Strength, it is that we want so much in this life, for what we call sin &

sorrow have all one cause, and that is our weakness. With weakness

comes ignorance, and with ignorance comes misery.

- - Swamy Vivekananda

CPC 3.2: Ms. ML, 18y, Thrush. Recurrent thrush*, boils*, tired*, (months) Obese*, junk food, no exercise*, polyuria, polydipsia* , Abd. Striae*, Mom, Granny DM2*, smoker 30/d, social drinker, Dipstick: Nitrate +, WCC 3+, Blood 2+, Prot. 2+, Glucose

2+ MSU: Ecoli >108, swab: Candida 4+, RBGL 35.

• ? Key points: • ? DD: Thrush, UTI, PID, Preg, DM 1, 2, 1.5, MODY, LADA*

• ? Next step:

? Pathogenesis of DM “recurrent infections”

1 2 3 4 5

0% 0% 0%0%0%

1. Associated AIDS

2. Hyperglycemia

3. Cell starvation.

4. Blood Vessel damage.

5. All of the above.

Features supporting diagnosis of DM2 ?

1. On & off for long time.

2. Always drinking.

3. Obesity.

4. Recurrent boils.

5. Mom has DM2

1 2 3 4 5

0% 0% 0%0%0%

Significance of Nitrite in Urine?

1. Ketone bodies.

2. Gram -ve bacteria

3. Lymphocytes

4. Neutrophils

5. Gram +ve bacteria.

1 2 3 4 5

0% 0% 0%0%0%

Etiology of Thrush ?

1. Proteinuria

2. Bacterial infection

3. Glycosuria

4. Trichomoniasis

5. Candidiasis

1 2 3 4 5

0% 0% 0%0%0%

II NIDDMII GDMI IDDM

Sec IDDMSec IDDM

I LADASec IDDM

I IDDMLADA

MODY

Most likely .. What type of DM ?

1. 56 year male obese2. 30 year female following pregnancy3. 8 year old boy, poor growth, DKA.4. 24 year female Cushing’s sy5. 68 Year male following Ca. pancreas.6. 32 male, DM, BMI 18, Anti-GAD +ve.7. 34 year male, extensive tuberculosis.8. 12 year old female following viral fever9. 41y DM2, BMI 17.1, HbA1c 14.1, DKA10.15y male, BMI 16.2, recurrent infect.

DM Questions Definition? types common? Diagnosis? Primary & Sec? Congenital? Gestational? Monogenic? MODY, LADA, drugs? List functions of Insulin? Antagonists? Etiology & Pathogenesis of Type 1 & 2. Stages of DM & their pathological basis? Obesity & Insulin resistance *

• FFAs, PKC, Adipkines, PPARγ• Inflammation & Insulin resistance.

Mechanism of β cell destruction type 1, 2. Islet Amyloid PolyPeptide (IAPP)?

DM Questions MODY & LADA – pathogenesis, subtypes. Pathogenesis of Complications:

• Mechanism: AGEs, Activate of PKC, & Polyols.• Infections – common & pathogenesis.• Foot ulcer, Retinopathy (prol & non-prol), • Neuropathy? Central, peripheral, autonomic…• Difference Angiopathy Micro & Macro? MI, Stroke.• Diabetic Nephropathy – albuminuria, KW lesion,

Papillary Necrosis, Pyelonephritis, CRF.• Hypertension, Cataract,

Metabolic: Diabetic Coma, DKA, HONK **

CPC32-Diabetes: Pathology Major CLI:

• Diabetes Overview & Classification. • Complications Micro & Macroangiopathy. Retinopathy,

nephropathy, neuropathy, dermatopathy. • Metabolic complications (ketoacidosis etc)• Laboratory diagnosis of diabetes. (GTT, HBA1c, etc)

Pathology Minor CLI:• Metabolic Syndrome (Syndrome X).• Hypoglycemia syndromes, Insulinoma, (glucoganoma)• MODY, LADA, type 1.5, Gestational & Secondary DM.• Bronze Diabetes.

“Nothing great in the world has ever been accomplished without

passion”

- - CHRISTIAN FRIEDRICH HEBBEL

Pathology of Diabetes

Dr. Venkatesh M. ShashidharAssoc. Prof. & Head of Pathology

Diabetes..

“….a wonderful but not very frequent affection among men, being a melting down of the flesh and limbs into urine…Life is short,

offensive, and distressing, thirst unquenchable, death inevitable…”

-- Aretaeus of Cappadocia (AD 81-3)

• 150 AD – Aretaeus, named "diabetes“ Greek for "siphon” “Sweet” • 1788 – Cawley – damaged pancreas in DM.• 1921 – Banting & Best, Insulin

unite for diabetesworld diabetes day

14 November

Introduction Most Common non communicable disease (3%) Incidence increasing alarmingly (259m 2025) Asia Pacific – maximum Increasing incidence. High Morbidity & mortality. Shortens life (15y) – HTPN, MI, Stroke, CRF. 7th top cause of death, 50% unaware (Au)

World Statistics:

Diabetes Mellitus - Definition

2nd Century, Greek physician, Aretus named Diabetes from diabainein, “to flow through or siphon & Mellitus meaning sweet/Honey.

• * insipidus tasteless – dilute urine.

Disorder of metabolism (Carb, Prot & Fat)

Absolute/Relative deficiency of insulin. Characterized by hyperglycemia. Polyuria, Polydypsia, Polyphagia.

Criteria for the Diagnosis of Diabetes

1. Random blood glucose - 11.1mmol/L or high,

2. Fasting glucose - 7mmol/L or high

3. HbA1C of > 6.5%• On more than one occasion + classical signs & symp.

4. OGTT for borderline cases (5.5 - 6.9 mmol/L), >11mmol/L at 2 hours after a 75 gm of oral glucose.

Why Oral GTT - not IV..? * What is normal blood glucose..? <7..? Why glucose needs tight control..?

Pancreas Normal Anatomy:

Normal Pancreas:

Normal Pancreas:

Islet of Langerhans (Endocrine Pancreas)

Pancreatic acini (Exocrine Pancreas)

Normal Pancreatic Islet: (ipx stain)

α cells 20% (Glucagon) ß cells 70% (Insulin)

ßα

Other Cells in Islets: δ cells - Somatostatin

PP Cells - pancreatic polypeptideD1 cells – Vasoactive Intestinal PolypeptideEnterochromaffin – Seratonin.

Blood Glucose & Hormones

Hormones Insulin Glucortocoids Glucagon Growth Hormone Epinephrine

Action Glucose Glucose Glucose Glucose Glucose

Maintained within 3.5-5.5 mmol/l.

Insulin secretion:

InsulinAnabolic Steroid

GLUT4 *

only these tissue….!

Insulin - Anabolic Steroid

Transmembrane transport of glucose (Liver, muscle & adipose tissue. Maintain metabolism: • Striated Muscle glucose uptake

• Adipose tissue lipogenesis

• Hepatic gluconeogenesis.

Protein & triglyceride synthesis Nucleic acid & Protein synthesis

In DM Insulin glucose & catabolism (glycolysis, lipolysis, proteolysis)

Obesity & Diabetes: Relationship Excess free fatty acids (FFAs): Increased FFAs increase

insulin resistance. Inflammation: FFAs result in release from macrophages

and β cells of IL-1β – Pro-Infl. Adipokines: Adipocytes release pro inflammatory

cytokines in response to increased FFAs. (Also release adipnectins – anti inflammatory)

Peroxisome proliferatory-activated receptor-γ (PPARγ): activation of PPARγ improves insulin sensitivity. (thiazolidinediones - antidiabetics Pioglitazone).

Obesity & Insulin resistance.

Diabetes is a state of inflammation

Metabolic Syndrome (X) - IDF criteria

Central Obesity • >90cm male, >80 fem – Asian, chinese, Jap.• >94cm male, >80 fem – Europ, Africa, Arab.

+ Any two of the following.• Raised triglycerides >1.7mmol/l or treat.• Reduled HDL-C <1.03mmol/l or treat.• Hypertension 130/85 or treat.• Fasting plasma glucose >5.6mmol/l or DM2.

Australia prevalence 2005 – 30.7% 10 Year CVD risk - 23.4%

New in DM Pathogenesis: Incretins. Insulin release through Incretins (from intestine)

in response to glucose intake. • Glucagon-Like Peptide-1 (GLP-1)• Glucose-dependent Insulinotropic Polypeptide (GIP)

Stimulate β cells (Insulin) & Inhibit α (glucagon) Destroyed by dipeptidyl peptidase (DPP). Dysregulation in DM2 (early breakdown). Two new drugs, exenatide (GLP-1 mimetic) and

sitagliptin [DPP 4 inhibitor] – Approved for PBS. http://www.medscape.com/infosite/dia/article-3

GIP : glucose-dependent insulinotropic polypeptide (GIP)GLP-1: glucagon-like peptide-1 (GLP-1)DPP 4: enzyme dipeptidyl peptidase-4 (DPP-4) – breaks down GIP & GLP-1

Insulin Resistance:

JCU Research…!

The foundation of lasting self-confidence and self esteem is

excellence, mastery of your work.

- Brian Tracy

Diabetes Classification: (not a single disease)

• Type I – IDDM / Juvenile – 5-10%.• Type II – NIDDM /Adult onset – 90-95%.• MODY – 5% Maturity Onset Diabetes of Youth

□Genetic, sub types MODY 1–6 (3 & 2 common),

• LADA – Latent Autoimmune Diabetes in Adults (LADA)• Gestational Diabetes Mellitus.• Other. (neonatal diabetes, – Insulin gene defects)

Endocrinopathy, Downs Sy.

• Excess hyperglycemic stimulus (drugs & disease).□Cushings, Phaeochromocytoma, acromegaly, Steroid therapy.

• Beta cell destruction:□Pancreatitis/tumors/Hemochromatosis – Bronze diabetes.□Infectious – congenital rubella, CMV, TB,

MODY: Maturity Onset Diabetes of Young.

5% of DM in Young*, non obese, insulin release defect*

Like DM2, non-ketotic hyperglycemia, no DM Antibodies.

Auto. Dom. - Monogenic – Genetic testing*.

Treatment is specific to type. Unlike type 1 or 2

Subtypes: 1,2,3,4,5,6 – type 3 & 2 common.

1,3,4,5,6 – Insulin transcription defect HNF.

Type 2 – Enzyme glucokinase, defective β cell response.

Type 2 in children

LADA: Late onset Autoimmune DM

Rapid onset & progression to insulin dependency. Immune markers like type 1 diabetes, May lack ketoacidosis symptoms. Incidence: 6-10% (UK). Diagnosis: Elevated pancreatic autoantibodies Risk factors: Metabolic Syndrome LADA + Metabolic syndrome = DM Type 1.5. Features & complications of both type 1 & 2.

Type 1 in Adults

One machine can do the work of fifty ordinary men. No machine

can do the work of one extraordinary man.

- - Elbert Hubbard

Pathogenesis of Type I DM

Genetic HLA-DR3/4

EnvironmentViral infe..?

Insulin deficiency

Autoimmune InsulitisAb to ß cells/insulin

ß cell Destruction

Secondary DMInflammation,

Tumor, InfectionTrauma

Pancreatitis

Antibodies:Islet cell Ab - ICA

Insulin Auto Ab - IAAGlut. Acid Decarb - GAD65

Type-1 clinical course

Type IIPathogenesis

Relative

Insulin Def.β cell

dysfunction

?

Β cell ExhaustionIDDM

Progression of Type II

Years ..

DM2 Islets: Normal early amyloid late:

Normal.Loss of ß cells (only in late stage) replaced by Amyloid protein deposit (hyalinization).

Type-I Type-II Less common (10%) Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic complications Autoantibody: Yes Family History: No Insulin levels: low Islets: Insulitis 50% in twins

More common (90%) Adult >25 Years NIDDM* Months to years Chronic Vascular

complications. No Yes Normal or high * Normal / Exhaustion ~100% in twins

Type-I Type-II

Insulitis:Lymphocytic infiltrate within islets.

Islet Hyalinization:Central hyaline deposits replacing

dead beta cells(only in late stage…!)

Being a good human is maintaining complete harmony between thought, word and deed. Divergence between thought, word and deed is the cause of all our problems…!- BABA.

DM Complications: Glucose is like burning coal*

Glucose is highly reactive - damages proteins, cells & tissues.

Insulin - safely uses & stores glucose. – mom..!* Diabetes is state of insulin deficiency. Hyperglycemia PPP Tissue damage

Complications. Clinical symptoms & signs are mainly due to

complications. Acute: metabolic - DKA / HONK. Chronic: BV - Kidney, CNS & immune system.

Diabetes Complications:

Short term Complications: (metabolic)• Hypoglycemia • Diabetic Ketoacidosis DKA• Hyper Osmolar Non Ketotic coma HONK

Long term Complications: (Angiopathy)• Microngiopathy - Retinopathy, Nephropathy,

Neurophathy, dermatopathy.• Macroangiopathy – Atherosclerosis.

Pathogenesis of complications:

Insulin dependant tissue: Striated muscle, adipose tissue & Liver.

• Low glucose inside cell decreased cell metabolism. Starvation.

• High glucose outside Glycosylation damage (AGE), cross linking, trap plasma

proteins, LDL, cholesterol* - “diabetic pathy’s”

Insulin independent tissue:BV, nerve, (kidney, eye, CNS)

• Excess glucose□ Sorbitol, Polyol osmotic damage*□ Activation of Protein Kinase C Inflam. angiogenesis,

fibrosis.

DM2: Pathogenesis of complicationsInsulin Requiring Cells Striated Muscle Liver Adipose Tissue

Intra cellular hypoglycemia Low glucose: Liver: Gluconeogenesis Adipose: Lipolysis FFA

Extracellular hyperglycemia: Acute: DKA, HONK. Chronic: AGE deposition, glycosylation of cells, matrix, proteins -

Vascular & tissue damage, micro & macro angiopathy, ischemia, infarction, …*

Non-Insulin Requiring Cells Blood Vessels Nerves & Brain Kidney, Eye Lens

Intracellular Hyperglycemia Excess glucose: Glucose Aldose reductase

Sorbitol (Polyol) Osmotic cell swelling and dysfunction.

Activation of Protein Kinase C – Inflam. - IL-β

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

-- Latin quote

DM:Complications:

Macroangiopathy:

Atherosclerosis. Glycosylation of BM

DM Microangiopathy – pathogenesis

Normal

Diabetic

Glucose Glycosylation BM damage leak ‘AGE’ deposition

PATHOGENESIS OF DM COMPLICATIONS:1. Chronic Hyperglycemia.2. Glycosylation of BV B. membrane 3. Leakage of proteins, excess BM matrix.4. Narrow, thick, fragile, Leaky BV + Inflam.5. Leakage of LDL, protein, angiogenesis.

• Ischemia• Proteinuria (kidney)• Micro Aneurysms (retina)• Atherosclerosis.

Neuropathy – glucose neurotoxicity

Glucose polyol sorbitol fructose. Uses NADPH, increased oxidative damage. Loss of myelin (Sensory nerves). Peripheral Neuropathy

• Bilateral, symmetric• Progressive, irreversible• Paraesthesia, pain, muscle atrophy

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

DM-Neuropathy – Myelin stain

Normal

Neuropathic ulcer

Etiology: peripheral sensory loss Trauma ulcer.

Features: Deep punched out. callus around ulcer. Intact circulation. no

ischemia / gangrene*

Nephropathy Deposition of ‘AGE’ within glomerulus as nodules -

Nodular Glomerulo Sclerosis (KW) later diffuse sclerosis. Initial leakage microalbuminuria Nephrotic syndrome macro albuminuria End stage renal failure. Atherosclerosis of RA. Ischemia, infarctions. Papillary necrosis Infections – Pyelonephritis, abscess. Tubular damage – BM thickening.

Diabetic Glomerulosclerosis

B

A

A: Nodular glomerulosclerosis. B: Hyaline Arteriolosclerosis.

What is the pathogenesis?

Small contractedIrregular, scarredGranular surfaceThin cortex.

DM Kidney: thickening of BM (PCT)

PCT

DCT

PCT: Proximal Convoluted Tubule, DCT: Distal Convoluted Tubule

Nephropathy Progression

Nephropathy Classes: I - IV

DM kidney: papillary necrosis:

Papillary necrosis

Retinopathy: Non Proliferative

• Microaneurysms, • Dots & blots• Hard exudates - protein• Soft Cotton wool – infarcts• Macular edema.

Proliferative.• Neovascularization • Large hemorrhages• Retinal detachment.

Diabetic Retinopathy• Dots• Blots• Exudates• Infarcts• Neovascularisation• Hemorrhages• Retinal detachment• Fibrosis.

Cataract – Sorbitol.. Polyol..osmotic..

Lens epithelium (Insulin independent) is exposed to Hyperglycaemia, excessive flux of glucose to sorbitol by the polyol pathway. The accumulation of intracellular sorbitol exerts osmoprotection and prevents cell shrinkage. The excessive accumulation of sorbitol, causes an increased osmotic load within the lens causing swelling, fibre breakdown, and opacification (the osmotic hypothesis). Other mechanisms, including glycation and oxidative stress, may also be responsible for lens opacification.

infections: Fungal - Candidiasis

Immunosuppression. Not hyperglycemia ..! Multifactorial.

Pathogenesis of Infections in DM:

Multifactorial: Impaired inflammation – BV thickening. Decreased metabolism. WBC & chemical mediator glycosylation. Glycosylation of immunoglobulins. Tissue damage: Ischemia & infarctions. Increased glucose is not the cause*

You must learn to distinguish between good and bad, truth and untruth. You must use your

education for the purpose of serving community.

- Sai Baba

Summary Glucose is burning charcoal - complications. Glucose – Intestine - Incretins – B cells – tissues. Type 1 – destruction of B cells child - fast. Type 2 – Insulin dysfunction - adult – slow. Complications: excess glucose. Acute – DKA, HONK Chronic – BV & tissue damage. Micro & Macro

angiopathy. Immunosuppression, Macro angiopathy – Atherosclerosis. Microangiopathy – Artereolosclerosis. Pathy.. Retino, Neuro, Dermo, Nephro etc..

New Developments:

Incretin pathway GLP-1 & GIP DPP-4 inhibitors – gliptins. Or Incretin mimitics -

Always do your best. What you plant now, you will harvest later.

- - Og Mandino

Macrosomia With Polycythemia

Acanthosis Nigricans

Insulin resistance…

DM Amyotrophy - Painful muscle wasting

Pain & weakness of lower limb muscles. Neuropathy. Muscle wasting. Minimal sensory loss. Loss of knee reflex. Inflammation in spinal cord.

Diabetic Amyotrophy

Painful, proximal Asymmetrical, motor neuropathy.

Poor diabetic control – hyperglycemia – AGE.

Occlusion of capillaries of proximal lumbar plexus nerve damage. (no myelin degeneration*)

It is multiple mononeuropathy

Diabetic Xanthoma:

Reddish yellow, pruritic, painful, High blood glucose & lipids (Lipemic serum) Subcutaneous fat necrosis, foamy macrophages and free lipids. Risk of Pancreatitis. Control of glucose and lipids resolution. Erruptive Xanthoma – sudden crop of xanthomas * severe.

ComplicationsSummary:

"Decision and determination are the engineer and fireman of

our train to opportunity and success."

-- Burt Lawlor

Laboratory Diagnosis:

Urine glucose - dip-stick –Screening Fasting > 7mmol, Random >11mmol If Fasting level is 5.5 to 7 OGTT HbA1c - for follow-up, not for diagnosis Fructosamine – similar to HbA1c - long

term maintenance. Antibodies – Type-1 Gene testing: MODY

CPC-3.2– KFP Questions: DM – Definition, epidemiology Type I,II, NIDDM, IDDM, GDM, MODY. Etiology, Risk factors Pathogenesis of Clinical features – PPP Complications

• Acute – metabolic – ketoacidosis, coma• Chronic – vascular – Micro/Macro

Glycosylation, AGE, Polyols Lab Diagnosis – FBS, GTT, KFT, Lipids.

Points to remember/review:

Diabetes is a state of hyper ketabolism. Increased fat & protein breakdown, wt loss. Blood vessel damage – arteriosclerosis is central to

chronic complications. Increased Infections – why?. Glucose control is critical * why? Hypoglycemia is more dangerous. Not hyper FBS, GTT & HbA1C – interpretation.

Questions.. How – Ketoacidosis? How – hypoglycemia ? Macro Angiopathy ? – (atherosclerosis) Micro Angiopathy “Pathy” (arteriolosclerosis) Retinopathy – types, morphology, Nephropathy – types, morphology. Dermatopathy – morphology. Diabetic Amyotrophy - What is Diabetes insipidus ?

56y woman, nocturia 56y Fem, 3/12 nocturia excessive thirst and

polyuria(1-4 times) disturbing her sleep. Recently noticed blurring of vision, & tingling

sensation in her toes on both sides. Weight 94kg & height 1.71m. BMI 32. Hypertensive

for several years. Mother diabetic type2. Glucometer capillary BS is 15mmol/L.

What further Investigations? Ans: Twice..Lab RBS/FBS, GTT. Why not HbA1c for diagnosis? 60% of new diabetics have normal HbA1c. What other investigations should be done? Retina, urine, Lipid profile, Cardiac exam.

Endocrinology Other : (Brief notes)

Tumours – adenomas of endocrine gl. Cushings disease. Pheochromocytoma. Zollinger Ellison syndrome. MEN Syndromes – MEN type 1 & 2.

HHNK

Slower Onset

Glucose 600-2000

No Acidosis

Normal Breath

Shallow Respirations

DKA vs HHNKDKA

Faster Onset

Glucose 300-800

Acidosis

Fruity Breath

Kussmaul Respirations