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  1. 1. Diabetes Mellitus Pathophysiology
  2. 2. Diabetes Mellitus <ul><li>Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. </li></ul><ul><li>The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. </li></ul><ul><li>The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs. </li></ul>
  3. 3. Insulin secretion
  4. 5. Action of insulin
  5. 6. Action of insulin on CHO, Fat and Protein Metabolism <ul><li>Carbohydrate </li></ul><ul><li>Facilitates the transport of glucose into muscle and adipose cells </li></ul><ul><li>Facilitates the conversion of glucose to glycogen for storage in the liver and muscle. </li></ul><ul><li>Decreases the breakdown and release of glucose from glycogen by the liver </li></ul>
  6. 7. <ul><li>Protein </li></ul><ul><li>Stimulates protein synthesis </li></ul><ul><li>Inhibits protein breakdown; diminishes gluconeogenesis </li></ul>
  7. 8. <ul><li>Fat </li></ul><ul><li>Stimulates lipogenesis- the transport of triglycerides to adipose tissue </li></ul><ul><li>Inhibits lipolysis – prevents excessive production of ketones or ketoacidosis </li></ul>
  8. 9. Major Reason for Insulin Secretion <ul><li> secretion </li></ul><ul><ul><li>Elevated blood glucose levels </li></ul></ul><ul><ul><li>Increased fatty acids </li></ul></ul><ul><ul><li>GI hormones </li></ul></ul><ul><ul><li>Glucagon, growth hormone, cortisol </li></ul></ul><ul><ul><li>Insulin resistance </li></ul></ul><ul><li> secretion </li></ul><ul><ul><li>Decreased blood glucose levels </li></ul></ul><ul><ul><li>Decreased food intake (fasting) </li></ul></ul>
  9. 10. Hyperglycemia <ul><li>an excessive amount of glucose circulates in the blood plasma </li></ul><ul><li>chronic levels exceeding 125 mg/dl can produce organ damage </li></ul>
  10. 11. Glucose Homeostasis
  11. 12. What goes wrong in Diabetes ? <ul><li>Multitude of mechanisms </li></ul><ul><ul><li>Insulin </li></ul></ul><ul><ul><ul><li>Regulation </li></ul></ul></ul><ul><ul><ul><li>Secretion </li></ul></ul></ul><ul><ul><ul><li>Uptake or breakdown </li></ul></ul></ul><ul><ul><li>Beta cells </li></ul></ul><ul><ul><ul><li>damage </li></ul></ul></ul>
  12. 13. Type 1 Diabetes <ul><li>Low or absent endogenous insulin </li></ul><ul><li>Dependent on exogenous insulin for life </li></ul><ul><li>Onset generally < 30 years </li></ul><ul><li>5-10% of cases of diabetes </li></ul><ul><li>Onset sudden </li></ul><ul><ul><li>Symptoms: 3 P’s: polyuria, polydypsia, polyphagia </li></ul></ul>
  13. 14. Type 1 Diabetes cell
  14. 16. Metabolic defects in Type 1 Diabetes <ul><li>Hyperglycemia and ketoacidosis </li></ul><ul><li>Hypertriacylglycerolemia </li></ul>
  15. 17. Type 2 Diabetes <ul><li>Insulin levels may be normal, elevated or depressed </li></ul><ul><ul><li>Characterized by insulin resistance, </li></ul></ul><ul><ul><li>diminished tissue sensitivity to insulin, </li></ul></ul><ul><ul><li>and impaired beta cell function (delayed or inadequate insulin release) </li></ul></ul><ul><li>Often occurs >40 years </li></ul>
  16. 18. Type 2 Diabetic cell
  17. 19. Insulin Receptors <ul><li>REMEMBER: the main action of the insulin receptor is to signal the cell to absorb glucose . </li></ul><ul><li>A decrease in insulin receptor signaling leads to type 2 diabetes mellitus. </li></ul><ul><ul><li>Thus, the cells are not able to take up glucose, leading to hyperglycemia (an increase in glucose circulating in the blood), and all the resulting sequelae. </li></ul></ul>
  18. 20. Type 2 Diabetes <ul><li>Risk factors: family history, sedentary lifestyle, obesity and aging </li></ul><ul><li>Controlled by weight loss, oral hypoglycemic agents and or insulin </li></ul>
  19. 21. Metabolic defects in Type 2 Diabetes <ul><li>Hyperglycemia </li></ul><ul><li>Hypertriacylglycerolemia ----- low levels of insulin ---- decreased activity of lipoprotein lipase ------ raised plasma level of VLDL </li></ul>
  20. 22. Long term effects of Diabetes Mellitus <ul><li>Microvascular complications :- </li></ul><ul><li>- retinopathy </li></ul><ul><li>- nephropathy </li></ul><ul><li>- neuropathy </li></ul><ul><li>Macrovascular complications :- </li></ul><ul><li>- stroke </li></ul><ul><li>- cardiovascular disease </li></ul>
  21. 23. Screening/Diagnosis of Diabetes
  22. 25. Diabetic Process <ul><li>Decreased insulin production or action </li></ul><ul><ul><li>-> Increased glucose accumulates in blood </li></ul></ul><ul><ul><li>-> hyperglycemia </li></ul></ul><ul><ul><li>-> need to dilute glucose in circulating blood </li></ul></ul><ul><ul><li>-> fluids drawn from intracellular spaces to vascular bed </li></ul></ul><ul><ul><li>-> Thirst (polydipsia) </li></ul></ul>
  23. 26. Diabetic Process <ul><li>Thirst (polydipsia) </li></ul><ul><ul><li>-> increased fluid intake </li></ul></ul><ul><ul><li>-> increased fluid volume </li></ul></ul><ul><ul><li>-> kidneys need to excrete excess volume </li></ul></ul><ul><ul><li>-> Polyuria (frequent urination) </li></ul></ul><ul><ul><ul><li>Glycosuria (excretion of glucose into urine) </li></ul></ul></ul>
  24. 27. Diabetic Process: <ul><li>Lack of glucose for energy/metabolism </li></ul><ul><ul><li>-> cells starve </li></ul></ul><ul><ul><li>-> increased hunger ( Polyphagia ) </li></ul></ul><ul><ul><li>-> increased food intake (weight gain) </li></ul></ul><ul><li>No glucose to metabolize </li></ul><ul><ul><li>-> protein metabolism (nitrogen imbalance) </li></ul></ul><ul><ul><li>-> fat metabolism: (ketone bodies (ketosis)) </li></ul></ul>
  25. 28. Diabetic Process: <ul><li>Polydipsia, polyuria and polyphagia can lead to a fluctuations in blood glucose levels (hyperglycemia and hypoglycemia) </li></ul><ul><ul><li>-> damage to small blood vessels throughout the body </li></ul></ul><ul><ul><li>-> serious impairment, especially kidneys, eyes, and heart </li></ul></ul><ul><li>In pregnancy: decreased glucose to uterus and increased glucose to fetus </li></ul><ul><ul><li>-> hypoglycemia at birth </li></ul></ul>
  26. 29. Importance of glucose regulation <ul><li>The brain: normally dependent on glucose for oxidative metabolism and function </li></ul><ul><li>Hypoglycemia </li></ul><ul><ul><li>brain fuel deprivation </li></ul></ul><ul><ul><ul><li>functional brain failure </li></ul></ul></ul><ul><ul><ul><ul><li>corrected by raising plasma glucose concentrations </li></ul></ul></ul></ul><ul><li>Hyperglycemia </li></ul><ul><ul><li>Osmotic water loss (cellular and systemic) </li></ul></ul><ul><ul><ul><li>Damages blood vessels </li></ul></ul></ul>
  27. 30. Hyperglycemia Symptoms <ul><li>Classic Hyperglycemic Triad (the 3 P’s of diabetes): </li></ul><ul><ul><li>Polydipsia </li></ul></ul><ul><ul><ul><li>frequent thirst </li></ul></ul></ul><ul><ul><ul><li>excessive thirst </li></ul></ul></ul><ul><ul><li>Polyuria </li></ul></ul><ul><ul><ul><li>frequent urination </li></ul></ul></ul><ul><ul><ul><li>excessive urination </li></ul></ul></ul><ul><ul><li>Polyphagia </li></ul></ul><ul><ul><ul><li>frequent hunger </li></ul></ul></ul><ul><ul><ul><li>pronounced hunger </li></ul></ul></ul>
  28. 31. Additional Symptoms of Hyperglycemia <ul><li>Blurred vision </li></ul><ul><li>Fatigue </li></ul><ul><li>Weight loss </li></ul><ul><li>Poor wound healing </li></ul><ul><li>Dry mouth </li></ul><ul><li>Dry or itchy skin </li></ul><ul><li>Impotence (male) </li></ul><ul><li>Recurrent infections </li></ul><ul><li>Kussmaul hyperventilation: deep, rapid breathing </li></ul><ul><li>Fruity/acetone smell on the breath </li></ul><ul><li>Cardiac arrhythmia </li></ul><ul><li>Stupor </li></ul><ul><li>Coma </li></ul><ul><li>Death </li></ul>
  29. 32. Glycemic Control <ul><li>Glucose cycle: glucose in the bloodstream is made available to cells in the body </li></ul><ul><ul><li>dependent upon </li></ul></ul><ul><ul><ul><li>glucose entering the bloodstream </li></ul></ul></ul><ul><ul><ul><li>insulin allowing appropriate uptake into the cells of the body. </li></ul></ul></ul><ul><ul><li>Both require management. </li></ul></ul>
  30. 33. Glycemic Control <ul><li>Management </li></ul><ul><ul><li>highly intrusive </li></ul></ul><ul><ul><li>compliance is an issue </li></ul></ul><ul><ul><ul><li>relies on user lifestyle change </li></ul></ul></ul><ul><ul><ul><li>often on regular sampling and measuring of blood glucose levels </li></ul></ul></ul><ul><li>Highly individual </li></ul>
  31. 34. Glycemic Control <ul><li>Many of the long-term complications of diabetes, especially microvascular complications, result from many years of elevated blood glucose levels. </li></ul><ul><li>Good glycemic control, (70-130 mg/dl, or 3.9-7.2 mmol/L) is the important goal of diabetes care. </li></ul>
  32. 35. Glycemic control <ul><li>The hemoglobin A1c (glycosylated hemoglobin) reveals “average” glucoses over the preceding 2-3 months. </li></ul><ul><li>In normal glucose metabolism, the glycosylated hemoglobin is usually 4-6% by the most common methods (normal ranges may vary by method). </li></ul>
  33. 36. Glycemic Control <ul><li>&quot;Perfect glycemic control&quot; </li></ul><ul><ul><li>glucose levels were always within the normal range (70-130 mg/dl, or 3.9-7.2 mmol/L) </li></ul></ul><ul><li>“ Perfect” glycemic control very difficult, and even &quot;good glycemic control&quot; usually describes blood glucose levels that average somewhat higher than the normal range. </li></ul><ul><li>“ Poor glycemic control” </li></ul><ul><ul><li>Persistently elevated blood glucose and glycosylated hemoglobin levels </li></ul></ul><ul><ul><li>May persist over months and years before severe complications develop. </li></ul></ul>
  34. 37. Summary <ul><li>Diabetes occurs when either there is inadequate insulin production in the pancreas or there is inadequate absorption of insulin into the cells. </li></ul><ul><li>Insulin is needed for metabolism of glucose for energy at the cellular level </li></ul><ul><li>Lack of glucose for metabolism  metabolism of fat and protein for energy, polyuria, polydipsia, and polyphagia (classic symptoms of diabetes) and others listed earlier </li></ul><ul><li>Chronic condition that can lead to multiple serious complications </li></ul><ul><li>Goal: glycemic control </li></ul>
  35. 39. Hypoglycemia symptoms <ul><li>Shakiness </li></ul><ul><li>Nervousness </li></ul><ul><li>Sweating </li></ul><ul><li>Dizziness or light-headedness </li></ul><ul><li>Sleepiness </li></ul><ul><li>Confusion </li></ul><ul><li>Another clue to nocturnal hypoglycemia is postprandial hyperglycemia after breakfast </li></ul><ul><li>Difficulty speaking </li></ul><ul><li>Anxiety </li></ul><ul><li>Weakness </li></ul><ul><li>Hypoglycemia can also happen during sleep </li></ul><ul><ul><li>crying out or having nightmares </li></ul></ul><ul><ul><li>finding pajamas or sheets damp from perspiration </li></ul></ul><ul><ul><li>feeling tired, irritable, or confused after waking up </li></ul></ul>
  36. 40. Hypoglycemia <ul><li>Hypoglycemia, also called low blood glucose or low blood sugar, </li></ul><ul><ul><li>occurs when blood glucose drops below normal levels. </li></ul></ul>