Pathology of Diabetes

1. Pathology of Diabetes Always do your best. What you plant now, you will harvest later.- - OgMandino<br />

2. CPC 3.2: Ms. ML, 18y, Thrush.<br />Recurrent thrush*, boils*, tired*, <br />Obese*, junk food, no exercise*, <br />polyuria, polydipsia* , Abd. Striae*, <br />Mom DM2*, smoker, social drinker.<br />Dipstick: Nitrate +, WCC 3+, Blood 2+, Prot. 2+, Glucose 2+ <br />MSU: Ecoli >108, swab: Candida 4+, RBGL 35.<br />? Key points: <br />? Differential Diagnosis: Thrush, UTI, STI, Pregn, DM<br />? Further questions:<br /> CPC 3.2: Ms. ML, 18y, Thrush.<br />Recurrent thrush*, boils*, tired*, <br />Obese*, junk food, no exercise*, <br />polyuria, polydipsia* , Abd. Striae*, <br />Mom DM2*, smoker, social drinker.<br />Dipstick: Nitrate +, WCC 3+, Blood 2+, Prot. 2+, Glucose 2+ <br />MSU: Ecoli >108, swab: Candida 4+, RBGL 35.<br />? Key points: <br />? Differential Diagnosis: Thrush, UTI, STI, Pregn, DM<br />? Further questions:<br />

3. CPC 3.1: Molly 15y.. Wee problem.<br />Molly is a 15 year old Y10 student comes to ED with her Aunty Ada, community health worker. Ada says Molly has ‘wee’ problem.<br />Molly : ‘I’m going to the toilet often to pass wee and it is sore and itchy afterwards’<br />? Key points: <br />? Differential Diagnosis: <br />? Further questions<br />? DM type <br />? How to confirm Investigations?<br />? Complications Prognosis? <br />? Management<br /> CPC 3.1: Molly 15y.. Wee problem.<br />Molly is a 15 year old Y10 student comes to ED with her Aunty Ada, community health worker. Ada says Molly has ‘wee’ problem.<br />Molly : ‘I’m going to the toilet often to pass wee and it is sore and itchy afterwards’<br />? Key points: <br />? Differential Diagnosis: <br />? Further questions<br />? DM type <br />? How to confirm Investigations?<br />? Complications Prognosis? <br />? Management<br />

4. ?Pathogenesis: “recurrent multisite infections”<br />Associated AIDS<br />Hyperglycemia<br />Ischemia<br />Immunodeficiency<br />Multifactorial<br /> ?Pathogenesis: “recurrent multisite infections”<br />Associated AIDS<br />Hyperglycemia<br />Ischemia<br />Immunodeficiency<br />Multifactorial<br />

5. Specific features for diagnosis of DM2?<br />On & off for long time.<br />Always drinking.<br />Obesity.<br />Recurrent boils.<br />Mom has DM2<br /> Specific features for diagnosis of DM2?<br />On & off for long time.<br />Always drinking.<br />Obesity.<br />Recurrent boils.<br />Mom has DM2<br />

6. Miss ML: Most likely diagnosis:<br />DM Type 1<br />DM Type 2<br />MODY 1<br />MODY 2<br />LADA<br /> Miss ML: Most likely diagnosis:<br />DM Type 1<br />DM Type 2<br />MODY 1<br />MODY 2<br />LADA<br />

7. ?Pathogenesis: Whitish vaginal discharge. <br />Proteinuria<br />Bacterial infection<br />Glycosuria<br />Trichomoniasis<br />Candidiasis<br /> ?Pathogenesis: Whitish vaginal discharge. <br />Proteinuria<br />Bacterial infection<br />Glycosuria<br />Trichomoniasis<br />Candidiasis<br />

8. “Nothing great in the world has ever been accomplished without passion”<br />- - CHRISTIAN FRIEDRICH HEBBEL<br /> “Nothing great in the world has ever been accomplished without passion”<br />- - CHRISTIAN FRIEDRICH HEBBEL<br />

9. Most likely .. What type of DM ? <br />56 year male obese<br />30 year female following pregnancy<br />8 year old boy, poor growth, DKA.<br />24 year female Cushing’s sy<br />68 Year male following Ca. pancreas.<br />32 male, DM, BMI 18, Anti-GAD +ve.<br />34 year male, extensive tuberculosis.<br />12 year old female following viral fever<br />41y DM2, BMI 17.1, HbA1c 14.1, DKA<br />15y male, BMI 16.2, recurrent infect.<br />II NIDDM<br />II GDM<br />I IDDM<br />Sec IDDM<br />Sec IDDM<br />I LADA<br />Sec IDDM<br />I IDDM<br />LADA<br />MODY<br /> Most likely .. What type of DM ? <br />56 year male obese<br />30 year female following pregnancy<br />8 year old boy, poor growth, DKA.<br />24 year female Cushing’s sy<br />68 Year male following Ca. pancreas.<br />32 male, DM, BMI 18, Anti-GAD +ve.<br />34 year male, extensive tuberculosis.<br />12 year old female following viral fever<br />41y DM2, BMI 17.1, HbA1c 14.1, DKA<br />15y male, BMI 16.2, recurrent infect.<br />II NIDDM<br />II GDM<br />I IDDM<br />Sec IDDM<br />Sec IDDM<br />I LADA<br />Sec IDDM<br />I IDDM<br />LADA<br />MODY<br />

10. . The foundation of lasting self-confidence and self esteem is excellence, mastery of your work.- Brian Tracy<br />

11. . Pathology of Diabetes<br />Dr. Venkatesh M. Shashidhar<br />Assoc. Prof. & Head of Pathology<br />

12. . What is Diabetes?<br />“….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…”<br />-- Aretaeus of Cappadocia (AD 81-3)<br /><ul><li>150 AD – Aretaeus, named "diabetes“ Greek word for "siphon”

13. . 1788 – Cawley – damaged pancreas in DM.

14. . 1921 – Banting & Best, Insulin</li></li></ul><li>Introduction<br />Diabetes mellitus (sweet urine)<br />3% of world population, 100m.<br />Incidence increasing alarmingly (259m 2025)<br />Most Common non communicable disease.<br />High Morbidity & mortality.<br />DM shortens life span by 15 years. <br />Leading cause of blindness and Kidney dis.<br />Pacific Islands – leaders in DM & Obesity…!<br />Aus: 7th leading cause of death, 1M.. half of whom may be unaware of their disease.<br />

15. . World Statistics:<br />

16. . Diabetes Mellitus - Definition<br />2nd Century, Greek physician, Aretus named Diabetes from diabainein, “to flow through or siphon & Mellitus meaning sweet/Honey. <br />* insipidus  tasteless – dilute urine.<br />Disorder of metabolism (Carb, Prot & Fat)<br />Absolute/Relative deficiency of insulin.<br />Characterized by hyperglycemia.<br />Polyuria, Polydypsia, Polyphagia.<br />

17. . Criteria for the Diagnosis of Diabetes<br />A random blood glucose concentration of 11mmol/L or higher, with classical signs and symptoms. or<br />A fasting glucose concentration of 7mmol/L or higher on more than one occasion. or<br />An abnormal oral glucose tolerance test (OGTT, done for borderline 5.5-6.9 mmol/L ), in which the glucose concentration is >11mmol/L at 2 hours after a standard carbohydrate load (75 gm of glucose).<br />

18. . Pancreas Normal Anatomy:<br />

19. . Normal Pancreas:<br />

20. . Normal Pancreas:<br />Duct<br /> Islet of Langerhans (Endocrine Pancreas)<br />Pancreatic acini (Exocrine Pancreas)<br />

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

22. . Blood Glucose & Hormones<br />Hormones<br />Insulin<br />Glucortocoids<br />Glucagon<br />Growth Hormone<br />Epinephrine<br />Action<br /> Glucose<br /> Glucose<br /> Glucose<br /> Glucose<br /> Glucose<br />Maintained within 3.5-5.5mmol/l. <br />

23. . Insulin secretion:<br />

24. . Insulin - Anabolic Steroid<br />Transmembrane transport of glucose (Liver, muscle & adipose tissue. Maintain metabolism: <br />Striated Muscle glucose uptake<br />Adipose tissue lipogenesis<br />Hepatic gluconeogenesis. <br /> glycogen & gluco-neogenesis.<br /> lipolysis  Lipogenesis.<br /> Protein & triglyceride synthesis<br /> Nucleic acid & Protein synthesis<br />In DM  Insulin   glucose &  catabolism<br />

25. . InsulinAnabolic SteroidGLUT4*<br />only these tissue….!<br />

26. . DM2: Pathogenesis – 3 mechanism.<br />Non-Insulin Requiring Cells<br />Blood Vessels<br />Nerves & Brain<br />Kidney, Eye Lens<br />Intracellular Hyperglycemia<br />Glucose polymers “Polyol” damage<br />Excess glucose:<br />Glucose  Aldosereductase Sorbitol (Polyol)  Osmotic cell swelling and dysfunction.<br />Insulin Requiring Cells<br />Striated Muscle<br />Liver<br />Adipose Tissue<br />Intra cellular hypoglycemia<br />Low glucose:<br />Liver: Gluconeogenesis<br />Adipose: Lipolysis  FFA<br />Extracellular hyperglycemia<br />Vascular & tissue damage…*<br />

27. . DM2: Pathogenesis<br />Liver & skeletal muscle insulin resistance<br />β-cell hypersecretion β-cell failure<br />Lipotoxicity<br />decreased incretin secretion<br />increased glucagon secretion<br />increased renal glucose re-absorption<br />appetite dysregulation<br />

28. . New in DM Pathogenesis: Incretins.<br />Insulin release through Incretins (from intestine) in response to glucose intake. <br />Glucagon-like Peptide-1 (GLP-1) <br />Glucose-dependent InsulinotropicPolypeptide (GIP)<br />stimulate βcells (Insulin) & Inhibit α (glucagon)<br />Destroyed by dipeptidyl peptidase (DPP).<br />Dysregulation in DM2 (early breakdown).<br />Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [DPP 4 inhibitor] – Approved for PBS.<br />http://www.medscape.com/infosite/dia/article-3<br />http://video.medscape.com/pi/editorial/cmecircle/2004/3418/flash/beaser/index.html<br />

29. . Incretins: physiology<br />

30. . Diabetes Classification: (not a single disease)<br />Primary DM<br />Type I – IDDM / Juvenile – 5-10%.<br />Type II – NIDDM /Adult onset – 90-95%.<br />MODY – 5% Maturity Onset Diabetes of Youth<br />Genetic, sub types MODY 1–6,<br />LADA – Latent Autoimmune Diabetes in Adults (LADA)<br />Gestational Diabetes Mellitus.<br />Other.<br />Secondary DM<br />Excess hyperglycemic stimulus.<br />Cushings, Phaeochromocytoma, acromegaly, Steroid therapy.<br />Beta cell destruction:<br />Pancreatitis/tumors/Hemochromatosis<br />Infectious – congenital rubella, CMV, TB, <br />Endocrinopathy, Downs Sy.<br />

31. . Metabolic Syndrome (X) - IDF criteria<br />Central Obesity <br />>90cm male, >80 fem – Asian, chinese, Jap.<br />>94cm male, >80 fem – Europ, Africa, Arab.<br />+ Any two of the following.<br />Raised triglycerides >1.7mmol/l or treat.<br />Reduled HDL-C <1.03mmol/l or treat.<br />Hypertension 130/85 or treat.<br />Fasting plasma glucose >5.6mmol/l or DM2.<br />Australia prevalence 2005 – 30.7% <br />10 Year CVD risk - 23.4%<br />

32. . LADA: Late onset Autoimmune DM<br />Features of both type 1 and type 2. Younger, Rapid onset & progression to insulin dependency. Immune markers like type 1 diabetes, may lack ketoacidosis symptoms. <br />Incidence: - 6-10% (UK). <br />Diagnosis: Elevated pancreatic autoantibodies<br />Risk factors: Metabolic Syndrome <br />LADA + Metabolic syndrome = DM Type 1.5.<br />Complications of both type 1 & 2. (metabolic, Macro & Microangiopathy etc).<br />

33. . MODY: Maturity Onset Diabetes of Young.<br />5% of DM, Young*, non obese, insulin release defect*<br />Like DM2, non-ketotichyperglycemia, no DM Antibodies.<br />Auto. Dom. - Monogenic – Genetic testing*.<br />Treatment is specific to type. Unline type 1 or 2 <br />Also known as Type 1.5 (MODY + LADA)<br />Subtypes: 1,2,3,4,5,6 – type 3 & 2 common.<br />1,3,4,5,6 – Insulin transcription defect  HNF.<br />Type 2 – Enzyme glucokinase, defective β cell response.<br />

34. . One machine can do the work of fifty ordinary men. No machine can do the work of one extraordinary man.- - Elbert Hubbard<br />

35. . Pathogenesis of Type I DM<br />Other Autoimmune disorders:<br /><ul><li>PS Glomerulonephritis

36. . Graves, Hashimoto thyroiditis.

37. . Rheumatic heart disease

38. . SLE, Collagen vascular disease

39. . Rheumatoid arthritis.</li></ul>Insulin deficiency<br />ß cell <br />Destruction<br />Antibodies:<br />Islet cell Ab - ICA<br />Insulin Auto Ab - IAA<br />Glut. Acid Decarb - GAD65<br />Autoimmune Insulitis<br />Ab to ß cells/insulin <br />Secondary DM<br />Inflammation, <br />Tumor, <br />Infection<br />Trauma<br />Pancreatitis<br />Environment<br />Viral infe..?<br />Genetic <br />HLA-DR3/4<br />

40. . Insulitis – Type I<br />Lymphocytes.<br />

41. . DM1Course:<br />

42. . Progression of Type II<br />Years ..<br />

43. . Relative <br />Insulin Def.<br />Pathogenesis of Type II DM<br />ß cell <br />Exhaustion<br />(IDDM)<br />

44. . Insulin Resistance:<br />Diabetes <br />

45. . Insulin Resistance:JCU Research…!<br />

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

47. . Type-I Type-II<br />Less common (10%)<br />Children < 25 Years<br />Insulin- Dependent <br />Duration: Weeks<br />Acute Metabolic complications<br />Autoantibody: Yes<br />Family History: No<br />Insulin levels: low<br />Islets: Insulitis<br />50% in twins<br />More common (90%)<br />Adult >25 Years<br />NIDDM* <br />Months to years<br />Chronic Vascular complications.<br />No<br />Yes<br />Normal or high *<br />Normal / Exhaustion<br />~100% in twins<br />

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

49. . 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.<br />

50. . DM Complications: <br />Glucose is highly reactive - damages tissues.<br />Glucose absorption, storage & use – Timely Insulin release - critical.<br />Diabetes is state of insulin deficiency.<br />Absolute/Delayed/inappropriate insulin response <br />Glucose excess – Hyperglycemia. <br />Neo-glucogenesis – Proteolysis, lipolysis<br />Clinical symptoms & signs are mainly due to complications.<br />Complications: <br />Acute Metabolic & Chronic Vascular.<br />Damage to BV, Kidney, CNS & immune system.<br />