Diabetes is a Vasculopathy: Not a lone Endocrinopathy.DR.SATCHI A.SURENDRANPOST GRADUATE , DEPT OF GENERAL MEDICINE, MGMCRI. 07.11.2016

‘’ 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

MICRO VASCULAR COMPLICATIONS

Diabetic retinopathy

Diabetic Nephropathy

Diabetic Neuropathy

MACRO VASCULAR COMPLICATIONS

Cardiovascular

Cerebovascular

Peripheal vascular disease

The Endocrine “Double Trouble” of Diabetic Vasculopathy

DIABETE

S

Hyperglycemia (Insulin

Deficiency)

Insulin Resistance

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.

Mechanisms of Underlying Impaired Endothelium derived VasodilatationDecreased production of EDRF

Increased inactivation of EDRF

Impaired EDRF diffusion to underlying smooth muscle cells

Decreased smooth muscle cell responsiveness to EDRF

Diabetes

Glucose Auto Oxidation

Polyol Pathway Activation

AntiOxidant Defense

Protein Kinase C Formation

Arachidonic acid metabolism

Advanced Glycation End Products

Oxidative Stress

ATHEROGENESIS

Illustration

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.

Hyperglycemia AGE

AGE+RAGE

Oxidative StressHyperglycemia

Overproduction of ROS (Reactive Oxygen Species)

DNA damage especially Mitochondrial DNA

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

Oxidative Stress (Contd.,) ROS Mediated cellualr injury may be a form of ‘Pathological Memory’ that persists even after glucose normalisation

Hyperglycemic Low Grade Inflammation Loss of Non-adhesive Property of Endothelial Cells

• Increases permeability to inflammatory monocytes• Early step in atherogenesis

Together with AGE/Oxidative Stress triggers

• endothelial cells themselves to produce superoxides

Increased expression of Matrix metallo proteinase

• Plaque rupture/arterial wall remodelling• Vascular smooth muscle cell proliferation / migration/ altered activity

Increased expression of Pro infalmmatory markers

• CRP/IL6/Fibrinogen/Plasminogen Activator Inhibitor – all elevated with the onset of DM

Hallmark Pathology of Diabetic MicroAngiopathy

Increased ECM Protein Synthesis

Capillary Basement Membrane Thickening

Happens even before overt Hyperglycemia

Predominant Sites

•Retina•Glomeruli•Myocardium•Cerebrum•Skin•Muscle

Resultant pathophysiology•Tissue Hypoxia•Hypertension•Delayed wound healing

NeoVascularisation of VasoVasorum

Hypoxia

Hypoxia Inducible Factor/ VEGF

Proliferation of VasoVasorum

Plaque Burden

Plaque Inflammation

Plaque Perfusion

Intra Plaque Hemorrhage

Diabetic Retinopathy - Statistics Statistics ( Prevalance of DR among self reported Diabetic Population in TamilNadu):

1. CURES (Chennai Urban rural Epidemic Study) (2005) – 17.6%

2.Sankara Nethralaya DR Epidemic& Molecular Genetic Study (2009) – 18% (Urban) ; 10% (RUral)

3. Aravind Comprehensive Eye Study – (2011) – 10.5%

US – leading cause of Blindness in 20-74 years of Age group

Duration of DM and degree of DM control are the best predictors of retinopathy

Diabetic Retinopathy –Non Proliferative

( Late in the 1 st decade/ early in the 2nd decade)◦ Micro aneurysms◦ Blot Hemorrhages◦ Cotton Wool Spots

Pathophysiology:◦ Loss of retinal pericytes / increased retinal vascular permeability/ abnormal retinal blood flow◦ All leading to retinal Ischemia.◦ New Concept: Inflammatory processes at the retinal neurovascular unit (neurons/glia/astrocytes)

Diabetic Retinopathy – Proliferative Stage

Not all NP – develop into Proliferative Stage ; Severe NP progesses in 5 years.

Hence Early detection of DR is important.

Pathophysiology:

Hallmark – Neovascularisation in response to Hypoxia

Vitreous Hemorrhage, Fibrosis, retinal Detachment

Diabetic Retinopathy – Macular Edema

Occurs in the context of Both Non Proliferative and Proliferative stages

Diagnosed by Fluorescein angiography & Optical Coherence tomography

25% chance of moderate visual loss over the next 3 years

Diabetic Retinopathy - Treatment

Primary:

Glycemic Control (Intensive) – delay the progression in both T1/T2 DM.

Comprehensive Eye Examinations - yearly

Secondary Prevention:

Proliferative Type – Pan Retinal Photocoagulation

Macular Edema - Focal laser Photocoagulation / Anti VEGF Therapy (ocular Injection)

Diabetic Nephropathy Statistics United Kingdom Prospective Diabetes Study (UKPDS) :

Involved > 5000 Type 2 Diabetic Patients followed up for more than 10 years

2% Increase in the Incidence of Microalbuminuria /Year

It progressed to 25% in 10 years post diagnosis.

Indian Studies:

CURES – 26.9% Micro Albuminuria / 2 % Overt DN prevalence

John et al. 1991 – Vellore – 19.7% Micro Albuminuria /8.9% DN

Mohan et al. 2000 – Chennai - Macroproteinuria with retinopathy 6%

Diabetic Nephropathy – Risk Factors

Independent and Modifiable risk factors:

1. Hyperglycemia

2. Hypertension

3. LDL/TG

Diabetes Control and Complications Trial (DCCT): (>1500 T1DM; Mean Follow up 6.5 Years)

1. Intensive Glycemic Control – 39% reduction in Micro Albuminuria/ 54% reduction in Clinical Nephropathy.

2. Reduction in Systolic BP by 10 mmHg – 13% reduction in Microvascular Complications

Treatment Options MicroAlbuminuria: Strict Glycemic Control; BP target of <140/90 mmHg Use of ACE Inhibitos/ARBs – to be titrated to maximum tolerated dose.

Concomitant use is detrimental. BP not controlled with above measures/ use of ARBs/ACE inhibitors not possible – CCBs, BetaBlockers can be used – to reduce intraglomeular pressure and inhibition of angiotensin driven sclerosing pathways

Treatment OptionsOvert Nephropathy:

In Macro Albuminuria, whether Improved glycemic control is useful is still unclear

Those diabetics with advanced renal disease requiring HD, are more prone to develop Hypotension (due to autonomic neuropathy)

Complications of Atherosclerosis is leading cause of death in this sub group, hence dyslipidiemia to be treated aggressively.

Combined Pancreas /renal transplant offers the promise of Normoglycemia/freedom from dialysis (T1DM).

Diabetic Neuropathy - PathologyChronic Hyperglycemia

induced Endothelial Dysfunction

Increased Endoneurial

Vascular resistance

Endoneurial Hypoxia

reduced Nerve Na+/K+ Activity

Impaired Axonal Transport

Diabetic NeuropathyBoth Myelinated/Demyelinated Fibres affected.Can be Sensory/ Motor (Mono/Poly neuropathy)/Cranial Nerves / AutonomicTreatment of primary risk factorsAvoidance of Neuro Toxins (Smoking/Alcohol)Symptomatic Treatment – Duloxetine/Pregabalain – FDA approved agents for D.NeuropathyAutonomic Neuropathy esp., Orthostatic Hypotension : Fludrocortisone, midodrine, clonidine, octreotide etc., have been tried with limited benefits.

SourceChawla A, Chawla R, Jaggi S. Microvascular or Macovascular 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 Internal Medicine

Emedicine.Medscape article

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