anial Ne r ves / Autonomic T r eatment of p r imary r isk factors Avoidance of Neu r o Toxins (Smoking/Alcohol) Symptomatic Treatment – Duloxetine/ Pregabalain – FDA app r oved agents fo r D.Neuropathy Autonomic Neu r opathy esp., O r thostatic Hypotension : Fludrocortisone, midod r ine , clonidine, oct r eotide etc., have been t r ied with limited benefits.

26. Source Chawla A, Chawla R, Jaggi S. Microvascular o r Macovascula r Complications in diabetes mellitus: Distinct o continuum?. Indian Journal of Endocr Metab 2016; 20:546-551 Adopted as a chapter in API’s Medicine Update Textbook - 2016 Harrison’s Principles of Inte r nal Medicine Emedicine.Medscape article

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