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Pathology of Diabetes

Medical school lecture for preclinical students. Updated Jul 2013.

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Pathology of Diabetes

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  1. Pathology of Diabetes 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

  2. 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: 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:

  3. ? 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. ? 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.

  4. 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% 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%

  5. 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% 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%

  6. Etiology of Thrush ? 1. Proteinuria 2. Bacterial infection 3. Glycosuria 4. Trichomoniasis 5. Candidiasis 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%

  7. II NIDDM II GDM I IDDM Sec IDDM Sec IDDM I LADA Sec IDDM I IDDM LADA MODY Most likely .. What type of DM ? 1. 56 year male obese 2. 30 year female following pregnancy 3. 8 year old boy, poor growth, DKA. 4. 24 year female Cushing‟s sy 5. 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 fever 9. 41y DM2, BMI 17.1, HbA1c 14.1, DKA 10.15y male, BMI 16.2, recurrent infect. II NIDDM II GDM I IDDM Sec IDDM Sec IDDM I LADA Sec IDDM I IDDM LADA MODY Most likely .. What type of DM ? 1. 56 year male obese 2. 30 year female following pregnancy 3. 8 year old boy, poor growth, DKA. 4. 24 year female Cushing‟s sy 5. 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 fever 9. 41y DM2, BMI 17.1, HbA1c 14.1, DKA 10.15y male, BMI 16.2, recurrent infect.

  8. 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  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)?

  9. 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 ** 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 **

  10. . 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.

  11. . “Nothing great in the world has ever been accomplished without passion” - - CHRISTIAN FRIEDRICH HEBBEL

  12. . Pathology of Diabetes Dr. Venkatesh M. Shashidhar Assoc. Prof. & Head of Pathology

  13. . 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 diabetes world diabetes day 14 November

  14. . 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)

  15. . World Statistics:

  16. . 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.

  17. . 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..?

  18. . Pancreas Normal Anatomy:

  19. . Normal Pancreas:

  20. . Normal Pancreas: Islet of Langerhans (Endocrine Pancreas) Pancreatic acini (Exocrine Pancreas)

  21. . Normal Pancreatic Islet: (ipx stain) α cells 20% (Glucagon) ß cells 70% (Insulin) ßα Other Cells in Islets: δ cells - Somatostatin PP Cells - pancreatic polypeptide D1 cells – Vasoactive Intestinal Polypeptide Enterochromaffin – Seratonin.

  22. . Blood Glucose & Hormones Hormones  Insulin  Glucortocoids  Glucagon  Growth Hormone  Epinephrine Action  Glucose  Glucose  Glucose  Glucose  Glucose Maintained within 3.5-5.5 mmol/l.

  23. . Insulin secretion:

  24. . Insulin Anabolic Steroid GLUT4 * only these tissue….!

  25. . 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)

  26. . 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).

  27. . Obesity & Insulin resistance. Diabetes is a state of inflammation

  28. . 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%

  29. . 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

  30. . 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

  31. . Insulin Resistance: JCU Research…!

  32. . The foundation of lasting self- confidence and self esteem is excellence, mastery of your work. - Brian Tracy

  33. . 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,

  34. . 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

  35. . 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

  36. . One machine can do the work of fifty ordinary men. No machine can do the work of one extraordinary man. - - Elbert Hubbard

  37. . Pathogenesis of Type I DM Genetic HLA-DR3/4 Environment Viral infe..? Insulin deficiency Autoimmune Insulitis Ab to ß cells/insulin ß cell Destruction Secondary DM Inflammation, Tumor, Infection Trauma Pancreatitis Antibodies: Islet cell Ab - ICA Insulin Auto Ab - IAA Glut. Acid Decarb - GAD65

  38. . Type-1 clinical course

  39. . Type II Pathogenesis Relative Insulin Def. β cell dysfunction ? Β cell ExhaustionIDDM

  40. . Progression of Type II Years ..

  41. . DM2 Islets: Normal early  amyloid late:  Normal. Loss of ß cells (only in late stage) replaced by Amyloid protein deposit (hyalinization).

  42. . 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

  43. . Type-I Type-II Insulitis: Lymphocytic infiltrate within islets. Islet Hyalinization: Central hyaline deposits replacing dead beta cells (only in late stage…!)

  44. . 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.

  45. . 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.

  46. . Diabetes Complications:  Short term Complications: (metabolic) • Hypoglycemia • Diabetic Ketoacidosis DKA • Hyper Osmolar Non Ketotic coma HONK  Long term Complications: (Angiopathy) • Microngiopathy - Retinopathy, Nephropathy, Neurophathy, der matopathy. • Macroangiopathy – Atherosclerosis.

  47. . 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.

  48. . DM2: Pathogenesis of complications Insulin 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

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

  50. . DM: Complications:

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