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Pathology of Diabetes

Definition Histology
Group of Chroni c Metabolic Disorders
Characterised by Hyperglycemia
(Normal Blood Glu cose 70-120 mg/dL)
Affects metabolism of Carbohydrate, Fat, Protein
Glycosuria
When Blood Glucose excee ds Renal Threshold
Glucose appear in Urine
Long Term Uncontrolled Diabetes Normal Pancreas
Glucose may not appear in Urine despite Hyperglycemia Islet of Langerhans in centre
Surrounded by Exocrine Pancreatic Tissue

Glucagon Secreting α (20%) cells Insulin Secreting β (68%) cells

Mechanism of Insulin Secretion

Meal (Large Glucose Intake)
↓
Glucose taken by β cells (pancreas)
Diagnosis From Blood, with the help of GLUT-2
↓
Elevated Blood Glucose (1 of 3 Criteria) Glucose undergo Oxidative Metabolism
Random Glucose > 200 mg/dL (>1 1.1 mmol/ L) with classical signs, symptoms Produce ATP
Fasting Glucose > 126 mg/dL (> 7mmol/L) on more than 1 occasion (inside β cells)
Abnormal OGTT, Glucose > 200 mg/dL (> 11.1 mmol/L) 2 hours after CHO load ↓

Classical Symptoms ATP Inhibits K+ Channel Receptor

↓
Polyuria
Lead to Membrane Depolarization
Polydipsia
Influx of Ca2+, Release of stored Insulin
Polyphagia
Insulin acts on Cells by Binding
Extreme Metabolic Derangement (Ketoacidosis)
with Insulin Receptors
(Liver, Muscle, Adipose Tissue)
Impaired Glucose Tolerance (IGT) ↓
Fasting Glucose Level 110 – 126 mg/dL Binds the α subunit
(6.1 – 7 mmol.L) Activates, Initiates
OGTT (2 Hours) 140 – 200 mg/dL Kinase Activity in β subunit
(7.8 – 11.1 mmol/L) ↓
Phosphorylation Cascade
↓
Significance Multiple downstream target proteins
Risk of Progressing to Frank Diabetes over time Metabolic actions of Ins ulin are 1° mediated by
At Risk For Phosphatidylinositol-3-kinase (PI3 -K) pathway
Cardiovascular Disease (due to abnormal CHO metabolism) PI3-K Pathway
Coexistence of other Risk Factors - ↓ HDL, Hypertryglyceridemia Translocates GLUT-4 containing vesicles to surface
↑ Density on Membrane
Blood Gl ucose ↑ Rate of Glucose Influ x
Energy source – Brain Functions
Hypoglycaemia Hyperglycaemia Promotes Synthesis of Promotes
Damage to Brain Damage to Blood Vessels Glycogen Cell Survival
Protein Cell Proliferation
Normal Glucose Homeostasis Lipid
Regulated by 3 Interrelated Processes Inhibits
Glucose Produ ction in Liver (Gluconeogenesis) Lipolysis
Glucose Uptake, Utilization by Peripheral Tissues (chiefly Skeletal Muscle) Mitogen Activated Protein Kinase (MAP-Kinase) Pathway
Action on Glucose by Insulin, Counter Regulatory Hormones, Glucagon Mediate Mitogenic Functions of Insulin, Insulin like Growth Factors
Insulin Glucagon
Secreted by Pancreatic β cells (B cells) Secreted by Pancreatic α cells (A cells) Insulin
↓ Blood Glucose Level ↑ Blood Glucose Level ↓ Blood Gl ucose Levels
Other Diabetogenic Hormones that ↑ Blood Glucose Level Helping Entry of Glucose into Cells
Epinephrine Enhancing Glucose Anabolism
Steroid Metabolic Effects
Growth Hormone Metabolism Carbohydrate Fat Protein
Stimulates Glycogenesis Lipogenesis Protein
Anatomy Glycolysis Synthesis
Inhibits Glycogenolysis Lipolysis Proteolysis
Gluconeogenesis
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Classification of Diabetes
Type I (IDDM, Juvenile Diabetes) Type II (NIDDM)
Absolute Insulin Deficiency (β-cell Destruction) Relative Insulin Deficiency (Insulin Resistance)
Pathogenesis Pathogenesis –Unknown
Severe lack of Insulin caused by Immune mediated destruction of β cells Genetic Environment
Autoimmune disease – Islet Cell Destruction More important than Type I DM Sedentary Life Style
• Caused 1° by T Lymphocytes reacting against poorly defined β cell antigens Concordance rate Dietary Habits - Obesity
(maybe β-cell enzyme, glutamic acid, decarboxylase (GAD), insulin) Identical Twins (50-90%)
• CD4+, CD8+ are involved st
1 Degree Relatives
Kill β cells ↑ Risk of Developing (20-40%)
• Directly [Normal Population (5-7%)]
• Injury by producing Cytokines (activate Macrophages)(Release TNF, IL-1) Genes not related to
Genetic Environment Immune Tolerance
MHC Class II (HLA) Infection caused by Viruses Regulation
Chromosome 6p21 (HLA-D) Trigg er Autoimmunity No evidence suggesting autoimmune
MHC Molecules Viruses Characteristic Metabolic Defects
Normally function to display peptides to T Coxsackie B viruses, Cytomegalovirus, Insulin Resistance
cells (contribute to Autoimmunity) Mumps, Measles, Rubella (Peripheral Tissue ↓ ability to respond to Insulin)
Trigger Autoimmunity Universal finding in an Obese Diabetic
• Infection induce Tissue Damage, Complex, Multifactorial phenomenon
Inflammation lead to release of β Often detected 10-20 years before onset of Type II Diabetes
cell antigen, recruitment of (best predictor for subsequent progression to diabetes)
lymphocytes, inflammatory cells Leads to
• Viruses produce proteins that • ↓ Uptake of Glucose in Muscle, Adipose Tissue
mimic self-antigens, immune • Inability of Hormone to Suppress Hepatic Gluconeogenesis
response to viral protein cross- Insulin Signalling Pathway
reac ts with self tissue • ↓ Regulate Insulin Receptors
Autoimmune attack begins Early • ↓ Insulin Receptor Phosphorylation, Tyrosine Kinase Activity
Classic manifestations of disease (Hyperglycemia, Ketosis) occur Late • ↓ Active Intermediates in Signalling Pathway
(> 90% of β cells have been destroyed) • Impair Translocation, Docking, Fusion of GLUT-4 containing vesicles
Most commonly develops in Childhood, manifest at Puberty, progresses with Age with plasma membrane
Depend on Insulin for survival Culprits (Responsible for Insulin Resistance)
Without Insulin, patients develop • Genetic Def ects of Insulin Receptor, Insulin Signalling Pathway (Unclear)
Acute Ketoacidosis • Obesity, Insulin Resistance
Coma o Insulin Resistance is Acquired (majority of individuals)
Stages in Development of Type 1 Diabetes Mellitus Obesity is central to this phenomenon
o Insulin Resistance – present in simple obesity unaccompanied by
hyperglycaemia
o Obesity exert Diabetog enic Effect via Insulin Resistance
o Risk for Diabetes ↑ as BMI ↑
o Central (Abdominal) Obesity ↑ Likely to be related
Peripheral (Gluteal, Subcutaneous) Fat depots ↓ Likely
Pathways Leading to Insulin Resistance
Peroxisome Proliferator
Free Fatty Acids (FFAs) Adipokines Activated Receptor
Gamma (PPAR γ)
Fasting plasma FFA is Abnormal regulation of Nuclear receptors present
inversely related to Adipokines secretion in adipocytes, activated
Insulin Sensitivity cause Insulin Resistance by a group of antidiabetic
Morphology of Pancreas ↑ Intracellular Leptin agents Thiazolizenediones
Lesions are Inconstant, Rarely Diagnostic Triglycerides, Products of Act on CNS receptors (TZD) that results in
Fatty Acid Metabolism are ↓ Food Intake modulation of gene
Distinctive changes ↑ common (compared to Type 2 DM)
• ↓ Number, Size of Islets (most of them small, not easily detectable) Potent Inhibitors of Induce Satiety expression in adipocytes
Insulin Signalling Deficiency cause Ultimately leading to
• Leukocytic Infiltration of Islets (Insulitis) (Principally T Lymphocytes)
Lead to Acquired Insulin Insulin Resistance that is ↓ Insulin Resistance
• β cell Degranulation (depletion of stored insulin in damaged β cells)
Resistance rev ersed by Leptin
administration
β cell Dysfunction
(Inadequate Insulin Secretion – Insulin Resistance, Hyperglycaemia)
Qualitative Defect Quantitative Defect
Loss of ↓ β-cell mass, Islet Degeneration,
Normal Pulsatile, Deposition of Islet Amyloid
Oscillating Pattern of Insulin Secretion Islet Amyloid Protein
Attenuation of Rapid Phase Present in > 90% of Diabetic Islets
Insulitis in an Islet of Langerhans Following an ↑ of Plasma Glucose Characteristic of Type II Diabetes
Patient will later develop Type I Diabetes Metabolic Staging of Type 2 Diabetes Mellitus Relation - Obesity, Insulin Resistance
Islet is Infiltrated by Lymphocytes

Summary
Type I DM Type II DM
Clinical
Onset < 20 y/o > 30 y/o
Body Weight Normal Obese
Blood Insulin Markedly ↓ ↑ (early)
Normal → Moderate
↓ (late)
Anti-Islet Cell Abs Present Absent
Ketoacidosis Common Rare; Nonketotic hyperosmolar
coma
Genetics Concordance in Twins 30-70% Concordance in Twins 50-90%
Morphology of Pancreas
Linked to MHC Class II HLA HLA Linkage Absent; Linked to
Subtle ↓ in Islet Cell Mass
genes Diabetogenic genes
Amyloid Replacement of Islets
Pathogenesis Autoimmune destruction of Insulin Resistance
• Amorphous Pink Material (between cells, in and
β cells β cell dysfunction
around capillaries)
Absolute Insulin Deficiency Relative Insulin Deficiciency
• At advanced stage, Islets are virtually obliterated
Islet Cells Insulitis early No Insulitis
Fibrosis
Marked Atrophy, Fibrosis, β-cell Focal Atrophy
• Long standing DM
Depletion Amyloid Deposition Amyloid Deposition
• Can be found in Elderly Non-Diabetics
Mild β-cell Depletion in Pancreatic Islet
(part of Normal Aging)
↑ in Number, Size of Islets in Non-Diabetic Newborns in Type II Diabetes
of Diabetic Mothers 2° Hyperplasia of Fetal Islets in
response to Maternal Hypercalcaemia
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Acute Complications of Diabetes Long-Term Complications of Diabetes

Diabetic Ketoacidosis (DKA)
Hyperosmolar Non Ketotic Diabetic Coma (HONKC)
Sequence of Metabolic Derangements leading to Diabetic Coma Type 1 DM
Absolute Insulin Deficiency
Catabolic State
Ketoacidosis
Severe Volume Depletion
CNS compromise
Lead to Coma, Death (if untreated)
Pathogenesis of Chroni c Complications
Complication of DM are consequences of Hyperglycaemia
Non-Diabetic Donor’s Kidney + Diabetic Recipient → Diabetic Nephropathy
Diabetic Nephropathy Kidney + Normal Recipient → Lesion Reversed (Normal)
Additional Factors modulating individual risk for microvascular disease
Genetic
Formation of
Advanced Glycation
End Products
(AGEs)
Damaging Ef fects on
• Extracellular Matrix
components
• Intracellular, Plasma
Proteins of Target Cells
(eg. Endothelial cells)
Contribute to
↑ Thickening of BM
Endothelial Dysfunction
Extracellular Matrix
Components
(Collagen, Laminin)
Cross-linking of
polypeptides
↓ effec ts)
Abnormal Matrix-Matrix
and Matrix-Cell Interaction
Eg. Cross-linkage between
Collagen Type 1 in Large
Vessels → ↓ Elasticity,
Predisposed to Shear
Stress, Endothelial Injury
Eg. Trapping of LDL retards
its efflux from vessel wall,
Enhance cholesterol
deposition in intima →
Accelerate Atherogenesis
Circulating Plasma Protein
AGE Receptor Ligation
generates ROS, Activates
NF-κB on Target Cells
(endothelium, mesangial
cells, macrophages)
• Cytokines, GF Secretion
• Induction of
Procoagulant activity
• ↑ Vascular Permeability
• Enhanced Extrac ellular
Matrix production by
Fibroblast/ Smooth
muscle
Microvascsular Macrovascular
(Capillaries in Target Organs) (Aorta, Large, Medium Sized Arteries)
Characterized by Accelerated Artherosclerosis
Diffuse Thickening of capillary (↑ Severe, Earlier than non-diabetics)
Basement Membrane (BM) Myocardial Infarction
Thickening (evident in capillaries of) (Coronary Artery Atherosclerosis)
Skin, Skeletal Muscle, Retina, Renal Stroke
Glomerulus, Renal Medulla, Non- (Atherosclerosis of Cerebral Vessels)
Vascular Structures – Renal Tubules, Lower Extremity Gangrene
Bowman Capsule, Peripheral Nerve, (100X ↑ common than non-diabetics )
Placenta Hyaline Arteriolosclerosis
↑ Leaky than Normal (Vascular changes in DM, HPT)
To Plasma Proteins
Although ↑ Thickness
Nephropathy
Renal Failure (2nd after MI as cause of
death in Diabetics)
3 Lesions in Ki dney
Glomerular Lesions
Renal Vascular Lesions
Pyelonephritis including necrotizing
Atherosclerotic Changes i n Aorta
papillitis
(Topmost is the most advanced)
Glomerular Lesions
Capillary BM Thickening
Diffuse Mesangial Sclerosis
Nodular Glomerulosclerosis Coronary Artery Sections
• Ball-like deposits at periphery of Atherosclerotic Narrowing of Lumen
glomerulus (Left one is from Proximal Part)
(Kimmelstiel-Wilson Le sion)
Renal Atherosclerosis,
Arteriolosclerosis (macrovascular)
Changes in Arteries, Arterioles are the
same throughout the body
Hyaline Arteriolosclerosis – affect
Activation of Intracellular both Afferent, Efferent Arterioles
Protein Kinase C Hyperglycemia with Pyelonephritis
(PKC) distrubances i n Acute, Chronic Inflammation Kidneys A Thrombus in Coronary Artery
Polyol Pathways Begins in Interstitium,
Effects of PKC Activation Some Tissues do not Spreads to affect tubules
• Production of require Insulin Necrotizing papillitis (papillary
proangiogenic VEGF for Glucose Transport necrosis) - ↑ Prevalent in Diabetics
(neovascularisation) Nerves
• ↑ Vasoconstriction Lenses
(↓ Vasodilation) Kidney Diabetic Gangrene (amputated)
• Production of Blood Vessels
Profibrogenic molecules
(deposition of
Extracellular matrix,
Basement material)
• Production of
Nodular Glomerulos clerosis
Procoagulant molecule
(vascular occlusive Retinopathy
Cause Blindness
• Production of New Blood Vessel Formation
Proinflammatory (Neovascularization) is fundame ntal
Cytokines lesion of this retinopathy
Overlapping Effects of Other eye changes
AGEs, PKCs activation Glaucoma
Therapeutic Inhibition of
Cataract formation
PKCs
Retard progression of
Retinopathy
Oxidative Stress
Neuropathy
Central, Peripheral Nervous Systems
Atherosclerosis of Cerebral Artery
leads to Stroke
Peripheral Nerves include
• Distal Symmetric Sensory
• Sensorimotor Neuropathy
NADPH – Cofactor (requ ired t o generate GSH)
• Autonomic Neuropathy
GSH – Important Anti-Oxidant
• Focal, Multifocal
Sustained Hyperglycaemia Asymmetric Neuropathy
↓
Progressive Depletion of Intracellular NADPH
by Aldose Reductase
↓
Compromise GSH Regeneration
↓
Deleterious Effects
↓
↑ Cellular Susceptibility to Oxidative Stress
Eg. Aldose Re ductase Inh ibitor – Improve Diabet ic Neuropa thy
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Maturity Onset Diabetes of Young (MODY) Classification of Diabetes Mellitus

Different from Type I, Type II Diabetes Type I Diabetes
Result from Either (β-cell Destruction – lead to Absolute Insulin Deficiency)
1° Defect in β-cell function Immune Mediated
Defect in Insulin/ Insulin Receptor Signalling Idiopathic
Outcome of heterogeneous group of genetic defe cts Type II Diabetes
Characteristics (Insulin Resistance with Relative Insulin Deficiency)
Autosomal Dominant Inheritance as a monogenic defect, with ↑ penetrance Genetic Defects in Insulin Pr ocessi ng or Insulin Action
Early Onset, usually < 25 y/o Defects in Proinsulin conversion
Absence of Obesity Insulin Gene Mutations
Lack of Islet cell Autoantibodies, Insulin Resistance Syndrome Insulin Receptor Mutations
Genetic Defects of β-cell Function
Gestational Diabetes Maturity-onset Diabetes of the Young (MODY) caused by Mutations in
Diabetes occurs in Pregnancy Hepatocyte Nuclear Factor 4α [HNF-4α] MODY 1
Pathogenesis Glucokinase MODY 2
Placental Hormones ↑ Insulin Resistance, Lead to Diabetes Hepatocyte Nuclear Factor1α [HNF-1α] MODY 3
Risk Factors Insulin Promoter Factor [IPF-1] MODY 4
Family History of Type II Diabetes Hepatocyte Nuclear Factor 1β [HNF-1β] MODY 5
Maternal Age – Risk ↑ with Age Neurogenic Differentiation Factor1 [NeuroD1] MODY 6
Ethnic Background – African, Hispanic ancestry Mitochondrial DNA Mutations
Obesity Exocrine Pancreatic Defects
Gestational Diabetes during Previous Pregnancy Chronic Pancreatitis
Previous delivery of a child with a birth weight of ≥ 9 pounds Pancreactectomy
Presentation Neoplasia
Asymptomatic Cystic Fibrosis
Polydipsia Haemachromatosis
Polyuria Fibrocalculous Pancreatopathy
Fatigue Endocrinopathy
Nausea Acromegaly
Vomiting Cushing Syndrome
Urinary Tract Infection Hyperthyroidism
Vaginal Candidiasis Pheochromocytoma
Blurring of Vision Glucagonoma
Management Infections
Strict control of Blood Glucose by Diet Cytomegalovirus
Exercise Coxsackie Virus B
Insulin (if needed ) Drugs
Complications Glucocorticoids
Baby Mother Thyroid Hormone
Miscarriage Disturbed Blood Glucose Levels α-Interferon
Birth Defects Hypoglycaemia without warning Protease Inhibitors
Growth Restriction during Pregnancy β-Adrenergic Agonists
Growth Acceleration ↑ Risk of developing Thiazides
Foetal Obesity (Macrosomia) Frank Diabetes in the future Nicotinic Acid
Polyhydramnios Phenytoin
Genetic Syndromes Associated with Diabetes
Down Syndrome
Kleinfelter Syndrome
Turner Syndrome

Gestational Diabetes Mellitus