Pathogenesis - Chronic Complications of Diabetes

Non-E nzymatic Glycosylation Activation of Protein Kinase C (PKC) Intracellular Hyperglycaemia with

Disturbance of Polyol Pathway

Process where Glucose Attach to Proteins (chemically)

without aid of Enzyme

Intracellular Hyperglycaemia ↓

Stimulates de novo synthesis for Diacylglycerol (DAG)

from glycolytic intermediates

(DAG = 2nd

messenger in signal transduction) ↓

Activate Protein Kinase C ↙ ↓ ↘

Produce

Plasminogen

Inhibitor

Produce

Vascular

Endothelial GF

Produce Pro-

Fibrogenic

Molecules (Transforming GF) ↓ ↓

↓ Fibrinolysis Neo-

vascularization

↓

↓ ↑ Deposition

Of ECM &

BM Material

Vascular

Occlusions

(Abnormal Vesse ls)

↓

Diabetic

Retinopathy

Does not require Insulin for Glucose Transport

Nerves, Lens, Kidneys, Blood Vessels

Degree of Glycosylation

Directly related to Blood Glucose Level

During Hyperglycaemia → ↑ Intracellular Glucose

Many cells contain Aldose Reductase

Excess Sorbitol Cannot Exit Cell, Coverted to Fructose

Glucose + Hb chain = Glycated HbA (HbA1c)

In Diabetics, ↑ HbA1c

HbA1c Reflects average level of glucose over 120 days

Checking Blood Sugar in Pre-Diabetic

Monitor Blood Sugar Control in Diabetic Patients

Irreversible Advanced Glycosylation End Pr oducts

(AGEs)

• Glycosylation of Collagen, Long-lived Proteins in

Blood Vessels, Interstitial Tissues

• Accumulate in Blood Vessels and cause

Microvascular, Macrovascular Lesions

Accumulation of Sorbitol (Polyol), Fructose ↓

↑ Intracellular Osmolality, H2O Influx ↓

Cell Injury

Endothelial cells

Lens (Cataract)

Nerve (↓ Nerve Conduction)

AGEs bind to ECM proteins

on Basement Membrane (BM ) ↓

Accumulation of AGEs ↓

Trap Non-Glycosylated

Plasma Protein, Interstitial Protein ↙ ↘

Trapping of LDL at

Vessel Wall accelerates

Atherogenesis

Trapping Albumin at

BM of capillaries cause

Thickening of BM

(Diabetic

Glomerulopathy)

Continuous Aldose Reductase Pathway ↓

Diminished NADPH ↓

↓ Formation of Reduced Glutathione (GSH) ↓

Cells prone to Oxidative Stress

Circulating Plasma Protein ↓

Binds to AGE Receptors on

Endothelial Cells, Mesangial Cells, Macrophages ↓

Effects of AGE Receptor Signalling

Release Cytokines, GF

↑ Endothelial Permeability

Induce Procoagulant Activity

Enhance ECM Synthesis

Chronic Complications

Macrovascular Microvascular

Stroke Diabetic Retinopathy

IHD Diabetic Nephropathy

Peripheral Vascular Disease Diabetic Neuropathy

Macrovascular Complication

Cardiovascular Cerebrovascular Peripheral Vascular

Angina Coma Gangrene

MI Stroke

IHD

HPT

Pathophysiol ogy (Macrovascular Complication)

Hyperglycaemia ↓

Nonenzymatic Glycosylation of Collagen, Proteins in

Interstitial Tissue, Blood Vessel Wall ↓

Formation of Irreversible Advanced Glycosylation End Products

(AGEs) ↓

Cause Cross Link between Polypeptides ↓

Trap Plasma, Interstitial Proteins including LDL ↓

Promote deposition of Cholesterol in blood vessel intima ↓

Accelerate Atherogenesis ↓

Form Atherosclerotic Plaque ↓

Atherosclerosis

Insulin Deficiency/ Insulin Resistance ↓

Impaired Glucose Uptake, Utilization ↓

↑ Lipolysis ↓

↑ Circulating Glucose

↑ Free Fatty Acid

↓ HDL ↓

Atherosclerosis

Atherosclerosis

↓

Coronary Artery Lower Extremities Brain Vessel

Vessel

↓

Compromise d Blood Supply ↙ ↓ ↘

Myocardial Infarction Coagulative Necrosis Stroke

Infections

↓

Wet Gangrene

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Microvascular Complication

Diabetic Microangiopathy

Diabetic Neuropathy

Diabetic Retinopathy

Diabetic Neuropathy

Diabetic Ulcer

Diabetic Microangiopathy

Diffuse Thickening of Capillary Basement Membrane (BM)

Diabetic Capillaries are ↑ Leaky to Plasma Proteins (compared to Normal)

Thickening is Most Evident in Capillaries of

Vascular Structures Non-Vascular Structures

Skin Renal Tubules

Skeletal Muscle Bowman Capsule

Retina Peripheral Nerve

Renal Glomerulus Placenta

Renal Medulla

Underlies the development of Diabetic

Nephropathy, Retinopathy, Neuropathy (some form)

Diabetic Nephropat hy

Kidney – Prime Targets of Diabetes

Renal Failure 2nd

after MI (main cause of death in Diabetics)

Glomerular Lesions

Capillary BM

Thickening

Diffuse Mesangial

Sclerosis Nodular Glomerulosclerosis

BM Thickened

throughout

entire length

Diffuse ↑ in Mesangial

Matrix along with

Mesangial Cell

Proliferation

Kimmelstiel-Wilson Lesion

Glomerular Sclerosis involving

development of nodular lesion in

glomerular capillaries

↓

Impaired Blood Flow with

Progressive Loss of

Kidney Function

↓

Renal Failure

Thickening BM

Manifest Nephrotic

Syndrome (proteinuria,

hypoalbuminaemia,

edema)

Chronic Hyperglycaemia ↓

Non-Enzymatic Glycosylation of

Terminal Amino Group ↓

AGEs ↓

Affect Structure, Function of Capillaries

(Vasodilation) ↓

↑ in Sheer Forces

Glomeruli Damage

↓

↑ Mesangialhypertrophy ↓

↑ Secretion of

Mesangialextracellular Matrix

↑ Collagen Production

↓

Thickening of Glomerular BM

↓

Glomerulosclerosis ↓

Capillaries ↑ Leaky to Plasma Proteins

↓

Proteinuria ↓

Peripheral Edema, Hypoalbuminemia ↓

Hypertension

Pathognomonic for Diabetic Pt.

Nodular Glomerulosclerosis in

Diabetic Nephropathy

(Kimmelstiel-Wilson Lesion)

Renal Vascular Lesion

Principally

Atherosclerosis

Arteriolosclerosis

DM

↓

Plasma Proteins penetrate into

abnormally permeable wall of arterioles

↓

Plasma Proteins trapped ↓

Vessel Hypertrophy, Hyalinization ↓

Thickening of wall of arterioles

↓

Narrowing of lumen ↓

Ischaemic Damage to Kidney

↓

Renal Failure

Part of Macrovascular disease

Changes same throughout body

Arteries

Arterioles

Morphology

Arteriolar lesions with hypertrophy,

hyalinization of vessels

Hyaline arteriolosclerosis

(affe ct Afferent, Efferent Arteriole)

Pyelonephritis

Acute, Chronic Inflammation of Kidneys

Usually begin in Interstitial Tissue (then spread to affect Tubules)

Pathophysiol ogy

Autonomic Neuropathy → Bladder Stasis → VUR → Infection

Untreated Infection

Renal Papillary Necrosis

Diabetic Retinopathy

Retinal changes – Long term Diabetes

Cause Visual Impairment, Total Blindness

Pathogenesis

↑ Glucose in Non-Insulin Dependent Cels

(Nerves, Lens, Blood Vessels) ↓

Activate Polyol Pathway

↓

↑ [Sorbitol]

↓

Inhibit Myoinositol Uptake

Impair Na+/K+ ATPase

↓

Damage Pericytes of Retinal Capillary

↙ ↘

Retinal Microthrombi formation ↑ Vascular Permeability

↙ ↘ ↙ ↘ Vascular Occlusion Outpouching

occur at local

point of weakness

due to loss of

pericytes

Fluid Infiltration Leakage of Fat,

Protein ↓ ↓

Hypoxia Edema ↓

↓ Hard Exudate

Neovascularization

↓

Microaneurysm

Non-Proliferative Proliferative

Microaneurysms

(Dot, Blot Haemorrhage)

Earliest clinical abnormally detected

Resulting from loss of pericytes

Outpouching occur at local point of

weaknening due to loss of pericytes

Morphology

Tiny Discrete

Circular/ Saccular

Dark Red Spots near to retinal vessels

Haemorrhages

Leakage of blood into deeper layers

Dot Blot

Red Red

Small Larger

Round Irregular Shape

Regular

Shape, Margin

Sharp Margin

Consequences of Hypoxia due to

Occluded Vessels

Neovascularization (hallmark)

Morphology

Branch Repeated

Fragile

Bleed Easily

Fibrous Tissue Reaction

(due to lack of supportive tissue)

Retinal Exudates

Soft Exudates

Due to Microinfarct (Nerve Fibers)

Morphology

• Greyish white

• Indistinct margins

• Dull matt surface

(Cotton-Wool spots)

Similar to Hypertension

Hard Exudates

Leakage of Plasma from Abnormal

Retinal Capillary

Morphology

• Bright Yellowish White

• Irregular outline

• Sharply defined Margin

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Diabetic Maculopathy

↓ Common than Retinopathy

Due to Maculo Edema

(hard exudates within 1 disc width of macula)

Affects

Older Patient with Type 2 Diabetes

Asymptomatic

Important to test Visual Acuity of patients with diabetes yearly

May lead to Blindness

Cataract

Permanent lens opacity

Causes

Intralenticular accumulation of Sorbitol

Non-Enzymatic Glycation of Lens Protein

Most common in Elderly with DM

Young patient with Poorly Controlled Diabetes

Pathogenesis Diabetes Mellitus

↓

↑ Glucose in Non Insulin-Dependent Cells

(Lens)

↓

Activate Polyol Pathway

↓

↑ Sorbitol accumulation in Lens ↓

↑ Intracellular Osmolarity

↓

Influx of H2O, Plasma Protein into cells

↓

Lens Swelling, Opacity ↓

Cataract

Glaucoma

↑ Intraocular Pressure

Retinal Neovascularization

Pathogenesis

Prolong Hyperglycaemia ↓

Activate Protein Kinase C Pathway

↓

Develop Neovascular membrane on Iris

surface

(2° to ↑ VEGF in Aqueous Humor)

↓

Contraction of Neovascular membrane ↓

Adhesions between Iris, Trabecular

Meshwork

↓

Occluding Aqueous Outflow ↓

↑ Intraocular Pressure

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Diabetic Neuropathy

Manifest on Peripheral Nervous System

Types

Symmetrical (mainly Sensory Polyneuropathy)

Acute Painful Neuropathy

Mononeuropathy, Mononeuritis Multiplex (Multiple Mononeuropathy)

Diabetic Amyotrophy

Autoimmune Neuropathy

Pathogenesis

Hyperglyc aemia

↓

↑ Intracellular Glucose

↓

Stimulate Polyol Pathway ↓

Accumulation Sorbitol + Fructose in Schwann cells

↑ IC Osmolality ↓

Influx of H2O

↓

Osmotic Cell Injury

↓

Damage Schwann Cell ↓

Demyeliniation of Axon

↓

Axon degeneration irreversibly

↓

Disrupt Neural Function ↓

Diabetic Neuropathy

Symmetrical Sensory Polyneuropathy

Early Signs Later Signs

Loss of Vibration, Pain, Temperature

sensation in Feet

Impaired Proprioception

Complication

Unrecognized Trauma (Blister → Trauma)

Loss of Tendon Reflux in Lower Limbs

Characteristics

Foot Ulcer

Charcot Neuroathropathy (ankle)

Hands

Small muscle wasting

Sensory changes (differ with Carpal Tunnel Syndrome)

Pathophysiol ogy Occlusion of Vaso Nervorum due to AGEs

↓

Ischaemic damage to Nerves

↓

Somatic Motor Neuropathy ↓

Loss of Innervations of Muscles

(which Maintain Plantar Arch) ↓

Unbalanced traction by long flexor muscles ↓

Exaggerated Plantar Arch (shape altered)

↓

Abnormal distribution of Pressure when walking

(↑ Distributed over Head of Metatarsal, Knuckles)

↓

Build up of hard skin (callus)

↓

Callus ↑ Pressure further ↓

Necrosis under callus

↓

Skin breaks down

Leaves clean, punched out Neuropathic Ulcer ↓

Bacteria enter broken skin

↓

Fever

Acute Painful Neuropathy

Burning, Crawling Pains

Feet, Shins, Anterior Thighs

Symptoms worse at night

Develop after sudden improvement of Glycaemic control

Remits spontaneously after 3-12 months

Monone uropathy (Long Standing Diabetes)

Any Nerve can be involved (Cranial, Peripheral)

Pathogenesis (Adult-Onset Diabetes)

Vascular Insufficiency → Ischaemic Injury of Peripheral Nerve

Severe, Rapid Onset with Full Spontaneous Recovery

Cranial Nerves Peripheral Nerves

Isolated Palsies to External Eye

Muscles (3rd

, 6th

Nerve)

Compression of Median Nerve

(Carpal Tunnel Syndrome)

C3, C6 (result in Diplopia)

Femoral Nerve

Sciatic Nerve

Lateral Popliteal Nerve Compression

(Foot Drop) Lateral Poplitea l Nerve = C ommon Peronea l Nerve

Diabetic Amyotrophy

Occur in Old Men with Diabetes

Period of Poor Glycaemic Control

Presentation

Painful wasting of Quadriceps Muscle (usually asymmetrical wasting)

Tender (affected area)

Extensor Plantar Response

Claw Toes with Wasting of Interosseous muscle

Extensor Plantar response is Abnormal Reflex

(in response to Cutaneous Stimulation of Plantar surface of Foot)

Dorsiflexion of Great Toe

Abduction of other toes

Claw Toe

Severe Atrophy of Intrinsic Foot Muscles (Lumbricals, Interossei)

(due to Motor Neuropathy)

(result in Imbalance of Foot Muscles, Cocked-up toes)

Diagnosis of Peripheral Neuropathy can be made (by Inspection alone)

Autonomic Neuropathy

May affect Sympathetic, Parasympathetic

CVS GIT GUT

Vagal Neuropathy

Tachycardia at rest

Loss of Sinus Arrhythmia

Dysphagia Loss of Bladder Sensation

Neurogenic Bladder

↑ Residual Volume

↑ UTI Risk

Gastroparesis

Intractable Vomiting

(esophageal reflux)

Delay gastric emptying

(Abdominal fullness)

Diarrhoea

(Bacterial Infection)

Heart Den ervated

(later stage) Disturb parasympathetic

Penile Vasodilation

Retrograde ejaculation

Impotence

Sexual dysfunction

Postural Hypotension

Loss of Sympathetic tone to

peripheral arterioles

Warm Foot

Bounding Pulse

Polyneuropathy

Peripheral Vasodilation

Autonomic Diarrhoea

At Night

Accompanied by

• Urgency

• Incontinence

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Diabetic Foot

Ulcer

Neuropathic Ulcer

Ischaemic Ulcer

Neuro-Ischaemic Ulcer

Charcot’s Joint

Gangrene

Foot Deformities (Claw Toes)

Ischaemia vs Neuropathy

Ischaemia Neuropathy

Symptoms Claudication

Rest Pain

Usually Painless

Painful Neuropathy

Inspection Dependent Rubor

Trophic changes

↑ Arch, Clawing of Toes

No Trophic changes

Palpation Cold

Pulseless

Warm

Bounding Pulse

Ulceration Painful

Heels, Toes

Painless Plantar

Ischaemic Foot Ulcer

Dorsum of 2nd

Toe

Ischaemic lesion

Whitish color on tip due to ischaemia

Neuropathic Foot Ul cer

Ulcer on 1st

Metatarsal Head

Healthy Granulation Tissue on its bed

Callus formation surrounding ulcer

Mixed Etiology

Neuro-Ischaemic Ulcer

Gangrene

Death of Tissue in considerable mass

Due to

• Loss of Vascular Supply

• Bacterial Infection

Charcot’s Foot (Neuro-Osteoathropat hy)

Osteolytic destruction of 2rd, 4th

Metatarsal Head

Widening 3rd

Metatarsophalangeal joint

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