"Never offer the devil a ride. He will always want to be in the driving seat…!"

Pathology of Diabetes

Dr. Venkatesh M. ShashidharAssociate Professor of Pathology

Fiji School of Medicine

Diabetes Mellitus

Disorder of metabolism (Carb, Prot & Fat)

Due to Absolute/relative deficiency of insulin. Characterized by hyperglycemia.

Clinically : Polyuria, Polydypsia, Polyphagia.

Introduction Diabetes mellitus (sweet urine) 3% of world population, 100 million people Incidence is increasing alarmingly (40% in the

past decade, more in future. 259 m by 2025. Most Common non communicable disease High Morbidity & mortality. DM shortens life span by 15 years. Leading cause of blindness and Kidney dis. Pacific Islands – leaders in DM & Obesity…!

World Statistics:

Normal Pancreatic Islet:

ß cells ß cells (Insulin) αα cells cells (Glucagon)

δδ cells cells (Somatostatin) pp Cells pp Cells (pan prot)

ßß αα

Insulin - Anabolic Steroid Transmembrane transport of glucose Liver, muscle & fat blood glucose Liver & skeletal muscle - glycogen Converts glucose to triglycerides Nucleic acid & Protein synthesis Diabetes Diabetes Increased catabolism. Increased catabolism. Hyperglycemia, protein synthesis, Liplysis,

wasting, weight loss.

Blood Glucose & Hormones

Hormone Insulin Glucortocoids Glucagon Growth Hormone Epinephrine

Action Glucose Glucose Glucose Glucose Glucose

Cellular Glucose Uptake

Insulin Requiring Striated Muscle Cardiac Muscle Fibroblasts FAT

Non-Insulin Requiring Blood Vessels Nerves Kidney Eye Lens

Pathology in Diabetes:

Low glucose inside cell decreased cell metabolism (muscle,

liver)

High glucose outside Glycosylation damage (BV)Polyol products – osmotic damage*

Classification Primary DM – (primary - no other disease)

Type I – IDDM / Juvenile – 10%. Type II – NIDDM /Adult onset – 80%. MODY – 5% maturity onset - Genetic Gestational Diabetes

Secondary DM – (secondary to other dis.) Pancreatitis/tumors/Hemochromatosis. Infectious – congenital rubella, CMV. Endocrinopathy, downs. Drugs – Corticosteroids.

Pathogenesis of Type I DMGenetic Genetic

HLA-DR3/4HLA-DR3/4 EnvironmentEnvironment

Viral infe..?Viral infe..?

Insulin deficiencyInsulin deficiencyType I / IDDMType I / IDDM

Autoimmune InsulitisAutoimmune Insulitis

Ab to ß cells/insulin Ab to ß cells/insulin

ß cell ß cell DestructionDestruction

• PS Glomerulonephritis• Graves, Hashimoto thyroiditis.• Rheumatic heart disease• SLE, Collagen vascular disease• Rheumatoid arthritis.

Progression of Type I

IDDMIDDM

Genetic /Genetic /

ß cell defectß cell defect

Pathogenesis of Type II DMObesity /Obesity /

Life style ?Life style ?

ß cell ß cell

exhaustionexhaustion

Type II NIDDMType II NIDDM

Abnor. SecretionAbnor. Secretion

Insulin ResistanceInsulin Resistance

Relative Relative

Insulin Def.Insulin Def.

“Things may come to those who wait, but only the things left by those who hustle.”

– Abraham Lincoln

What type?

1. 56 year male obese2. 30 year female following

pregnancy3. 8 year old boy.4. 24 year female with Cushing’s

sy5. 68 Year male following

Carcinoma of pancreas.6. 34 year male with extensive

tuberculosis.

II NIDDM

II GDM

I IDDM

Sec IDDM

Sec IDDM

Sec IDDM

Type-I Type-II

Less common Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic

complications Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis 50% in twins

More common Adult >25 Years Insulin Independent * Months to years Chronic Vascular

complications. No Yes Normal or high * Normal / Exhaustion 60-80% in twins

Insulitis – Type I

InsulinitisInsulinitis

Islets in Type II Diabetes:

Loss of ß cells, replaced by Amyloid deposits (hyalinization)Loss of ß cells, replaced by Amyloid deposits (hyalinization)

Islets in Type II Diabetes:

Loss of ß cells, replaced by Amyloid deposits (hyalinization)Loss of ß cells, replaced by Amyloid deposits (hyalinization)

Complications: Short term Complications: (metabolic)

Hypoglycemia Diabetic Ketoacidosis Non Ketotic hyperosmolar diabetic coma Lactic acidosis

Long term Complications:(Angiopathy) Microngiopathy - Retinopathy,

Nephropathy, Neurophathy, dermatopathy. Macroangiopathy – Atherosclerosis.

Microangiopathy Pathogenesis:

Hyperglycemia chronic. Glycosylation of basement membrane

proteins Leaky blood vessels. Excess deposition of proteins –

glycosylation cycle. Thick and Leaky blood vessels. Narrow lumen Ischemic Organ damage...

Diabetic Microangiopathy

Normal

Diabetic

Glucose Glycosylation BM damage leak ‘AGE’ deposition

Neuropathy Sensory Motor (myelin) Peripheral Neuropathy

Bilateral, symmetric Progressive, irreversible Paraesthesia, pain, muscle

atrophy

Visceral neuropathy Cranial nerve – diplopia, Bell palsy GIT- constipation, diarrhoea CVS – orthostatic hypotension

Neuropathy

Myelin loss in nerve

Chronic Polyneuropathy

Claw foot – Dermopathy & Neuropathy

Diabetic Amyotrophy

Painful muscle wasting

Diabetic Neuropathic ulcer

Neuropathic ulcer

Etiology: peripheral sensory

neuropathy, Trauma & deformity.

Factors: Ischemia, callus

formation, and edema.

Neuropathic ulcers

FEATURES:Painless, surrounded by callus At pressure points. associated with good foot pulsesMay not be associated with gangrene

Nephropathy Nodular Glomerulo

Sclerosis. Common morbidity &

mortality. Deposition of ‘AGE’

Advanced Glycosylation End-products as nodules.

Nephrotic syndrome Pyelonephritis End stage renal failure

Diabetic Nephropathy

Microangiopathy, atherosclerosis & infections: Diffuse or nodular diabetic

glomerulosclerosis (Kimmelstiel Wilson Sy) Renal arteriolosclerosis & atherosclerosis Necrotizing renal papillitis. Pyelonephritis. End stage kidney.

Nodular Glomerulosclerosis – KW lesion.

Diabetic Glomerulosclerosis

Hyaline nodulesHyaline nodules

Diabetic Glomerulosclerosis

Normal Retina

Non Proliferative Retinopathy Venous dilation and small red dots posterior retinal

pole - capillary micro-aneurysms. Dot and blot retinal hemorrhages and deep-lying

edema and lipid exudates impair macular function. Late generalized diminution of vision due to

ischemia and macular edema - common cause of visual defect (best detected by fluorescein angiography)

Cotton-wool spots (soft exudates) - microinfarcts due to ischemia. They are white and obscure underlying vessels. Hard exudates are caused by chronic edema. They are yellow and generally deep to retinal vessels.

Proliferative Retinopathy Neovascularization - which grows into the vitreous

cavity. In advanced disease, neovascular membranes can

occur, resulting in a traction retinal detachment. Vitreous hemorrhages may result. sudden severe loss of vision can occur when there is

intravitreal hemorrhage. Poor visual prognosis if severe retinal ischemia,

extensive neovascularization, or extensive fibrous tissue formation.

Panretinal photocoagulation may diminish or eliminate proliferative retinopathy

Retinopathy Non Proliferative

Microaneurysms, Dot blot hemorrhages Hard and soft exudates Cotton wool – infarcts Macular edema.

Proliferative. Neovascularization Large hemorrhages Retinal detachment.

Diabetic Retinopathy

Neovascularization Cotton wool spots

Diabetic Retinopathy

Dot blot – Hemorrhages (Microaneurysms)

Diabetic Retinopathy

Pre retinal Hemorrhage - detachment

Diabetic Retinopathy

Advanced fibrous plaques

“The past cannot be changed, but the future can.. by actions in the present time.” --BK

Past is history, Past is history,

Future is mysteryFuture is mystery

Present is the gift…!Present is the gift…!

Label the diagram.

1.

2.

3.

4.

5.

Hard dep.

Optic disc

Macula

Blot hem

Cotton wool

Macroangiopathy Atherosclerosis

Dyslipidemia HDL Non-Enzymatic Glycosylation Platelet Adhesiveness

Thromboxane A2

Prostacyclin Endothelial damage Atherosclerosis MI, CVA, Gangrene of Leg (PVD), Renal

Insufficiency

Atherosclerosis:

Slide Show

Diabetic Gangrene

Fungal infections: Candidiasis

Macrosomia

With Polycythemia

Blood vessel calcification:

Amputated thumb

Cataract

Acanthosis Nigricans

Insulin resistance…

Acanthosis Nigricans

Insulin resistance…

Label the diagram.

1.

2.

3.

4.

Capillary

Nodule – AGE

Bowman caps

Hyaline arteriolo sclerosis in arteriole.

Infections in Diabetes:

Decreased metabolism – low immunity. Decreased function of lymphocytes &

neutrophils – glycosylation. Glycosylation of immune mediators. Ab Capillary thickening – impaired inflammation. Ischemia & infarctions. Increased glucose (alone is not the cause*)

Diabetes State of immunosuppression.

Laboratory Diagnosis:

Urine glucose - dip-stick –Screening Random or fasting blood glucose (<11) Fasting > 7mmol, Random >11mmol If Fasting level is between 7-11 then OGTT

HbA1c - for follow-up, not for diagnosis Fructosamine - for long term maintenance.

Points to remember:

Disorder of metabolism – Insulin Type-I Children, Acute, Metabolic compl. Type-II Adults, Chronic, Vascular compl.

Angiopathy (micro/macro), Heart, Brain, Kidney, Retina, Skin, BV.

Increased Infections – know reasons. Hypoglycemia is more dangerous. Not hyper Glucose control is critical * FBS, GTT & HbA1C.

Questions..

How – Ketoacidosis? How – hypoglycemia ? Angiopathy – Macro & Micro ? Infections in Types of retinopathy ? Diabetes insipidus ? Nephrotic / Nephritic syndrome ? Kidney damage in Diabetes ?

The best gift of Nature to man is the briefness of his life…! Latin quote

“It's not that I'm so smart, it's just that I stay with problems longer”--Albert Einstein