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Pathogenesis - Chronic Complications of Diabetes

Intracellular Hyperglycaemia with

Non-E nzymatic Glycosylation Activation of Protein Kinase C (PKC)
Disturbance of Polyol Pathway
Process where Glucose Attach to Proteins (chemically) Intracellular Hyperglycaemia Does not require Ins ulin for Glucose Trans port
without aid of Enzyme ↓ Nerves, Lens, Kidneys, Blood Vessels
Stimulates de novo synthesis for Diacylglycerol (DAG)
Degree of Glycosylation During Hyperglycaemia → ↑ Intracellular Glucose
from glycolytic intermediates
Directly related to Blood Glucose Level
(DAG = 2nd messenger in signal transduction)
Glucose + Hb chain = Glycated HbA (HbA1c ) ↓
In Diabetics, ↑ HbA 1c Activate Protein Kinase C
HbA 1c Reflects average level of glucose over 120 days ↙ ↓ ↘

Checking Blood Sugar in Pre-Diabetic Produce Produce Produce Pro-

Monitor Blood Sugar Control in Diabetic Patients Plasminogen Vascular Fibrogenic
Irreversible Advanced Glycosylation End Pr oducts Inhibitor Endothelial GF Molecules
↓ ↓ (Transforming GF)
(AGEs) Many cells contain Aldose Reductase
↓ Fibrinolysis Neo- ↓
• Glycosylation of Collagen, Long-lived Proteins in ↓ vascularization ↑ Deposition Excess Sorbitol Cannot Exit Cell, Coverted to Fructose
Blood Vessels, Interstitial Tissues (Abnormal Vesse ls) Accumulation of Sorbitol (Polyol), Fructose
Vascular Of ECM &
• Accumulate in Blood Vessels and cause Occlusion s
↓
BM Material ↓

Microvascular, Macrovascular Lesions Diabetic ↑ Intracellular Osmolality, H2O Influx

↓
AGEs bind to ECM proteins Retinopathy
Cell Injury
on Basement Membrane (BM ) Endothelial cells
↓
Accumulation of AGEs Lens (Cataract)
↓ Nerve (↓ Nerve Conduction)
Trap Non-Glycosylated Continuous Aldose Red uctase Pathway
Plasma Protein, Interstitial Protein ↓
↙ ↘ Diminished NADPH
Trapping of LDL at Trapping Albumin at ↓
Vessel Wall accelerates BM of capillaries cause ↓ Formation of Reduced Glutathione (GSH)
↓
Atherogenesis Thickening of BM
Cells prone to Oxidative Stress
(Diabetic
Glomerulopathy)
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 Pathophysiol ogy (Macrovascular Complication)

Macrovascular Microvascular Hyperglycaemia
↓
Stroke Diabetic Retinopathy
Nonenzymatic Glycosylation of Collagen, Proteins in
IHD Diabetic Nephropathy
Interstitial Tissue, Blood Vessel Wall
Peripheral Vascular Disease Diabetic Neuropathy ↓
Formation of Irreversible Advanced Glycosylation End Products
(AGEs)
↓
Cause Cross Link between Polypeptides
↓
Trap Plasma, Interstitial Proteins including LDL
↓
Promote deposition of Ch olesterol 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
↓

Macrovascular Complication Atherosclerosis

Cardiovascular Cerebrovascular Peripheral Vascular Atherosclerosis
↓
Angina Coma Gangrene
MI Stroke Coronary Artery Lower Extremities Brain Vessel
IHD Vessel
↓
HPT
Compromise d Blood Supply
↙ ↓ ↘
Myocardial Infarction Coagulative Necrosis Stroke
Infections
↓

Wet Gangrene
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Microvascular Complication Diabetic Retinopathy
Diabetic Microangiopathy Retinal changes – Long term Diabetes
Diabetic Neuropathy Cause Visual Impairment, Total Blindness
Diabetic Retinopathy Pathogenesis
Diabetic Neuropathy ↑ Glucose in Non-Insulin Dependent Cels
(Nerves, Lens, Blood Vessels)
Diabetic Ulcer ↓
Activate Polyol Pathway
Diabetic Microangiopathy ↓
↑ [Sorbitol]
Diffuse Thickening of Capillary Basement Membrane (BM) ↓
Diabetic Capillaries are ↑ Leaky to Plasma Proteins (compared to Normal) Inhibit Myoinositol Uptake
Thickening is Most Evident in Capillaries of Impair Na+/K+ ATPase
↓
Vascular Structures Non-Vas cular Structures Damage Pericytes of Retinal Capillary
Skin Renal Tubules ↙ ↘
Skeletal Muscle Bowman Capsule Retinal Microthrombi formation ↑ Vascular Permeability
↙ ↘ ↙ ↘
Retina Peripheral Nerve Vascular Occlusion Outpouching Fluid Infiltration Leakage of Fat,
Renal Glomerulus Placenta ↓ occur at local ↓ Protein
Renal Medulla Hypoxia point of weakness Edema ↓

Underlies the development of Diabetic ↓ due to loss of Hard Exudate

Nephropathy, Retinopathy, Neuropathy (some form) Neovascularization pericytes
↓

Microaneurysm
Diabetic Nephropat hy Non-Proliferative Proliferative
Kidney – Prime Targets of Diabetes Microaneurysms Consequen ces of Hypoxia due to
Renal Failure 2nd after MI (main cause of death in Diabetics) (Dot, Blot Haemorrhage) Occluded Vessels
Glomerular Lesions Earliest clinical abnormally detected Neovascularization (hallmark)
Capillary BM Diffuse Mesangial
Nodular Glomerulosclerosis Resulting from loss of pericytes Morphology
Thickening Sclerosis
Outpouching occur at local point of Branch Repeated
BM Thickened Diffuse ↑ in Mesangial Kimmelstiel-Wilson Lesion
throughout Matrix along with Glomerular Sclerosis involving weaknening due to loss of pericytes Fragile
entire length Mesangial Cell development of nodular lesion in Morphology Bleed Easily
Proliferation glomerular capillaries Tiny Discrete Fibrous Tissue Reaction
Thickening BM ↓ Circular/ Saccular (due to lack of supportive tissue)
Impaired Blood Flow with
Manifest Nephrotic Dark Red Spots near to retinal vessels
Progressive Loss of
Syndrome (proteinuria, Haemorrhages
Kidney Function
hypoalbuminaemia, ↓ Leakage of blood into deeper layers
edema) Renal Failure Dot Blot
Chronic Hyperglycaemia Pathognomonic for Diabetic Pt. Red Red
↓
Non-Enzymatic Glycosylation of Small Larger
Terminal Amino Group Round Irregular Shape
↓
Regular Sharp Margin
AGEs
↓ Shape, Margin
Affect Structure, Function of Capillaries
(Vasodilation) Nodular Glomerulosclerosis in
↓ Diabetic Nephropathy
↑ in Sheer Forces (Kimmelstiel-Wilson Lesion)
Glomeruli Damage
↓
↑ Mesangialhypertrophy
↓
↑ Secretion of
Mesangialextracellular Matrix
↑ Collagen Production
↓
Thickening of Glomerular BM
↓
Glomerulosclerosis
↓
Capillaries ↑ Leaky to Plasma Proteins
↓
Proteinuria
↓
Peripheral Edema, Hypoalbuminemia Retinal Exudates
↓
Hypertension Soft Exudates
Due to Microinfarct (Nerve Fibers)
Renal Vascular Lesion
Morphology
Principally DM
↓ • Greyish white
Atherosclerosis Plasma Proteins penetrate into • Indistinct margins
Arteriolosclerosis abnormally permeable wall of arterioles
Part of Macrovascular disease ↓
• Dull matt surface
Plasma Proteins trapped (Cotton-Wool spots)
Changes same throughout body ↓ Similar to Hypertension
Arteries Vessel Hypertrophy, Hyalinization
Arterioles ↓
Thickening of wall of arterioles
Morphology ↓
Arteriolar lesions with hypertrophy, Narrowing of lumen
hyalinization of vessels ↓
Ischaemic Damage to Kidney Hard Exudates
Hyaline arteriolosclerosis ↓ Leakage of Plasma from Abnormal
(affe ct Afferent, Efferent Arteriole) Renal Failure
Retinal Capillary
Pyelonephritis Morphology
Acute, Chronic Inflammation of Kidneys
• Bright Yellowish White
Usually begin in Interstitial Tissue (then spread to affect Tubules)
• Irregular outline
Pathophysiol ogy
• Sharply defined Margin
Autonomic Neuropathy → Bladder Stasis → VUR → Infection
Untreated Infection
Renal Papillary Necrosis
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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 Acute Painful Neuropathy

Manifest on Peripheral Nervous System Burning, Crawling Pains
Types Feet, Shins, Anterior Thighs
Symmetrical (mainly Sensory Polyneuropathy) Symptoms worse at night
Acute Painful Neuropathy Develop after sudden improvement of Glycaemic control
Mononeuropathy, Mononeuritis Multiplex (Multiple Mononeuropathy) Remits spontaneously after 3-12 months
Diabetic Amyotrophy
Autoimmune Neuropathy 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 Compression of Median Nerve
Muscles (3rd , 6th Nerve) (Carpal Tunnel Syndrome)
C3, C6 (result in Diplopia) Lateral Popliteal Nerve Compression
Femoral Nerve (Foot Drop)
Sciatic Nerve Lateral Poplitea l Nerve = C ommon Peronea l Nerve

Diabetic Amyotrophy
Occur in Old Men with Diabetes
Period of Poor Glycaemic Control
Pathogenesis Presentation
Hyperglyc aemia
Painful wasting of Quadriceps Muscle (us ually asymmetrical wasting)
↓
↑ Intracellular Glucose Tender (affected area)
↓ Extensor Plantar Response
Stimulate Polyol Pathway Claw Toes with Wasting of Interosseous muscle
↓
Accumulation Sorbitol + Fructose in Schwann cells Extensor Plantar response is Abnormal Reflex
↑ IC Osmolality (in response to Cutaneous Stimulation of Plantar surface of Foot)
↓
Dorsiflexion of Great Toe
Influx of H2O
↓ Abduction of other toes
Osmotic Cell Injury
↓
Damage Schwann Cell
↓
Demyeliniation of Axon
↓
Axon degeneration irreversibly
↓
Disrupt Neural Function
↓
Diabetic Neuropathy
Claw Toe
Symmetrical Sensory Polyneuropathy Severe Atrophy of Intrinsic Foot Muscles (Lumbricals, Interossei)
Early Signs Later Signs (due to Motor Neuropathy)
(result in Imbalance of Foot Muscles, Cocked -up toes)
Loss of Vibration, Pain, Temperature Impaired Proprioception
sensation in Feet Diagnosis of Peripheral Neuropathy can be made (by Inspection alone)
Complication
Autonomic Neuropathy
Unrecognized Trauma (Blister → Trauma)
May affect Sympathetic, Parasympathetic
Loss of Tend on Reflu x in Lower Limbs
CVS GIT GUT
Characteristics
Vagal Neuropathy Dysphagia Loss of Bladder Sensation
Foot Ulcer Tachycardia at rest Gastroparesis Neurogenic Bladder
Charcot Neuroathropathy (ankle) Loss of Sinus Arrhythmia Intractable Vomiting ↑ Residual Volume
Hands Heart Den ervated (esophageal reflux) ↑ UTI Risk
Small muscle wasting (later stage) Delay gastric emptying Disturb parasympathetic
Sensory changes (differ with Carpal Tunnel Syndrome) Postural Hypotension (Abdominal fullness) Penile Vasodilation
Pathophysiol ogy Loss of Sympathetic tone to Diarrhoea Retrograde ejaculation
Occlusion of Vaso Nervorum due to AGEs peripheral arterioles (Bacterial Infection) Impotence
↓ Warm Foot Autonomic Diarrhoea Sexual dysfunction
Ischaemic damage to Nerves Bounding Pulse At Night
↓ Polyneuropathy Accompanied by
Somatic Motor Neuropathy
↓
Peripheral Vasodilation • Urg ency
Loss of Innervations of Muscles • Incontinence
(which Maintain Plantar Arch)
↓
Unbalanced traction by long flexor muscles
↓
Exagg erated 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
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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 Usually Painless
Rest Pain Painful Neuropathy
Inspection Dependent Rubor ↑ Arch, Clawing of Toes
Trophic changes No Trophic changes
Palpation Cold Warm
Pulseless Bounding Pulse
Ulceration Painful Painless Plantar
Heels, Toes

Ischaemic Foot Ulcer Neuropathic Foot Ul cer

Dorsum of 2nd Toe Ulcer on 1st Metatarsal Head
Ischaemic lesion Healthy Granulation Tissue on its bed
Whitish color on tip due to ischaemia 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