Metabolic Changes in DM

Question 1

describe T1DM

Answer 1

• insulin dependent diabetes mellitus/juvenile onset
• autoimmune destruction of B-cells in the islets of the pancreas, causing a reduciton in insulin secretion
• presents during adolescence
• patients need to be on life-long insulin

Question 2

describe T2DM

Answer 2

• non-insulin dependent
• obesity is an important risk factor for dev. of T2D and insulin resistance
• target tissues for insulin (liver, muscle, adipose) do not respond to circulating insulin (insulin resistance) and there is a decrease in insulin secretion with time (B-cell dysfunction)
• usually respond to oral hypoglycemia agents

Question 3

describe the mechanisms of hyperglycemia in T1 and T2 diabetes

Answer 3

Question 4

why does gluconeogenesis occur in diabetics?

Answer 4

• the insulin/glucagon ratio is low (no insulin)
• key gluconeogenic enzymes are activated (induced)
  
  • pyruvate carboxylase
  • PEPCK
  • F1,6 BPase
  • G6Pase
  • amino acids from muscle proteolysis are used as well
• Glycolysis is inhibited in the liver
• glycogenesis is inactive in liver and muscle

Question 5

explain the basis of glycosuria and polyuria

Answer 5

• in hyperglycemia, a large amount of glucose is filtered that exceeds the reabsorptive capacity of the tubule
• glucose is osmotically active (holds water) that results in polyuria/osmotic diuresis

Question 6

describe the flowchart of problems caused by decreased secretion of insulin/insulin resistance

Answer 6

Question 7

describe why ketosis occurs in T1D

Answer 7

• insulin deficiency results in uncontrolled adipose tissue lipolysis
  
  • HSL is overactive due to low insulin/glucagon ratio makes HSL in the active, phosphorylated form
• this leads to an increase in free FA delivery to the liver
• increased rates of B-oxidation (active CPT-1 and increased free FAs) results in the formation of acetyl CoA that is used for ketone body synthesis
• ketogenesis in liver >>>> peripheral utilization of ketone bodies

Question 8

explain the cause of metabolic acidosis

Answer 8

• excessive ketone bodies are excreted in the urine (ketonuria)
• increased formation of 3-HB and acetoacetate; ketone bodies are weak acids and bicarb levels fall since they are used for buffering the excessive protons produced (metabolic acidosis)
• increased anion gap
• compensation by the resp system = increased rate and depth of ventilation (hyperventilation) = Kussmaul breathing

Question 9

describe effects of hyperglycemia

Answer 9

• elevated blood glucose levels leads to glycosuria which results in increased water loss –> dehydration -> stimulation of the thirst center
• coma is usually due to hyperglycemia (osmotic effect: water moves out of ICF resulting in neuronal dehydration) and is worsened by metabolic acidosis

Question 10

describe changes in potassium levels in a diabetic

Answer 10

• insulin deficiency and acidosis result in a shift of potassium from the ICF to the ECF
  
  • this results in loss of K in urine
  • whole body K is reduced even though serum K is high
• when insulin is injected during treatment, K moves back into the ICF
  
  • since K reserves are low, patient is in danger of hypokalemia; may have to give K along with insulin

Question 11

describe the hyperosmolar, hyperglycemia state in T2D

Answer 11

• most common in T2D, usually caused by infxn/acute illness which causes worsening of insulin resistance
• hyperglycemia: plasmua glucose levels are markedly elevated
• hyperosmolarity: osmolarity of blood is increased due to the high blood glucose levels (>320 mOsm/L)
• polyuria caused by excessive loss of water in urine
• low blood volume caused by polyuria
• ketone body prod. NOT significant
  
  • patients have some insulin secretion which inhibits ketogenesis

Question 12

explain the cause of a coma in hyperglycemia patients

Answer 12

• intracellular dehydration in the neurons, as ICF water moves into ECF
  
  • high plasma osmolarity since glucose is osmotically active, which causes changes in hydration of neurons, which leads to neurological deficits and unconsciousness (coma)

Question 13

what are chronic complications of diabetes?

Answer 13

• patients have a higher plasma glucose levels -> higher HbA1c levels
• microvascular: eyes, retina, neurons, kidney
• macrovascular: atherosclerosis

Question 14

explain how sorbitol causes microvascular complications

Answer 14

• in the lens, nerve and kidney, sorbitol is formed by aldose reductase
  
  • sorbitol is osmotically active and results in cell swelling due to water retention

Question 15

describe the effect of advanced glycation end products (AGE)

Answer 15

• non-enzymatic addition of glucose to intracellular and extracellular proteins (process similar to formation of HbA1c)
• glycation of proteins results in cross-linking of glycated proteins and altered function
  
  • this leads to glomerular dysfunction, endothelial damages and changes in extracellular matrix
• AGE modified proteins are also more prone to oxidative damage

Question 16

describe how AGE affects neurons, nephrons, endothelium

Answer 16

• AGEs alter metabolism and function of neuronal proteins
  
  • AGEs bind to their receptors and cause release of proinflammatory molecules
• alteration of the glomerular basement membrane proteins of nephron – loss of albumin in urine (microalbuminuria)
• changes in endothelium – peripheral vascular disease

Question 17

explain how dyslipidemia leads to macrovascular complications

Answer 17

• patients with T1 and T2D have hypertriglyceridemia (increased circulating triglycerides) = there is increased chylomicrons and VLDL in circulation
  
  • due to decreased action of endothelial LPL (induced by insulin)