Diabetes mellitus pathophysiol-vnw


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Overview of diabetes mellitus with a focus on pathophysiological aspects

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  • Balanitis – candadiasis;
  • Diabetes mellitus pathophysiol-vnw

    1. 1. Diabetes mellitus Pathophysiology
    2. 2. Obesity Diabetes mellitus Hypertension “Obesity is the mother of metabolic diseases” The 3 public health scourges of modern times
    3. 3. World-wide estimated number of adults with diabetes by age group and year
    4. 4. Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from • defects in insulin secretion, • defects in insulin action (“insulin resistance”), • or both. long-term damage, dysfunction, and failure of various organs, especially the eyes kidney nerves heart blood vessels. “Complications”
    5. 5. Classification of diabetes  Type 1 ( was called “insulin- dependent DM”/ juvenile type of DM) ( 5-10%)  Type 2 (was called “non insulin- dependent DM” /adult onset DM ) (90-95%)  The “pre-diabetic stage” (impaired glucose tolerance)  Gestational DM -any degree of glucose intolerance with onset or first recognition during pregnancy [in 2-5% of all pregnancies]  Other specific types (1% - 2%) – genetic syndromes (affecting insulin secretion or action) – endocrinopathies (Acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, thyrotoxicosis) – diseases of pancreas (chronic pancreatitis, cancer) – drug- or chemical-induced (corticosteroids, beta-blockers, thiazide diuretics) – infections (viral) The main focus of this plenary
    6. 6. Type 1 Diabetes “insulin- dependent DM” “ juvenile-onset DM” Type 2 Diabetes “Non insulin- dependent DM” “ adult-onset DM”
    7. 7. Type 1 Diabetes “insulin- dependent DM” “ juvenile-onset DM” Type 2 Diabetes “Non insulin- dependent DM” “ adult-onset DM” Many require insulin i.e. insulin- dependent May develop when much older Developing at younger age groups (childhood obesity)
    8. 8. Type 1 Diabetes Type 2 Diabetes diabetes due to insulin resistance and inadequate compensatory insulin secretory response diabetes due to absolute deficiency of insulin
    9. 9. Positive Family history Type 1 Diabetes Type 2 Diabetes (but ”obesity gene” not yet identified) 30 %10 %
    10. 10. Pathogenesis Susceptibility genes identified e.g. HLA haplotypes DR3 & DR4. cell-mediated autoimmune destruction of the beta-cells of the pancreas by auto- antibodies genetic predisposition environmental factors viral infections stress toxins e.g. rat poison Type 1 Diabetes absolute insulin deficiency
    11. 11. Sequence of events in the development of Pathogenesis Type 1 Diabetes
    12. 12. Pathogenesis genetic predisposition environmental factors Diet Physical inactivity relative insulin deficiency  Obesity insulin resistance and inadequate compensatory insulin secretory response Type 2 Diabetes
    13. 13. ?Exhaustion ?Glucotoxicity ? Amyloid deposition Postreceptor defects (refer to 2nd messenger systems mediating insulin action) Impaired insulin action Insulin Counter regulatory hormones: Cortisol Growth hormone Anti-insulin action hyperglycaemia Inadequate secretory response insulin resistance Type 2 DiabetesPathogenesis Glucagon Catecholamines Target cells Pancreatic beta-cells: Hyperglycaemic effect vs Diabetogenic effect
    14. 14. 2nd messenger systems mediating insulin action What and where is the postreceptor defect? • Multiple, but unified hypothesis yet to be made
    15. 15. Sympathetic nervescells cells Glucagon Insulin receptor (-) receptor (+) receptor (+) receptor (-) Sympathetic nerves Net effect: incr. glucagon secretion Net effect: decr. insulin secretion (-) (+) Islets of Langerhans  Insulin-glucagon interaction in normal conditions Paracrinepathway Start here
    16. 16. Sympathetic nerves Glucagon Insulin receptor (-) receptor (+) receptor (+) receptor (-) Sympathetic nerves Net effect: incr. glucagon secretion Net effect: decr. insulin secretion Paracrinepathway (-) (+) Islets of Langerhans  DM: Hyperglucagonaemia is a feature of DM  Beta-blockers may further impair insulin secretion Start here cells cells
    17. 17. Natural history of Type 2 Diabetes cell secretory response to progressive insulin resistance (Blood glucose normal) cells no longer able to compensate Type 2 Diabetes
    18. 18. Too late? At the time of diagnosis, 50% of cell function has already been lost ( A study on patients in the UK) Type 2 Diabetes
    19. 19. Clinical presentation of DM • Asymptomatic (particularly type 2 DM) • Features resulting from the effects of insulin deficiency/resistance (review insulin actions) – The 3 Polys : • Polyuria / nocturia • Polydipsia • Polyphagia (in the presence of unintentional weight loss) • Complications – Acute: coma (ketoacidosis) (particularly type 1 DM) – Chronic: macrovascular and microvascular
    20. 20. Pancreas beta cells Insulin actions Glucose entry and utilization (oxidation, storage) Glucose entry and oxidation TG synthesis insulin actions: a review
    21. 21. Pancreas beta cells Insulin actions Glucose entry and utilization (oxidation, storage) Glucose entry and oxidation TG synthesis Metabolic consequences of insulin deficiency/resistance
    22. 22. Clinical Features of DM due to insulin lack Polyphagia (decr. leptin?) Starvation in the midst of plenty Hyperosmolar hyperglycemic syndrome (HHS) Lactic acidosis Lactic acidosis Muscle protein breakdown Acetoacetate,0H-butyrate, acetone
    23. 23. • Ketoacidosis - Life threatening – medical emergency! Stressful situation Positive feedback cycleStart here
    24. 24. Stressful situation Positive feedback cycleStart here • Treatment: Fluids(normal saline), I.V. insulin. Monitor plasma glucose (and K+ as insulin promotes uptake of glucose and K+ by muscles and adipose tissue) Insulin pump Rehydration - fluids
    25. 25. • hyperglycaemia • Excess glucose  attaches nonenymatically to amino acids of proteins *“glycosylation”+ • Glycosylation of haemoglobin  HbA1C  refects glycaemic control for the past 2 months (half life for RBCs) • Glycosylation of plasma proteins  fructosamine levels  refects glycaemic control for the past 6 weeks(shorter half life) Complications: pathogenesis
    26. 26. Complications: pathogenesis • Hyperglycaemia •  Excess entry of glucose into non-insulin dependent tissues – Nerves – Lens – Kidneys – Blood vessels • Increased intracellular glucose metabolized to sorbitol  fructose  increased osmotic load  influx of water  osmotic cell injury • E.g. lens  cataract
    27. 27. Vascular complications: pathogenesis • “glyocosylation”of collagen and other long-lived proteins in tissues •  Irreversible formation of advanced glycosylation end products (AGEs) accumulation of AGEs over the lifetime of blood vessel walls  – Protein cross-linking and trapping of plasma lipoproteins in blood vessel walls – Reduction in protein breakdown – AGE binding to cell receptors/ endothelial dysfunction •  vasculopathy
    28. 28. Microvascular complications • Retinopathy • Nephropathy • Neuropathy • Impaired skin healing  foot ulcers
    29. 29. Microvascular complications • Diabetic Retinopathy: – Capillary microanuerysms – Macular oedema – neovascularization –  partial or total vision loss
    30. 30. Microvascular complications • Diabetic nephropathy: – Thickening of glomerular basement membrane – Mesangial cell expansion – glomerulosclerosis Glomerular hypertension Progressive decline in glomerular filtration rate  nephrotic syndrome (leakage of albumin)/ renal failure
    31. 31. Microvascular complications • Diabetic neuropathy – also due to direct effects of hyperglycaemia and intracellular metabolic changes •  impaired nerve function (sensory, motor) – Symmetric polyneuropathy (distal feet and hands) – Autonomic neuropathy – Cranial neuropathy – Mononeuropathy (median neerve, peroneal nerve) – “diabetic foot”
    32. 32. Macrovascular complications • Large vessel atherosclerosis (due to hyperinsulinaemia, dyslipidaemia, hyperglycaemia) • Coronary arteries  myocardial ischaemia /infarction • Cerebral arteries  transient ischaemic attacks; cerebrovascular events  stroke • Peripheral artery disease  ischaemia intermittent claudication
    33. 33. (1) Symptoms (thirst, increased urination, unexplained weight loss) + a random plasma glucose concentration >200 mg/dL (11.1 mmol/L). (2) Fasting plasma glucose (FPG) >126 mg/dL (7.0 mmol/L) after an overnight (at least 8-hour) fast (3) Two-hour plasma glucose greater than 200 mg/dL (11.1 mmol/L) during a standard 75-g oral glucose tolerance test (OGTT) [ should be confirmed on a later day with one of the three methods listed]
    34. 34. Oral Glucose Tolerance Test (OGTT) (how much one can tolerate a glucose load without undue rise in plasma glucose levels; reflects how efficiently insulin can handle the glucose load)) Procedure Overnight fast 75 g glucose in 300 ml water given orally over 5 minutes Basal plasma glucose & every 30 minutes for 2 hours Urine tested for sugar Indications Borderline fasting (FPG) or postprandial PG Persistent glycosuria Glycosuria of pregnancy Pregnant women with family history of DM or had large babies
    35. 35. Plasmaglucose(mmol/l)
    36. 36. Symptoms of HYPOGLYCAEMIA AUTONOMIC • Sweating • Trembling • Pounding heart • Hunger • Anxiety NUEROGLYCOPENIC • Confusion • Drowsiness • Speech difficulty • Inability to concentrate • In-coordination NON-SPECIFIC: Nausea, tiredness, headache Diabetics on Insulin therapy “Hypoglycaemia awareness”
    37. 37. American diabetic association. Diagnosis and classification of diabetes mellitus. Diabetic care, 2004, 27 (Suppl. 1); 55-60. Robbins Pathologic basis of disease. Pocket companion. Saunders. Holt RIG and Hanley N. Essential Endocrinology and Diabetes. 5th ed. 2007, Blackwell. Merck Manual. iPhone app. Agile Parters. www.Merck Manuals.com. Diabetes power point file. Prof. Hla-Yee-Yee, IMU.