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Biochemical Aspects of Diabetes Mellitus

Biochemical Aspects of Diabetes Mellitus. ENDO 412. Overview. DM is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by absolute or relative deficiency of insulin Two types of DM : Type 1 (insulin-dependent DM)

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Biochemical Aspects of Diabetes Mellitus

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  1. Biochemical Aspects ofDiabetes Mellitus ENDO 412

  2. Overview • DM is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by absolute or relative deficiency of insulin • Two types of DM: Type 1 (insulin-dependent DM) Type 2 (noninsulin dependent DM) • Prevalence of type 2 is increasing as: Aging (increase in rate of life-age of population) Increasing prevalence of obesity

  3. Comparison between type 1 & type 2 DM

  4. Type 1 Diabetes Mellitus

  5. Type 1 Diabetes Mellitus • about 10% of diabetics (in USA) • Onset: usually during childhood • Caused by absolute deficiency of insulin : maybecausedby autoimmune attack of b-cells of the pancreas, viral infection or toxin Destruction is enhanced by environmental factors as viral infection & a genetic element (that allows b-cells to be recognized as nonself) In identical twins if one sibling has type 1 DM, the other twin has only 30- 50% chance of developing DM • Rapid symptoms appear when 80-90% of the b-cells have been destroyed • Commonly complicated by diabetic ketoacidosis (DKA) • Treated only by insulin

  6. Onset of type 1 DM

  7. Metabolic changes of type 1 DM 1-Hyperglycemia 2-Diabetic Ketoacidosis (DKA) 3- Hypertriacylglyceridemia & hypercholestrolemia

  8. Metabolic changes of type 1 DM(cont.) 1-Hyperglycemia: increased glucose in blood Due to: Decreased glucose uptakeby muscles & adipose tissues (by GLUT-4) & Increased hepatic gluconeogenesis (& glycogenlysis) 2-DiabeticKetoacidosis (DKA): Increased ketone bodies in blood (ketonemia) leads to metabolic acidosis DKA occurs in untreated or uncontrolled cases of DM - In 25 – 40% of newly diagnosed type 1 DM (untreated & uncontrolled yet) - In stress states demanding more insulin (as during infection, illness or during surgery Uncontrolled DM) - No comply with therapy (intake of meals with no insulin medication i.e. Uncontrolled DM) Biochemical causes of diabetic ketoacidosis (DKA) Absence of insulin leads to increased mobilization of FFA from adipose tissues in the liver, FFA are oxidized to yield excess acetyl CoA that will synthesize KETONE BODIES.

  9. Metabolic changes of type 1 DM (cont.)Metabolic & Clinical Abnormalities in DKA Low Insulin Carbohydrates Metabolism In Sk. Ms. & Adipose In Liver Glucose Uptake Glycogenlysis Gluconeogenesis Lipids Metabolism Lipolysis in Adipose Tissue Fatty Acids in liver ketone Bodies (KETOGENESIS) Protein Metabolism Proteolysis Uptake of AA by liver Gluconeogenesis Hyperglycemia Plasma Osmolality Coma Prerenal Uremia Glycosuria Metabolic Acidosis Low Renal H+ Excretion Osmotic diuresis Ketonemia With Loss of water & Na+ & Hypovolemia Low Blood Bicarbonate Low pCO2 Nausea & Vomiting Acetone Smelt on Breath Increased Respiration Ketonuria Polyuria, & Dehydration Thirst Low GFR

  10. Metabolic changes of type 1 DM (cont.)Metabolic & Clinical Abnormalities in DKA Diagnosis of DKA 1- History (for a cause of DKA) 2- Clinical Examination 3- Lab Investigations: (to confirm the diagnosis & follow up of treatment) - Urineby dipstick: Glucose & Ketones +++ (RAPID TEST) - BloodChemistry Analysis: *Blood Glucose: High * Blood Urea: High (due to dehydration) * Electrolytes: Low (or normal) sodium High (or normal) potassium * Assessment of acid-base status: (metabolic acidosis) - Blood Bicarbonate: Low (usually below 5 mmol/L) - pCO2: Low (compensatory)

  11. Metabolic changes of type 1 DM (cont.)Metabolic & Clinical Abnormalities in DKA Biochemical Basis of Treatment of DKA AIM: (EMERGENCY TREATMENT) 1-Correction of dehydration(Hypovolemia): by IV fluids & Sodium 2- Correction of acidosis: by IV bicarbonate 3- Correction of metabolic abnormality: by insulin IV infusion 4- Potassiumis given with insulin treatment as insulin induces K+ entry into cells 5-IV GLUCOSESHOULD BE STARTED IN CASE GLUCOSE IN BLOOD FALLS BELOW 10 mmol/L (AVOID HYPOGLYCEMIA INDUCED BY INSULIN) 6-FOLLOW UP is QUITE IMPORTANT to monitor *Blood glucose level *Electrolytes (Na+ & K+) *Acid-base status (blood bicarbonate level)

  12. Metabolic changes of type 1 DM (cont.) 3- Hypertriacylglyceridemia & hypercholestrolemia: • Released fatty acids from adipose tissues are converted to triacylglycerol & cholesterol in the liver. Triacylglycerol is secreted from the liver in VLDL to blood (with liver cholesterol) • Chylomicrons(from diet fat) accumulates (due to low lipoprotein lipase activity as a result of low or absent insulin) Chylomicrons contain Triacyglycerols (mainly) & Cholesterol Increased VLDL & chylomicrons in blood results in hypertriacylglyceridemia & hypercholesterolemia

  13. Metabolic changes of type 1 DM

  14. Diagnosis of type 1 DM • Clinically: Age: during childhood or puberty (< 20 years of age) With Abrupt (Sudden) appearance of : Polyuria(frequent urination) Polydepsia(excessive thirst) Polyphagia(excessive hunger) Fatigue Weight loss Complicationas ketoacidosis (common, may be the cause of diagnosis) • Laboratory diagnosis: Fasting blood glucose: > or equal 126 mg/dl 100 – 125 mg/dl is called impaired fasting blood glucose HBA1c: High (more than 6% of normal hemoglobin) Insulin level in blood: low Circulating islet-cell antibodies detection

  15. Biochemical Aspects for Treatment & Control of Type 1 DM AIM Exogenous insulin by subcutaneous injection is given to: 1- Control Hyperglycemia (long run complications) & 2- Prevent occurrence of Ketoacidosis (emergency case!!) Strategies of Treatment 1- Standard Treatment 2- Intensive Treatment (Tight Control)

  16. Biochemical Aspects for Treatment & Control of Type 1 DM (cont.) 1- Standard Treatment: By one or two injections of insulin/day AIM: Mean blood glucose level225-275 mg/dl (normal: 110 mg/dl) HbA1c level: 8-9 % of total Hb(normal: 6% of total hemoglobin) HbA1c: is proportional to average blood concentration over the previous several months So, it provides a measure of how proper treatment normalized blood glucose in diabetic over several months

  17. Treatment of type 1 DM (cont.) 2- Intensive Treatment: (Tight control) By more frequent monitoring & subsequent injection of insulin (i.e. 3 or more times / day) It will more closely normalize blood glucose to prevent chronic complications of existence of hyperglycemia for a long period. AIM: Mean blood glucose levelsof 150 mg/dl HbA1c: approximately 7% of total hemoglobin Advantage: Reduction in chances of occurrence of chronic complications of DM: e.g. retinopathy, nephropathy & neuropathy by about 60%

  18. Biochemical Aspects for Treatment & Control of Type 1 DM (cont.) Complications of Treatment by Insulin Hypoglycemia is a common complication of insulin treatment (in more than 90% of patients on insulin medication) More Common with intensive treatment strategy Causes of hypoglycemia due to insulin treatment • Diabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia as: No glucagon (early in the disease) Noepinephrine (with progression of the disease diabetic autonomic neuropathy with inability to secrete epinephrine in response to hypoglycemia) So, patients with long-standing type 1 DM are particularly vulnerable to hypoglycemia • Hypoglycemia can be caused by strenuous exercise. Exercise promotes glucose uptake into muscles & decrease the need for exogenous insulin. So, blood glucose level should be checked before & after exercise to avoid hypoglycemia.

  19. Biochemical Aspects for Treatment & Control of Type 1 DM (cont.) Contraindications of Intensive Treatment • Children: risk of episodes of hypoglycemia may affect the brain development • Elderly people: as hypoglycemia can cause strokes & heart attacks in older people

  20. Type 2 Diabetes Mellitus

  21. Type 2 DM • 90%of diabetics (in USA) • Develops gradually • may be without obvious symptoms • may be detected by routine screening tests • BUT: many type 2 diabetics have symptoms of polyuria & polydepsia • In type 2 DM: a combination of insulin resistance & dysfunctional b-cells • Metabolic changes in type 2: are milder than type 1 as insulin secretion, although not adequate, restrains ketoacidosis • Diagnosis: blood glucose concentration equal or more than 126 mg/dl • Treatment: no requirement for insulin to sustain life BUT: insulin may be required to control hyperglycemia in some patients

  22. Causes of Type 2 DM Insulin Resistance & Dysfunctional b-cell Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulin Obesity is the most common cause of insulin resistance Obesity causes insulin resistance as: - substances produced by fat cells as leptin and resistin may contribute to development of insulin resistance - Free fatty acids elevated in obesity is involved in insulin resistance

  23. Causes of type 2 DM (cont.)Insulin Resistance & Dysfunctional b-cell Obesity, Insulin Resistance & DM • Obesity is the most common cause for insulin resistance. HOWEVER, Mostpeople with obesity & insulin resistance do notdevelop DM !! • How insulin resistance leads to DM?? 1- In the absence of defect in b-cell function, nondiabetic, obese individuals can compensate for insulin resistance by secreting highamounts of insulin from b-cell (i.e. Hyperinsulinemia) So, glucose levels in blood remain within normal range 2-In late cases, b-cell dysfunction with lowinsulin secretion occurs due to increased amounts of free fatty acids & other factors secreted by fat cells (as leptin & resistin) may end in development of type 2 DM (hyperglycemia).

  24. Causes of type 2 DM (cont.)Insulin resistance & dysfunctional b-cell In Type 2 DM Initially (In early stages : with Insulin resistance) the pancreas retainsb-cell capacity Insulin is secreted (may be higher than normal i.e. hyperinsulinemia) Normal blood glucose levels ________________________________________________ With time (late stages) b-cells become dysfunctional (low function) (due to harmful effects of FFAs & substances released by increased fat cells) b-cells fail to secrete enough insulin (low insulin) Increased blood glucose levels (hyperglycemia)

  25. Progression of Type 2 DM

  26. Metabolic changes in Type 2 DM Metabolic abnormalities of type 2 DM are the results of insulin resistance (in liver, muscle & adipose tissue) 1- Hyperglycemia 2- Hypertriacylglyceridemia 3-Nonketotichyperglycemic coma In cases with severe hyperglycemia especially in older age diabetics type 2 Hyperglycemia induces osmotic diuresis with loss of ECF The osmotic diuresis causes loss of water in excess of sodium leading to very high plasma osmolality (with hypernatremia) & marked dehydration No ketgenesisdue to presence of sufficient insulin to prevent DKA (or sometimes there is minimal ketogenesis with minimal metabolic acidosis i.e. Bicarbonate is not much lowered as in DKA) Treatment: Fluid replacement + Insulin IV infusion + follow up (Emergency Case!!)

  27. Metabolic changes in Type 2 DM

  28. Chronic Effects of DM The long-standing hyperglycemia causes the chronic complications of DM 1- Atherosclerosis:Diabetic Retinopathy Diabetic Nephropathy: glomerular proteinuria Diabetic Neuropathy: peripheral neuritis Cardiovascular Diseases (as MI) & strokes (as cereb. hge) 2- Sorbitol accumulation in certain cells with its complications 3- Glycated proteins formationwith microvascular complications For avoiding these complications, long-term control of hyperglycemia is recommended for all types of DM

  29. Chronic Effects of DM (cont.) In cells where entry of glucose is not dependent on insulin (eye lens, retina, kidney, neurones) Intracellular Levels of Glucose SORBITOL accumulation in these cells Cataract Diabetic Retinopathy Diabetic Nephropathy Diabetic Neuropathy

  30. Treatment of Type 2 DM • AIM: 1- To maintain blood glucose concentrations within normal limits 2- To prevent the development of long-term complications occurring due to prolonged hyperglycemia • Lines of treatment: 1- Weight reduction (to control insulin resistance) 2- Exercise 3- Dietary modification 4- Hypoglycemic agents 5- Insulin (required in some cases)

  31. Case Study Parents of a 15 years old boy was reported by his school that he was found drowsy & they have got to take him to hospital according to the advice of his school doctor. In the hospital, his mother told the doctor that her son seemed unusually thirsty for the last 3 months & she thought that he had lost weight. She admitted also that on the morning before leaving for school, he was complaining of abdominal pain & discomfort. On examination: • Semiconscious • Deep & rapid respiration • Pulse rate 120 beats/minute • BP: 90/50 • Cold extremities What investigations were recommended for him?? What is the diagnosis of this case?? What is the treatment ??

  32. Case Study cont. Clinical Biochemistry Lab Investigations Blood Chemistry • Random Blood Glucose: 550 mg/dl • Urea: 160 mg/dl (N: 20 -40) • Na+: 127 mmol/L (N: 135 – 145) • K+: 6.9 mmol/L (N: 3.5 – 4.5) • pCO2: 2.9 kPa (N: 4.4 – 6.1) • HCO3- : 7 mmol/L (N: 21 – 27.5) • pO2: 14 kPa (N: 12 – 17) Urine Analysis: • Urine Dipstick Test: - Glucose +++ - Ketone +++ - Albumin ++

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