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Best Answer: b. Glycosylated Albumin

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Best Answer: b. Glycosylated Albumin

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  1. Pakistan Society Of Chemical PathologistsDistance Learning Programme In Chemical PathologyLesson No 5Diabetes Mellitus (2nd Part)BySurg Commodore Aamir IjazMCPS, FCPS, FRCP (Edin)Professor Of Pathology / Consultant Chemical PathologistBahria University Medical & Dental College / PNS SHIFA Karachi

  2. Q 1: Which of the following tests is best indicator for assessment of intermediate- term control of diabetes mellitus:a. Fasting Plasma Glucoseb. Glycosylated albuminc. Glycosylated haemoglobind. OGTTe. Two hours post-prandial blood glucose • Best Answer: • b. Glycosylated Albumin

  3. Q 2: In diabetics there is an increase in Advanced Glycosylation End-products (AGE) production. The damage to which of the following organs /tissues leads to the start of a vicious cycle:a. Kidneyb. Lungsc. Liverd. Adipose tissuee. Muscles • Best Answer: • a. Kidney

  4. Mechanisms of Tissue Damage due to Hyperglycaemia Nonenzymaticglycosylation that generates Advanced Glycosylation End-products (AGEs) Activation of Protein Kinase C (PKC) Acceleration of the aldolasereductasepathway. Oxidative stress seems to be a theme common to all three pathways

  5. AGEs In chronic hyperglycemia, some of the excess glucose combines with free amino acids on circulating or tissue proteins. This nonenzymatic process initially leads to formation of Early glycosylation end products in the glomeruli of the kidneys. Later Advanced Glycosylation End Products (AGEs) are formed which are irreversible.

  6. AGEs (cont) Circulating levels of AGEs are raised, particularly due to renal insufficiency, since they are normally excreted in the urine. The net effect is tissue accumulation of AGEs that contributes to the associated renal and microvascular complications. AGE receptors called RAGE have also been found in various tissues

  7. Q 3: A 54 y male has Impaired Glucose Tolerance (IGT) for the last 10 years. Which of the following is the most important complication which his physician should keep in mind while monitoring him:a. Cardiovascular Diseaseb. Gangrene of the foot.c. Nephropathyd. Neuropathye. Retinopathy • Best Answer: • a. Cardiovascular Disease

  8. Macro-vascular Complications of DM IGT serves as a marker for the state of insulin resistance and predicts both large- and small-vessel vascular complications, independent of a patient’s progression to diabetes. Patients with IGT are at significantly increased risk for to macrovacular disease i.e. myocardial infarction and stroke than to microvascular complications(Nephropathy and retinopathy)

  9. Macro-vascular Complications of DM (cont) Cardiovascular complications associated with type 2 DM begin to develop well before type 2 DM is diagnosed. By that time, macrovascular damage may already be well advanced. IGT is more predictive of cardiovascular morbidity than IFG, probably because it is a better surrogate for the state of insulin resistance.

  10. Q 4: A 20 y female presented with obesity (BMI : 33 kg/m2), hirsuitism and menstrual irregularity. Her biochemical profile showed:• FPG : 6.8 mmol/L (123 mg/dl)• Trig: 4.9 mmol/L (431 mg/dl) • ALT: 82 U/L • HBsAg and Anti HCV: Negative• LH / FSH ratio: 3.28 • Testosterone: 4.25 ng/ml• Progesterone (21st day): 3.4 ng/ml She has been referred to you to find a cause which could explain all these findings. Which one of the following investigations will be the most helpful to find a common pathogenic mechanism in this patient:a. C-peptideb. Fasting Insulin c. HOMA-IRd. Leptine. Vitamin D3 • Best Answer: • c. HOMA-IR

  11. Methods for Demonstration of Insulin Sensitivity / Resistance Direct Methods HyperinsulinemicEuglycemic Glucose Clamp Insulin Suppression test

  12. Methods for Demonstration of Insulin Sensitivity / Resistance (Cont) Indirect Methods Intravenous glucose tolerance test Oral Glucose Tolerance Test Meal Tolerance Test

  13. Methods for Demonstration of Insulin Sensitivity / Resistance (Cont) Simple Surrogate Indexes For Insulin Sensitivity / Resistance Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Quantitative insulin sensitivity check index(QUICKI)

  14. Homeostatic model of assessment of insulin resistance (HOMA-IR) • HOMA-IR is a convenient and non-invasive method for the demonstration of IR. Its formula is : • Fasting Plasma Glucose x Serum Insulin • 22.5 • Normal Sensitivity = upto 2.24

  15. QUICKI QUICKI is another simple surrogate marker of IR / IS. It is calculated as following: 1/[log (fasting insulinin U/ml) + log (fasting glucose in mg/dl)

  16. Q 5:A 42 years male has following features:FPG: 5.9 mmol/L (109 mg/dl)Waist Circumference : 105 cm (42 inches)Triglyceride : 2.32 mmo/L (205mg/dl)Blood Pressure : 145/95 mmHGHDL-C : 1.2 mmol/L (40 mg/dl)What is the most probable diagnosis: Hyperlipidaemia Impaired Fasting Glycaemia (IFG) Metabolic Syndrome Obesity Systolic Hypertension • Best Answer: c.Metabolic Syndrome

  17. NCEP (ATP III) -NIH –USA 2001

  18. Metabolic Syndrome Three of these Five criteria should be fulfilled: Waist Circumference: > 87.5 cm (35 inches) in women and > 100 cm (40 inches) in men (abdominal obesity) Triglyceride: > 1.70 mmol/L (150 mg/dl) or higher) Blood Pressure: >130/85 mmHg or higher Fasting blood glucose: > 5.6 mmol/L (110 mg/dl) or higher HDL-C: < 1.29 mmol/L (50 mg/dl) in women and <1.1 mmol/L (40 mg/dl) for men

  19. Normal Insulin Function

  20. Insulin Resistance (IR)

  21. Q 6: It has been shown that intensive therapy with target A1C < 6.0% has no advantage in slowing macrovascular complications of DM. In this regard which of the following studies has shown strongest evidence:a. ACCORDb. DCCTc. INTERHEARTd. MRFITe. UKPDS • Best Answer: • a. ACCORD

  22. Macrovascular CVD Peripheral Artery Disease, Cerebrovascular disease Microvascular Retinopathy, Nephropathy, Neuropathy Chronic Complications of DM

  23. Glycemic Control and Vascular Complications in Type 2 DM The importance of tight glycemic control for protection against microvascular and cardiovascular disease in diabetes was established in the DCCT study for type 1 DM. Although the role of glycemic control on microvascular disease in type 2 diabetes was documented in the UKPDS, its role in reducing cardiovascular risk has not been established as clearly for type 2 DM.

  24. Hyperglycemia and Microvascular Disease The results of the UKPDS, Kumamoto, ADVANCE, and ACCORD trials show intensive therapy improves the outcome of microvascular disease (primarily retinopathy, nephropathy) as DCCT showed in Type 1 DM. So improved glycemic control improves the risk of microvascular complications in patients with type 1 and type 2 DM

  25. Hyperglycemia and MacrovascularDisease To date, no randomized clinical trial has convincingly demonstrated a beneficial effect of intensive therapy on macrovascular outcomes in individuals with long-standing type 2 diabetes But In ACCORD trial the patients on intensive blood glucose lowering therapy had a higher number of total and cardiovascular deaths (257 versus 203).

  26. Target Glycaemic Levels in Type 2 DM Fasting glucose of 3.9 to 7.2 mmol/L (70 to 130 mg/dL) or Postprandial glucose (90 to 120 minutes after a meal) < 10 mmol/L (180 mg/dL). or A1C value of ≤7.0 percent for most patients.

  27. Q 7: As per National Cholesterol Education Program (NCEP) guidelines DM has been assigned which of the following category of coronary heart disease (CHD) risk:a. Major risk factorb. Minor risk factorc. Non-modifiable risk factord. Not a risk factore. Risk Equivalent • Best Answer: • e. Risk Equivalent

  28. Cardiovascular risk factors Advancing age Diabetes and other high blood glucose conditions Dyslipidaemia Genetic background High alcohol consumption Hypertension Insulin resistance Left ventricular hypertrophy Male gender Menopause Obesity Sedentary lifestyle Smoking Bold text: modifiable risk factor

  29. The Risk Equivalence People with type 2 diabetes have the same risk of heart attack as people without diabetes who have already had a heart attack. Women with diabetes are subject to sudden death 300% more often and men with diabetes 50% more often than their counterparts without diabetes of the same age. Strokes occur twice as often in people with diabetes and hypertension as in those with hypertension alone. A person with diabetes has a two to three-fold greater risk of heart failure compared to a person without diabetes.

  30. Q 8:In a Tertiary Care Public Sector Hospital, facilities are available for Microalbuminuria test. It is being carried out on 24 h urinary sample by a ‘Dry’ method. But due to very high per test cost, increasing workload and paucity of funds it is becoming difficult to continue the facility. Moreover, the patients are also not very comfortable in carrying 24 h urine bottles after every few months for monitoring of their disease. Now considering all these issues please suggest answers of following questions: Microalbuminuriais a misnomer. Suggest a better name for this test. Can you carry out a preliminary test for selection of patients which should undergo microalbuminuria test? Suggest a change in the test protocol which will get rid of 24 h sample collection by the patient. What should be the cut off limits for the normal, microalbuminuria and overt proteinuria?

  31. Microalbuminuria Microalbuminuia is detection of small quantity of Albumin in the urine i.e 30-300 mg/d (and NOT small-size albumin) Urinary Albumin:Creatinine ratio is more useful (normal < 3.0 mg/mmol of creatinine)

  32. Microalbuminuria (cont) The normal rate of albumin excretion is less than 30 mg/day (20 µg/min) Persistent albumin excretion between 30 and 300 mg/day (20 to 200 µg/min) is called microalbuminuria In patients with diabetes it may be indicative of early diabetic nephropathy, unless there is some coexistent renal disease. Protein excretion above 300 mg/day (200 µg/min) is considered to represent macroalbuminuria (also called overt proteinuria, clinical renal disease, or dipstick positive proteinuria)

  33. Suggested Answer Q 8 a Microalbuminuria is a misnomer. Suggest a better name for this test. Paucialbuminuria Albumin Excretion Rate

  34. Suggested Answer Q 8 b Can you carry out a preliminary test for selection of patients which should undergo microalbuminuria test?  To meet the challenge of increasing workload and lack of funds, Urine Protein may first be tested by routine protein strips to rule out overt proteinuria in which case the proteins can be quantitated by a very less expensive method e.g. Pyrogellol dye method. One exception may be if albumin estimation is specially requested.

  35. Suggested Answer Q 8 c Suggest a change in the test protocol which will get rid of 24 h sample collection by the patient.  Albumin : Creatinine Ratio

  36. Suggested Answer Q 8 d What should be the cut off limits for the normal, microalbuminuria and overt proteinuria? Plz see next slide

  37. Suggested Answer Q 8 e Instead of Dry Method suggest a method which should be available on automation. Immunoturbidimetry

  38. Albumin : Creatinine Ratio The effect of variations in urine volume on the urine albumin concentration can be avoided by calculation of the urine albumin-to-creatinine ratio in a spot urine specimen. A value 30 to 300 mg/g of creatinine(3.4 to 34 mg/mmol of creatinine) suggests that albumin excretion is between 30 and 300 mg/day and, therefore, that microalbuminuria is present. Values > 300 mg/g (or 34 mg/mmol) are indicative of macroalbuminuria. This classification system requires that at least two of three specimens fall within the microalbuminuric or macroalbuminuric range over a three- to six-month period.

  39. Q 9: Please hypothesize two patients (A & B) admitted in an intensive care unit in semi-comatose condition. Capillary blood glucose of both patients is very high. Patient A is a known case of Type 1 DM and Patient B is known case of Type 2 DM. Now please answer following queries about these two patients: Name the most probable acute complication of DM in Patients A and Patient B. Their blood glucose was measured immediately after arrival. Which of these two patients will be having higher level of Blood Glucoseas compared to the other? Just in one line give biochemical reason of higher blood glucose in one patient than the other.   Name one biochemical abnormality which, if not treated, can lead to fatal outcome in each of these patients.

  40. Suggested Answer Q 9 a Name the most probable acute complication of DM in Patients A and Patient B.  Patient A -Diabetic Ketoacidosis Patient B - Hyperosmolar Hyperglycemic Diabetic Disease

  41. Suggested Answer Q 9 b Their blood glucose was measured immediately after arrival. Which of these two patients will be having higher level of Blood Glucose as compared to the other? Patient B with Hyperosmolar Hyperglycemic Diabetic Disease (may be around 40 mmol/L as compared to DKA in which it may be around 20 mmol/L)

  42. Suggested Answer Q 9 c Just in one line give biochemical reason of higher blood glucose in one patient than the other.   In Patient B there is relative insulin deficiency which is sufficient to take care of lipid metabolism. So in this patient glucose goes on increasing leading to hyperosmolalityand osmotic diuresis.

  43. Suggested Answer Q 9 d Name one biochemical abnormality which, if not treated, can lead to fatal outcome in each of these patients. Patient A : Hyperkalaemia Patient B : Dehydration

  44. Q 10: Diabetes Complications and Control Trial (DCCT) is a land mark study carried out in Type 1 DM and published in 1993. What do you know about this study regarding: a. What were the TWO chronic complications and ONE investigation of DM taken as the study outcome in this trial? b. What conceptual change in the management of Type 1 DM came after this study? c. Name a subsequent study which was carried out in Type 2 DM with similar results.

  45. Suggested Answer of Q 10 a What were the TWO chronic complications and ONE investigation of DM taken as the study outcome in this trial? Complications : Retinopathy and Nephropathy Investigation : HbA1C

  46. Suggested Answer of Q 10 b What conceptual change in the management of Type 1 DM came after this study? DCCCT Study showed that keeping blood glucose level as close to normal as possible, slows the onset of progression of eye, kidney and nerve complication.

  47. Suggested Answer of Q 10 c Name a subsequent study which was carried out in Type 2 DM with similar results. UKPDS (United Kingdom Prospective Diabetes Study)

  48. Q 11: Target Glycaemic Level in critical ill patients has been a controversial subject for the last one decade. Various levels have been suggested by different professional bodies. Specialist in-charge of the Intensive Care Unit (ICU) of your hospital requests you to help him in preparing a guidelines regarding Glycaemic Control in ICU. You need to find answers of following questions before writing these guidelines. Name a large landmark study which has forced international authorities to review the previous target levels and what is the most important conclusion of this study? Name the most common complication related with hyperglycaemia in critically-ill patients? What are the common causes of death of fatal hypoglycaemia in these patients? What is role of A1C estimation in these patients?

  49. Suggested Answer of Q 11a Name a large landmark study which has forced international authorities to review the previous target levels and what is the most important conclusion of this study?  NICE-SUGAR study Conclusion: intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg/dl resulted in lower mortality than did a target of 81 to 108 mg/dl.

  50. Suggested Answer of Q 11b Name the most common complication related with hyperglycaemia in critically-ill patients?  Sepsis

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