Pbl Exam 3 Case 4

Front 1

1. Role of water in the human body

Where do molecular interactions typically occur?

Back 1

1. Transport of molecules
2. Solubilization of molecules
3. Dissipation of heat
4. Participation in chemical reactions (i.e. hydrolysis)
5. Maintenance of osmalitiy

Molecular interactions typically occur in an aqueous environment.

Front 2

2. Fluid compartments in the body

Back 2

Comprises about 50-60% of body weight in adults and 75% of body weight in children.

Total body water is 40L in an average 70 kg man.

Front 3

3. Hydrogen bonds in water

What are the strength of H-bonds?

Back 3

1. Water is a dipolar molecule

2. One water molecule can form hydrogen bonds with 4 other water molecules.

Hydrogen bond -> 4 kcal; approx 1/20th the strength of the covalent O-H bond (80 kcal)

Front 4

4. Hydration shells

Back 4

Water forms a hydration shell around both cations and anions

Front 5

5. Hydrogen bonds and polar solutes

Back 5

Hydrogen bonds between water and polar solutes are dynamic

They continuously dissociate and reform.

Front 6

6. Hydrogen bonds and temp changes

Back 6

Water responds to the input of heat by decreasing the extent of hydrogen bonding and to cooling by increasing the bonding between water molecules.

Front 7

7. What are the two electrolytes in the ECF (plasma and interstitial fluid)?

Back 7

1. Na+
2. Cl-

Front 8

8. What are the two electrolytes in the ICF (intracellular fluid)?

Back 8

1. K+
2. Phosphates (HPO4 2-)

Front 9

9. What is diabetic ketoacidosis?

Back 9

When the amount of insulin injected is inadequate, the body remains in a condition similar to a fasting state even though food is ingested.

The liver continues to metabolize fatty acids to the ketone bodies acetoacetic acid and β-hydroxybutyric acid.

These compounds are weak acids that dissociate to produce anions and hydrogen ions, thereby lowering the blood and cellular pH below normal range.

B/c the dissociation of the ketone bodies is causing the acidosis, it is classified as ketoacidosis.

Front 10

10. Osmotic diuresis

Back 10

High levels of compounds pass from the blood into the glomerular filtrate in the kidneys and then into the urine.

As a consequence of high osmolality of the glomerular filtrate, much more water is being excreted in the urine than usual (polyuria).

As a result of water lost from the blood into the urine, water passes from inside cells into the interstitial space and into the blood, resulting in an intracellular dehydration which can result in a coma.

Front 11

11. Why is a 0.9% solution of NaCl via IV used to rehydrate someone instead of water?

Back 11

0.9% solution of NaCl is 0.9 g NaCl/100 ml, which is 9 g/L.

NaCl ahs a molar weight of 58 g/mol so the concentration of NaCl is 0.155 M.

If all the NaCl were dissociated, the osmolality would by 310 mOsm/kg water. However, b/c NaCl si not completely dissociated, the osmolality of isotonic saline is approximately 290 mOsm/kg water.

The osmolality of plasma, interstitial fluids, and ICF is also approx 290 mOsm/kg water, so no large shifts of water or swelling occur when isotonic saline is given via IV.

Front 12

12. pH of water, acids, and bases

Back 12

Water slightly dissociates into hydrogen ions and hydroxide ions.

Concentration of H+ ions in 10^-7 mol/L (10^-7 M)

pH = -log [H+]

pH of water = - log [10^-7] = 7

Neutral pH -> [H+] = [OH-]

Acidic pH -> [H+] > [OH-]

Basic pH -> [H+] < [OH-]

Front 13

13. Conjugate pair

Back 13

Acids and bases come in what are called conjugate pairs;

Acids dissociate into a proton and conjugate base when placed in an aqueous environment.

HA -> H+ + A-
HA is the acid
A- is the conjugate base

A- + H+ -> HA
A- is the base
HA is the conjugate acid

Front 14

14. The conjugate acid formed is called...?

Back 14

___________-ic acid (i.e. acetic acid)

Front 15

15. The conjugate base formed is called...?

Back 15

___________-ate (i.e. acetate)

Front 16

16. Strong acids vs. weak acids

Back 16

Strong acids completely dissociate in water (e.g. HCl)

Weak acids incompletely dissociate in water (e.g. acetic acid)

Front 17

17. Ka (dissociation constant of a weak acid)

Back 17

Higher Ka -> stronger acid

Lower Ka -> weaker acid

Ka = ([H+][A-])/[HA]

Front 18

18. pKa

Back 18

High pKa -> weaker acid

Low pKa -> stronger acid

pKa = -log [Ka]

Front 19

19. Kw

Back 19

The ion product of water.

Because Kw, the product of [H+] and [OH-], is always constant, a decrease in [H+] must be accompanied by a proportionate increase in [OH-]

Kw = [H+][OH-] = 1 x 10^ -14

Front 20

20. Henderson-Hasselbalch equation

Back 20

pH = pKa + log ([base]/[acid])

Used to describe the quantitative relationship between pH, pKa, and the concentrations of a weak acid and its conjugate base in an aqueous solution.

Can be used to calculate the ratio of the conjugate base to its un-dissociated weak acid at a given pH if the pKa is known

When pH=pKa, the dissociation of a weak acid is 50% (i.e. the concentration of the protonated form is equal to the concentration of the deprotonated form)

Front 21

21. Acetylsalicylic acids

Back 21

Aspirin is rapidly converted to salicylic acid in the body. The initial effect of aspirin is to produce a respiratory alkalosis caused by a stimulation of the "metabolic" central respiratory control center in the hypothalamus.

This increase the rate of breathing and the expiration of CO2.

This is then followed by a complex metabolic acidosis caused partly by the dissociation of salicylic acid (pKa = ~3.5)

Front 22

22. Buffers

Back 22

Buffers consist of a weak acid and a conjugate base.

They resist changes in pH when H+ or OH- are added

They are most effective within one pH unit of their pKa

More concentrated buffers are more effective simply because they contain a greater total number of buffer molecules per unit volume that can dissociate or recombine with hydrogen ions.

Front 23

23. Titration curves

Back 23

A plot of pH versus OH- equivalents added

When pH = pKa, the buffer is resistant to changes in pH and the titration curve flattens out.

Front 24

24. Maintenance of body pH

What are the three systems which maintain the body pH?

Back 24

Normal metabolism produces around 13 to 22 moles of acid per day.

Buffers provide protection against this acidity by resisting changes in pH.

Body pH is maintained by:
1. Buffers
2. Expiration off CO2 thru lungs
3. Excretion of ammonium ion thru the kidneys and into the urine.

Front 25

25. Bicarbonate buffer system

Back 25

Bicarbonate is the major buffer system in RBCs.

In RBCs, carbonic anhydrase catalyzes the formation of carbonic acid, the major acid produced by the body.

The dissociation of carbonic acid and protonation of bicarbonate acts as a buffer to prevent large changes in pH within RBCs.

Front 26

26. Bicarbonate and hemoglobin in RBCs

Back 26

CO2 generated by normal metabolism (TCA cycle) is released into the blood.

RBCs take up CO2 and convert it to carbonic acid (H2CO3) via carbonic anhydrase.

Carbonic acid then dissociates into bicarbonate (HCO3-) and a proton (H+)

Hemoglobin absorbs protons and thereby buffers changes in pH because of Histidine residues present within the hemoglobin molecule (pKa of 6.7).

Front 27

27. Kussmaul's breathing

Back 27

Stimulation of the respiratory center in the hypothalamus induced by acidosis leads to deeper and more frequent respiration.

CO2 is expired more easily and rapidly than normal and thus the blood pH rises.

Front 28

28. Intracellular pH

Back 28

Bicarbonate is transported out the RBC in exchange for a Cl- ion.

Excess protons inside the RBC or other cells combine with hydrogen phosphate (HPO4 2-) to form dihydrogen phosphate (H2PO4-) in order to buffer changes in pH (phosphate buffer system is the 2nd most important in the body)

Intracellular proteins that contain histidine act as buffers against changes in pH.

Metabolic anions are transported out of cells together with protons

If the cell is too acidic, more H+ is transported out in exchange for Na+ ions by a different transporter.

Front 29

29. Urinary hydrogen, ammonium, and phosphate ions

Back 29

Sulfuric acid is generated from the sulfate-containing AAs and is dissociated into H+ and sulfate anion in the blood an urine.

Urinary excretion of H2PO4- helps to remove acid,

Ammonium ions are major contributors to buffering urinary pH, but not blood pH.

Cells in the kidney generate NH4+ and excrete it into the urine in proportion to the acidity of the blood.

As the renal tubular cells transport H+ into the urine, they return bicarbonate anions to the blood.

Front 30

30. Normal arterial blood pH

Back 30

[H+] = 40 nEq/L

pH = -log [0.00000004]

pH = 7.4

Front 31

31. Normal venous blood pH

Why the difference?

Back 31

pH = 7.35

B/c of the extra amounts of CO2 released from the tissues to form H2CO3 in these fluids

Front 32

32. Intracellular pH

Back 32

Usually slightly lower than plasma pH b/c the metabolism of the cells produces acid, especially H2CO3.

Can range from 6.0 - 7.4

Front 33

33. What is the pH of urine?

pH of gastric HCl?

Back 33

Urine pH = 4.5 - 8.0

Gastric HCl pH = 0.8

Front 34

34. What are the three primary systems that regulate the H+ concentration in the body to prevent acidosis or alkalosis?

Back 34

1. Chemical acid-base buffer systems of the body fluids
-reacts w/in seconds to minimize

2. Respiratory center
-reacts within a few minutes to elimiinate CO2 and, therefore, H2CO3 from the body

3. Kidneys
-slower to respond; takes hours to days, but are the most powerful of the acid-base regulatory system.

Front 35

35. What occurs with the addition of a strong acid to the bicarbonate buffer system?

Back 35

1. Increased H+ is released from the acid and is buffered by HCO3-

2. As a result, more H2CO3 is formed, causing increased CO2 and H2O production.

3. The excess CO2 greatly stimulates respiration, which eliminates CO3 from the extracellular fluid.

Front 36

36. What occurs with the addition of a strong base to the bicarbonate buffer system?

Back 36

1. OH- is released from the base and is buffered by H2CO3 to form additional HCO3-.

2. At the same time, the concentration of H2CO3 decreases (because it reacts with OH-), causing more CO2 to combine with H2O to replace the H2CO3.

3. The net result, therefore, is a tendency for the CO2 level in the blood to decrease, but the decreased CO2 levels in the blood inhibits respiration and decreases the rate of CO2 expiration.

Front 37

37. How do you calculate the pH of a solution if the molar concentration of HCO3- and the pCO2 is known?

Back 37

pH = 6.1 + log [HCO3- / (0.03 x pCO2)]

(For the bicarbonate buffer system, the pK is 6.1)

-An increase in the HCO3- concentration causes the pH to rise, shifting the acid-base balance toward alkalosis

-An increase in pCO2 causes the pH to decrease, shifting the acid-base-balance toward acidosis

Front 38

38. Where are the bicarbonate and pCO2 concentrations regulated?

Back 38

The bicarbonate concentration is regulated by the kidneys, whereas the pCO2 in extracellular fluid is controlled by the rate of respiration.

Front 39

39. Metabolic acid-base disorder

Back 39

Results from a primary change in extracellular fluid bicarbonate concentration

Front 40

40. Respiratory acid-base disorder

Back 40

Results from a primary change in pCO2 concentration

Front 41

41. Effective pH range of the bicarbonate buffer system

Back 41

pH = 5.1 - 7.1

or

Within one pH unit of 6.1

Front 42

42. What is the role of the phosphate buffer system?

Back 42

Important in buffering renal tubular fluid and intracellular fluids

Front 43

43. What is the pKa of the phosphate buffer system?

Back 43

pKa = 6.8; this allows the system to operate near its maximum buffering power in the normal pH of blood.

Front 44

44. What are two reasons why the phosphate buffers system is important in the renal tubular fluids?

Back 44

1. Phosphate usually becomes greatly concentrated in the tubules, thereby increasing the buffering power of the phosphate system.

2. The tubular fluid usually has a considerably lower pH than the extracellular fluid does, bringing the operating range of the buffer closer to the pKa of the system.

Front 45

45. What is the importance of the phosphate buffer system in intracellular fluids?

Back 45

The concentration of phosphate in theis fluid is many times that in the extracellular fluid.

Also, the pH of intracellular fluid is lower than that of extracellular fluid and therefore is usually close to the pKa of the phosphate buffer system.

Front 46

46. Consequence of the diffusion of CO2 thru cell membranes

Back 46

This diffusion of the elements of the bicarbonate buffer system causes the pH in intracellular fluid to change when there are changes in the extracellular pH.

This is why the buffer systems within the cells help prevent changes in the pH of extracellular fluid, but may take several hours to become maximally effective.

Front 47

47. What is the importance of intracellular proteins?

Back 47

Approx 60-70% of the total chemical buffering of the body fluids is inside the cells, and most of this results from the intracellular proteins.

In addition, another factors that contributes to their buffering power is the facts that the pKa's of many of these protein systems are fairly close to 7.4

Front 48

48. What is the isohydric principle?

Back 48

Whenever there is a change in H+ concentrations in the extracellular fluid, the balance of all the buffer systems changes at the same time.

The implication of this principle is that any condition what changes the balance of one of the buffer systems also changes the balance of all the others b/c the buffer systems actually buffer one another by shifting H+ back and forth between them.

Front 49

49. Pulmonary expiration of CO2 does what?

Back 49

It balances the metabolic formation of CO2.

If the rate of metabolic formation of CO2 increases, the pCO2 of the extracellular fluid is likewise increased.

A decreased metabolic rate lowers the pCO2.

If the rate of pulmonary ventilation is increased, CO2 is blown off from the lungs, and pCO2 in the extracellular fluid decreases.

Front 50

50. Increasing alveolar ventilation does what?

Back 50

It decreases the extracellular fluid hdyrogen ion concentration and raises pH.

The higher the alveolar ventilation, the lower the pCO2; conversely, the lower the alveolar ventilation rate, the higher the pCO2.

When CO2 concentration increases, the H2CO3 concentration and H+ concentration also increases, thereby lowering extracellular fluid pH.

Front 51

51. An increased hydrogen ion concentration stimulates what?

Back 51

It stimulates alveolar ventilation

Not only does the alveolar ventilation rate influence H+ concentration by changing the pCO2 of the body fluids, but the H+ concentration affects the rate of alveolar ventilation.

Front 52

52. What is the effect of blood pH on the rate of alveolar ventilation?

Back 52

The change in ventilation rate per unit pH change is much greater at reduced levels of pH compared w/increased levels of pH.

The reason for this is that as the alveolar ventilation rate decreases, owing to an increase in pH, the amount of oxygen added to the blood decreases and the partial pressure of oxygen in the blood also decreases, which stimulates the ventilation rate.

Therefore, the respiratory compensation for an increase in pH is not nearly as effective as the response to a marked reduction in pH.

Front 53

53. Feedback control of H+ concentration by the respiratory system.

Back 53

B/c increased H+ concentration stimulates respiration, and because increased alveolar ventilation decreases the H+ concentration, the respiratory system acts as a typical negative feedback controller of H+ concentration.

↑[H+] ⇒ ↑Alveolar ventilation

↑Alveolar ventilation ⇒ ↓Pco2

↓Pco2 ⇒ ↓[H+]

Front 54

54. Efficiency of respiratory control of hydrogen ion concentration

Back 54

Respiratory control cannot return the H+ concentration all the way back to normal when a disturbance outside the respiratory system has altered pH.

The respiratory system has an effectiveness between 50 and 75%; corresponding to a feedback gain of 1 to 3.

That is, if the H+ concentration is suddenly increased by adding acid to the extracellular fluid and pH fall from 7.4 to 7.0, the respiratory system can return the pH to a value of about 7.2 to 7.3.

Front 55

55. Buffering power of the respiratory system

Back 55

Respiration regulation of acid-base balance is a physiologic type of buffer system b/c it acts rapidly and keeps the H+ concentration from changing too much until the slowly responding kidneys can eliminate the imbalance.

One to two times as much acid or base can normally be buffered by this mechanism as by the chemical buffers.

Front 56

56. Respiratory acidosis due to impaired lung function

Back 56

Abnormalities of respiration can also cause changes in H+ concentration; for example, an impairment of lung function decreases the ability of the lungs to eliminate CO2; this causes a buildup of CO2 and a tendency towards respiratory acidosis.

Also, the ability to respond to metabolic acidosis is impaired b/c the compensatory reductions in pCO2 that would normally occur by means of increased ventilation are blunted.

Front 57

57. Renal control of acid-base balance

Back 57

The kidneys control acid-base balance by excreting either an acidic or basic urine.

Front 58

58. Mechanism of kidney excretion of acids or bases

Back 58

1. Large numbers of HCO3- are filtered continuously and if they are excreted into the urine, bases are removed from the blood.

2. Large numbers of H+ are also secreted into the tubular lumen by the tubular epithelial cells, thus removing acid from the blood.

3. If more H+ is secreted than HCO3- if filtered, there will be a net loss of acid from the extracellular fluid.

4. Conversely, if more HCO3- is filtered than H+ is secreted, there will be a net loss of base.

Front 59

59. What are the three fundamental mechanisms by which the kidneys regulate extracellular fluid H+ concentration?

Back 59

1. Secretion of H+
2. Reabsorption of filtered HCO3-
3. Production of new HCO3-

Front 60

60. Where does hydrogen ion secretion and bicarbonate reabsorption occur?

Back 60

In virtually all parts of the tubules except the descending and ascending thin limbs of the loop of Henle.

About 80-90% of the bicarbonate reabsorption occurs in the proximal tubule, so that only a small amount of bicarbonate flows into the distal tubules and collecting ducts.

In the thick ascending loop of Henle, another 10% of the filtered bicarbonate is reabsorbed and the remainder of the reabsorption takes place in the distal tubule and collecting duct.

For each bicarbonate reabsorbed, a tubular secretion of H+ must occur.

Front 61

61. Secondary active transport of hydrogen ions

Back 61

The epithelial cells of the proximal tubule, the thick segment of the ascending loop of Henle, and the early distal tubule all secrete H+ into the tubular fluid by sodium-hydrogen counter-transport.

This secondary active secretion of H+ is coupled with the transport of Na into the cell at the luminal membrane by the sodium-hydrogen exchanger protein, and the energy for H+ secretion against a concentration gradient is derived from the sodium gradient favoring Na movement into the cell.

This gradient is established by the sodium-potassium ATPase pump in the basolateral membrane.

More than 90% of the bicarbonate is reabsorbed in this manner, required large amounts of H+ to be secreted each day by the tubules.

Front 62

62. Process of H+ secretion and bicarbonate reabsorption

Where does this occur?

Back 62

1. Active secretion of H+ into the renal tubule
2. Tubular reabsorption of bicarbonate ions by combination of H+ to form carbonic acid, which dissociates to form CO2 and water.
3. Sodium ion reabsorption in exchange for H+ secretion

This patten of H+ secretion occurs in the proximal tubule, the thick ascending segment of the loop of Henle, and the early distal tubule.

Front 63

63. Net result of H+ secretion and HCO3- reabsorption?

Back 63

For every H+ secreted into the tubular lumen, and HCO3- enters the blood.

Front 64

64. Can the bicarbonate ions permeate the luminal membranes of the tubular cells?

Back 64

Bicarbonate ions do not readily permeate the luminal membranes of the renal tubular cells.

Therefore, the HCO3- that is filtered by the glomerulus cannot be directly reabsorbed.

Front 65

65. How are filtered bicarbonate ions reabsorbed by the tubules?

Back 65

1. First, the bicarbonate ion must combine with a H+ to generate H2CO3.
2. The H2CO3 formed then dissociates into CO2 and H2O.
3. The CO2 can then move easily across the tubular membrane; therefore, it instantly diffuses into the tubular cell, where it recombines with H2O under the influence of carbonic anhydrase, to generate a new H2CO3 molecule.
4. This H2CO3 in turn dissociates to form HCO3- and H+
5. The HCO3- then diffuses thru the basolateral membrane into the interstitial fluid and is taken up into the peritubular capillary blood.

Front 66

66. What two processes facilitate the transport of HCO3- across the basolateral membrane?

Back 66

1. Na+_HCO3- co-transport

2. Cl-_HCO3- exchange

Front 67

67. What is the net result of hydrogen secretion and bicarbonate reabsorption?

Back 67

Each time an H+ is formed in the tubular epithelial cells, an HCO3- is also formed and released back into the blood.

The net effect of these reactions is the reabsorption of HCO3- from the tubules, although the HCO3- that actually enters the extracellular fluid is not the same as that filtered into the tubules.

Front 68

68. Titration of bicarbonate ions in metabolic acidosis or alkalosis

Back 68

In metabolic alkalosis, the excess HCO3- cannot be reabsorbed; therefore, the excess HCO3- is left in the tubules and eventually excreted into the urine.

In metabolic acidosis, there is excess H+ relative to HCO3-, causing complete reabsorption of the bicarbonate; the excess H+ passes into the urine.

Thus, the basic mechanism by which the kidneys correct either acidosis or alkalosis is incomplete titration of H+ of HCO3-; leaving one or the other to pass into the urine and be removed from the extracellular fluid.

Front 69

69. Primary active secretion of H+

Back 69

Beginning int he late distal tubules and continuing thru the remainder of the tubular system, the tubular epithelium secreted H+ by primary active transport.

H+ is transported, directly across the luminal membrane of the tubular cell by a specific protein, a hydrogen-transporting ATPase (uses ATP for pumping H+)

The primary active secretion of H+ occurs in a special type of cell called the intercalated cells of the late distal tubule and in the collecting tubules.

Front 70

70. What is the mechanism of primary active secretion of H+?

Back 70

1. The dissolved CO2 in the cell combines w/H2O to form H2CO3
2. The H2CO3 then dissociates into HCO3-, which is reabsorbed into the blood, plus H+, which is secreted into the tubule by means of the hydrogen ATPase mechanism.

For each H+ secreted, an HCO3- is reabsorbed, similar to the process in the proximal tubules.

Front 71

71. Whats the main difference between H+ secretion and HCO3- reabsorption in this later part of the nephron?

Back 71

The main difference is that H+ moves across the luminal membrane by an active H+ pump instead of by counter-transport, as occurs in the early parts of the nephron

Front 72

72. Significant importance of the later part of the nephron

Back 72

This mechanism is important in forming a maximally acidic urine.

In the proximal tubules, H+ concentration can only be increased about 3-4x.

However, in the distal collecting tubules, the H+ concentration can be increased as much as 900x normal!

Front 73

73. What happens where there's an excess of H+ in the urine?

Back 73

The H+ combines with buffers other than HCO3- and this results in the generation of new HCO3- that can also enter the blood.

Front 74

74. Phosphate buffer system

Back 74

Becomes concentrated in the tubular fluid b/c of their relatively poor reabsorption and b/c of the reabsorption of water from the tubular fluid.

Therefore, although phosphate is not an important extracellular fluid buffer, it is much more effective as a buffer in the tubular fluid.

The one difference between this buffer system and the bicarbonate system is that the HCO3- that is generated in the tubular cell and enters the peritubular blood represents a net gain of HCO3- by the blood, rather than merely a replacement of filtered HCO3-.

Front 75

75. Ammonia buffer system

Back 75

This is a second buffer system in the tubular fluid that is even more important quantitatively than the phosphate buffer system.

Composed of ammonia and ammonium ion.

Ammonium ion is synthesized from glutamine, which breaks down to form two ammonium ions and two HCO3-.

Thus, for each molecule of glutamine metabolized in the proximal tubules, 2 NH4+ are secreted into the urine and 2 HCO3- are reabsorbed into the blood.

The HCO3- generated by this process constitutes new bicarbonate as well.

Front 76

76. Mechanism of NH4+ addition to the tubular fluids

Back 76

H+ is secreted by the tubular membrane into the lumen, where it combines with NH3 to form NH4+, which is then excreted.

The collecting ducts are permeable to NH3, which can easily diffuse into the tubular lumen.

However, the luminal membrane of this part of the tubules is much less permeable to NH4+; therefore, once the H+ has reacted with NH3 to form NH4+, the NH4+ is trapped in the tubular lumen and eliminated in the urine.

For each NH4+ excreted, a new HCO3- is generated and added to the blood.

Front 77

77. Chronic acidosis and NH4+

Back 77

Increases NH4+ excretion which also generates new bicarbonate

Front 78

78. Determination of bicarbonate excretion

Back 78

Urine flow rate multiplied by urinary bicarbonate concentration

This number indicates how rapidly the kidneys are removing HCO3- from the blood

Front 79

79. Determining the amount of new bicarbonate contributed to the blood at any given time

Back 79

Calculated by measuring NH4+ excretion

(urine flow rate multiplied by urinary NH4+ concentration)

Front 80

80. Titratable acid

Back 80

This is the value that is used to determine the amount of the nonbicarbonate, non-NH4+ buffer excreted in the urine

Front 81

81. Net acid excretion

Back 81

net acid excretion =
(NH4+ excretion + urinary titratable acid - Bicarbonate excretion)

Front 82

82. Regulation of renal tubular hydrogen ion secretion

(What are the two most important stimuli for increasing the H+ secretion by the tubules in acidosis?_

Back 82

The most important stimuli for increasing H+ secretion by the tubules in acidosis are:

1. An increase in pCO2 of the extracellular fluid

2. An increase in H+ concentration of the extracellular fluid (decreased pH)

Front 83

83. Excessive aldosterone secretion

Back 83

Increases H+ secretion into the tubular fluid, and thus, increased amounts of bicarbonates added to the blood.

Causes alkalosis

Front 84

84. Increased angiotensin II leads to...?

Back 84

Also increases H+ secretion and HCO3- reabsorption

Causes alkalosis

Front 85

85. Extracellular fluid volume depletion leads to...?

Back 85

Stimulates sodium reabsorption by the renal tubules and increases H+ secretion and HCO3- reabsorption

Causes alkalosis

Front 86

86. How does extracellular fluid volume depletion causes increased secretion of H+?

Back 86

1. Increased angiotensin II levels, which directly stimulate the activity of the Na+_H+ exchanger in the renal tubules

2. Increased aldosterone levels, which stimulate H+ secretion by the intercalated cells of the cortical collecting tubules.

Front 87

87. Six factors that increase H+ secretion and HCO3- reabsorption

Back 87

1. ↑pCO2

2. ↑H+, ↓HCO3-

3. ↓Extracellular fluid volume

4. ↑Angiotensin II

5. ↑Aldosterone

6. Hypokalemia

Front 88

88. Six factors that decrease H+ secretion and HCO3- reabsorption

Back 88

1. ↓pCO2

2. ↓H+, ↑HCO3-

3. ↑Extracellular fluid volume

4. ↓Angiotensin II

5. ↓Aldosterone

6. Hyperkalemia

Front 89

89. Primary compensation for metabolic acidosis

Back 89

↑ Ventilation rate to reduce pCO2

Front 90

90. Primary compensation for respiratory acidosis

Back 90

↑ Plasma HCO3- concentration by the kidneys

Front 91

91. Primary compensation for metabolic alkalosis

Back 91

↓ Ventilation rate to raise pCO2

Front 92

92. Primary compensation for respiratory alkalosis

Back 92

↓ Plasma HCO3- concentration by the kidneys by increasing renal excretion of HCO3-

Front 93

93. What can cause respiratory alkalosis?

Back 93

1. Person ascending to a high altitude
2. Hyperventilation

Front 94

94. What can cause metabolic acidosis?

Back 94

1. Renal tubular acidosis
-defect in renal secretion of H+ or in reabsorption of HCO3- or both

2. Diarrhea
-loss of large amounts of sodium bicarbonate into the feces

3. Vomiting of intestinal contents
-deep GI vomiting causes loss of bicarbonate

4. Diabetes mellitus
-high blood acetoacetic acid levels

5. Ingestion of acids
-aspirin

6. Chronic renal failure

Front 95

95. What can cause respiratory acidosis?

Back 95

Pathological conditions that damage the respiratory centers or that decrease the ability of the lungs to eliminate CO2

This includes pneumonia, emphysema, etc...

Front 96

96. What can cause metabolic alkalosis?

Back 96

1. Administration of diuretics (except the carbonic anhydrase inhibitors)
-all diuretics cause increased flow of fluid along the tubules, which leads to increased resorption of Na+ which is coupled with H+ excretion

2. Excess aldosterone

3. Vomiting of gastric contents
-Lose HCl

4. Ingestion of alkaline drugs
-Tums

Front 97

97. Treatment of acidosis

Back 97

1. PA administration of Sodium bicarbonate

2. IV administration of sodium lactate and sodium gluconate

*careful not to infuse sodium bicarbonate via IV b/c of potentially dangerous side effects

Front 98

98. Treatment of alkalosis

Back 98

1. PO administration of ammonium chloride
-liberates HCl in the body

2. Lysine monohydrochloride

Front 99

99. Mixed acid-base disorder

Back 99

In some instance, acid-base disorders are not accompanied by appropriate compensatory responses.

Thus, there are two or more underlying causes for the acid-base disturbance

Front 100

100. Anion gap

Back 100

The difference between unmeasured anions and unmeasured cations.

Will increase if unmeasured anions rise or if unmeasured cations fall.

The gap is increased when there are excessive anions/acids in the blood.

This is either from too much acid production or insufficient removal of acids (either through the lungs, stomach, or kidneys).

Front 101

101. Causes of increased anion gap (Normochloremia)

Back 101

1. Diabetes mellitus (ketoacidosis)
2. Lactic acidosis
3. Chronic renal failure
4. Aspirin poisoning
5. Methanol poisoning
6. Ethylene glycol poisoning
7. Starvation

Front 102

102. Causes of normal anion gap (Hyperchloremia)

Back 102

1. Diarrhea
2. Renal tubular acidosis
3. Carbonic anhydrase inhibitors
4. Addison's disease

Front 103

103. Causes of a decreased anion gap #2

Back 103

The anion gap is decreased by free radical pathology due to overproduction of alkaloids. Other causes that have been reported associated with a reduced anion gap are Alkalosis for any reason

-Hyperchloremic acidosis (excess chloride)
-Multiple Myeloma
-Hyponatremia
-Hypoalbuminemia
-Bromide Ingestion (displaces chloride)
-Uncalculated blood cations (calcium, magnesium)
-Lithium toxicity (can be due to effects on sodium)
-Primary hypothyroidism
-Kidney disease (due to the loss of the cations sodium and or potassium)

Front 104

104. Causes of an increased anion gap #2

Back 104

The high anion gap indicates that the electrical charge of the fluids are too negative compared to the inside of the cell. Causes are:
-Ketoacid overproduction due to fat metabolism (diabetes, alcohol, starvation)
-Lactic Acid overproduction due to respiratory failure (the tissue has inadequate oxygen), genetic defects of enzymes of carbohydrate metabolism, nutritional deficiencies that impair the bodies ability to metabolize lactic acid (B vitamins, especially vitamin B1)
-Inability to excrete acids (sulfate and phosphate) due to renal disease (usually with an elevated BUN and creatinine).
-Dehydration.
-Medications such as salicylates causing a metabolic block.
-Toxins such as ethylene glycol, methanol, paraldehyde, propyl alcohol

Front 105

105. Hyperchloremic metabolic acidosis

Back 105

Plasma Cl- increases in proportion to the fall in plasma HCO3-, the anion gap will remain normal but HCO3- has been effectively replaced by Cl-

Front 106

106. What are the two most important hormones that the pancreas secretes?

What are the other hormones it secretes?

Back 106

Most important:
1. Insulin
2. Glucagon

Others:
a. Amylin
b. Somatostatin
c. Pancreatic polypeptide

Front 107

107. What two major types of tissues are present in the pancreas?

What do these tissues do?

Back 107

1. Acini
-secretes digestive juices into the duodenum

2. Islets of Langerhans
-secretes insulin and glucagon directly into the blood.

Front 108

108. Islets of Langerhans

Back 108

The human pancreas has 1-2 million islets, with each only about 0.3 mm in diameter and organized around small capillaries into which its cells secrete their hormones.

The islets contain three major types of cells, alpha, beta, and delta cells, which are distinguished from one another by their morphological and staining characteristics.

Front 109

109. Beta cells

Back 109

Constitute about 60% of all the cells of the islets.

They lie mainly in the middle of each islet and secrete insulin and amylin, a hormone that is often secreted in parallel w/insulin.

Front 110

110. Alpha cells

Back 110

Constitute about 25% of the total cells of the islets.

Secretes glucagon.

Front 111

111. Delta cells

Back 111

Constitute 10% of the total cells of the islets.

Secrete somatostatin.

Front 112

112. PP cells

Back 112

Present in small numbers in the islets and secretes a hormone of uncertain function called pancreatic polypeptide.

Front 113

113. Interrelations among cell types in the islets of Langerhans

Back 113

Insulin inhibits glucagon secretions, amylin inhibits insulin secretion, and somatostatin inhibits the secretion of both insulin and glucagon.

Front 114

114. Insulin and its effects on excess carbs and proteins

Back 114

First isolated from the pancreas in 1922.

Plays an important role in storing excess energy. In the case of excess carbs, it causes them to be stored as glycogen mainly i n the liver and muscles. Also, all the excess carbs that cannot be stored as glycogen are converted under the stimulus of insulin into fats and stored in the adipose tissue.

In the case of proteins, insulin has a direct effect in promoting AA uptake by the cells and conversion of these AAs into proteins. It also inhibits the breakdown of the proteins that are already in the cells.

Front 115

115. Physical structure of insulin

Back 115

It is a small protein, has a molecular weight of 5808. It is composed of two AA chains, connected to each other by disulfide linkages.

When the two AA chains are split apart, the functional activity of the insulin molecule is lost.

Front 116

116. Where and how is insulin synthesized?

Back 116

In the beta cells, beginning w/translation of the insulin RNA by ribosomes attached to the ER to form an insulin proprohormone.

Then, preprohormone is cleaved in the ER to form a proinsulin.

Most of this proinsulin is further cleaved int he Golgi apparatus to form insulin and peptide fragments before being packaged in the secretory granules.

However, about 1/6 of the final secreted product is still in the form of proinsulin which has virtually no insulin activity.

Front 117

117. What happens to insulin when it is secreted into the blood?

Back 117

It circulates almost entirely in an unbound form; it has a plasma half-life that averages only about 6 min, so that it is mainly cleared from the circulation w/in 10-15 min.

Except for that portion of the insulin that combines w/receptors in the target cells, the remainder is degraded by the enzyme insulinase, mainly in the liver.

This rapid removal from the plasma is important, b/c, at times, it is as important to turn off rapidly as to turn on the control functions of insulin.

Front 118

118. Activation of target cell receptors by insulin

Back 118

To initial its effects on target cells, insulin first binds w/and activates a membrane receptor protein.

It is the activated receptor, not the insulin, that causes the subsequent effects.

Front 119

119. Insulin receptors

Back 119

They are a combination of four subunits held together by disulfide linkages; two alpha subunits that lie entirely outside the cell membrane and two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm.

Front 120

120. Activation of target cell receptors by insulin (2)

Back 120

The insulin binds w/the alpha subunits on the outside of the cell, but b/c of the linkages w/the beta subunits, the portions of the beta subunits protruding into the cell become autophosphorylated.

Thus, the insulin receptor is an example of an enzyme-linked receptor.

Front 121

121. Autophosphorylation of the beta subunits of the receptor activates...?

Back 121

A local tyrosine kinase, which in turn causes phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS).

Front 122

122. Insulin-receptor substrates (IRS)

Back 122

Different types of IRS enzymes are expressed in different tissues.

The net effect is to activate some of these enzymes while inactivating others.

In this way, insulin directs the intracellular metabolic machinery to produce the desired effects on carbohydrate, fat and protein metabolism.

Front 123

123. Four end effects of insulin stimulation

Back 123

1. Within seconds after insulin binds w/its membrane receptors, the membranes of about 80% of the body's cells markedly increase their uptake of glucose (includes muscle cells and adipose cells, BUT NOT THE BRAIN!).
2. THe cell membrane becomes mroe permeable to many of the AA's, K+ ions, and phosphate ions, causing increased transport of these substances into the cell.
3. Slower effects occur during the next 10-15 mins to change the activity levels of many more intracellular metabolic enzymes.
4. Much slower effects continue to occur for hours and even several days.

Front 124

124. If insulin is removed quickly, how does it produce effects that continue for hours to days?

Back 124

This results from changed rates of translation of messenger RNA's at the ribosomes to form new proteins and still slower effects from changed rates of transcription of DNA in the cell nucleus.

In this way, insulin remolds much of the cellular enzymatic machinery to achieve its metabolic goals.

Front 125

125. Normal muscle glucose uptake and metabolism

Back 125

During much of the day, muscle tissue depends not on glucose for its energy but on fatty acids. The principal reason for this is that the normal resting muscle membrane is only slightly permeable to glucose, except when the muscle fiber is stimulated by insulin; between meals, the amount of insulin that is secreted is too small to promote significant amounts of glucose entry into the muscle cells.

Front 126

126. Under what two conditions do the muscles use large amounts of glucose?

Back 126

1. During moderate or heavy exercise. This usage of glucose does not require large amts of insulin, b/c exercising muscle fibers become more permeable to glucose even in the absence of insulin b/c of the contraction process itself.

2. During the few hours after a meal. At this time the blood glucose concentration is high and the pancreas is secreting large quantities of insulin. The extra insulin causes rapid transport of glucose into the muscle cells. This causes the muscle cell during this period to use glucose preferentially over fatty acids.

Front 127

127. Storage of glycogen in muscle

Back 127

If the muscle are not exercising after a meal and yet glucose is transported into the muscle cells in abundance, then most of the glucose is stored in the form of muscle glycogen instead of being used for energy.

The glycogen can later by used for energy by the muscle. It is especially useful for short periods of extreme energy used by the muscles.

Front 128

128. What is the quantitative effect of insulin to facilitate glucose transport?

Back 128

It is clear that insulin can increase the rate of transport of glucose into the resting muscle cell by at lead 15-fold.

Front 129

129. Insulin and liver uptake, storage, and use of glucose

Back 129

One of the most important of all the effects of insulin is to cause most of the glucose absorbed after a meal to be stored almost immediately in the liver in the form of glycogen.

Then, between meals, when food is not available, and the blood glucose concentration begins to fall, insulin secretion decreases rapidly and the liver glycogen is split back into the glucose, which is released back into the blood to keep the glucose concentration from falling too low.

Front 130

130. What are the three steps by which insulin causes glucose uptake and storage in the lever?

Back 130

1. Insulin inactivates liver phosphorylase
2. Insulin causes enhanced uptake of glucose from the blood by the liver cells.
3. Insulin also increase the activities of the enzymes that promote glycogen synthesis.

Front 131

131. How does insulin inactivate liver phosphorylase?

Back 131

Insulin inactivates liver phosphorylase, the principal enzyme that causes liver glycogen to split into glucose.

This prevents breakdown of the glycogen that has been stored in the liver cells.

Front 132

132. How does insulin cause enhanced uptake of glucose from the blood by the liver cells?

Back 132

Insulin causes enhanced uptake of glucose from the blood by the liver cells.

It does this by increasing the activity of the enzyme glucokinase, which is one of the enzymes that causes the initial phosphorylation of glucose after it diffuses into the liver cells.

Once phosphorylated, the glucose is temporarily trapped inside the liver cells b/c phosphorylated glucose cannot diffuse back thru the cell membrane.

Front 133

133. How does insulin increase the activities of the enzymes that promote glycogen synthesis?

Back 133

Insulin also increase the activities of the enzymes that promote glycogen synthesis, including especially glycogen synthase, which is responsible for polymerization of the monosaccharide units to form the glycogen molecules.

Front 134

134. What is the net effect of these steps?

Back 134

To increase the amount of glycogen in the liver.

The glycogen can increase to a total of about 5-6% of the liver mass, which is equivalent to almost 100g of stored glycogen in the whole liver.

Front 135

135. What are the four steps by which glucose is released from the liver between meals?

Back 135

1. The decreasing blood glucose causes the pancreas to decrease its insulin secretion.
2. The lack of insulin then reverses all the effects listed earlier for glycogen storage; essentially stopping further synthesis of glycogen.
3. The lack of insulin activates the enzyme phosphorylase, which causes the splitting of glycogen into glucose phosphate.
4. Glucose phopshatase now becomes activated by the insulin lack and causes the phosphate radical to split away from the glucose; this allows the free glucose to diffuse back into the blood.

Front 136

136. About what percent of the glucose in the meal is stored in the liver and then returned to the blood?

Back 136

About 60%

Front 137

137. Insulin and fatty acids

Back 137

Insulin promotes the conversion all excess carbohydrates into fatty acids.

These fatty acids are subsequently packaged as TAGs in vLDL's and transported in this form by way of the blood to the adipose tissue and deposited as fat.

Front 138

138. Insulin and gluconeogenesis

Back 138

Insulin inhibits gluconeogenesis.

It does this by decreasing the quantities and activities of the liver enzymes required for gluconeogenesis.

However, part of the effect is caused by an action of insulin that decreases the release of AAs from muscle and other extrahepatic tissues and in turn the availability of these necessary precursors required for gluconeogenesis.

Front 139

139. Insulin and glucose uptake and usage by the brain

Back 139

The brain is different from most other tissues of the body in that insulin has little effect on uptake or use of glucose.

Instead, the brain cells are permeable to glucose and can use glucose w/o the intermediation of insulin.

Front 140

140. Hypoglycemic shock

Back 140

When the blood glucose falls too low, into the range of 20-50 mg/100mL, symptoms of hypoglycemic shock develop, characterized by progressive nervous irritability that leads to fainting, seizures, and even coma.

Front 141

141. Effect of insulin on adipose cells

Back 141

The transport of glucose into adipose cells via insulin mainly provides substrate for the glycerol portion of the fat molecule.

Therefore, in this indirect way, insulin promotes deposition of fat in these cells.

Front 142

142. Insulin and fat synthesis and storage

Back 142

Insulin increases the utilization of glucose by most of the body's tissues, which automatically decreases the utilization of fat, thus functioning as a fat sparer

Insulin also promotes fatty acid synthesis which occurs in the liver cells and then is transported via vLDLs to the adipose cells to be stored.

Front 143

143. What are the different factors that lead to increased fatty acid synthesis in the liver?

Back 143

1. Insulin increases the transport of glucose into the liver cells. The glucose is first split to pyruvate in the glycolytic pathway, and the pyruvate is subsequently converted to acetyl-CoA, the substrate from which FA's are synthesized.

2. An excess of citrate and isocitrate is formed by the citric acid cycle when excess amounts of glucose are being used for energy. These ions then have a direct effect in activating acetyl-CoA carboxylase, the enzyme required to carboxylate acetyl-CoA to form malonyl-CoA, the first stage of FA synthesis

3. Most of the FA's are then synthesized w/in the liver itself and used to form TAGs. Insulin activates lipoprotein lipase, which splits the TAGs again into FA's in order for them to be stored in adipose cells.

Front 144

144. What are the two other essential effects that are required for fat storage in adipose cells?

Back 144

1. Insulin inhibits the action of hormone-sensitive lipase. This is the enzyme that causes hydrolysis of the TAGs already stored in fat cells.
2. Insulin promotes glucose transport through the cell membrane into the fat cells in exactly the same way that it promotes glucose

Front 145

145. Insulin deficiency and fat usage for energy

Back 145

All aspects of fat breakdown and use for providing energy are greatly enhanced in the absence of insulin.

Front 146

146. Insulin deficiency and fat usage #2

Back 146

The most important effect is that the enzyme hormone-sensitive lipase in the fat cells becomes strongly activated.

This causes hydrolysis of the stored TAGs, releasing large quantities of fatty acids into the circulating blood.

These free fatty acids then become the main energy substrate used by essentially all tissues of the body besides the brain.

Front 147

147. Insulin deficiency and plasma cholesterol and phospholipid concentrations

Back 147

The excess of FA's in the plasma associated w/insulin deficiency also promotes liver conversion of some of the fatty acids into phospholipids and cholesterol.

These two substances, along w/excess triglycerides formed at the same time in the liver, are then discharged into the blood in the lipoproteins.

Occasionally the plasma lipoproteins increase as much as 3x in the absence of insulin.

This high lipid concentration, especially the high concentration of cholesterol, promotes the development of atherosclerosis in people with serious diabetes.

Front 148

148. Formation of acetoacetic acid during insulin deficiency

Back 148

Insulin lack also causes excessive amts of acetoacetic acid to be formed int he liver cells.

In the absence of insulin but in the presence of excess fatty acids in the liver cells, the carnitine transport mechanism for transporting FA's into the mitochondria becomes increasingly activated.

In the mitochondria, beta oxidation of the FA's then proceeds very rapidly, releasing extreme amts of acetyl-CoA.

A large part of this excess acetyl-CoA is then condensed to form acetoacetic acid, which in turn is released into the circulating blood.

Front 149

149. Insulin lack and utilization of acetoacetic acid in the peripheral tissues

Back 149

At the same time, the absence of insulin also depresses the utilization of acetoacetic acid in the peripheral tissues.

Thus, so much acetoacetic acid is released from the liver that it cannot all be metabolized by the tissues.

Front 150

150. Ketosis and acidosis during insulin deficiency

Back 150

Some of the acetoacetic acid is also converted into β-hydroxybutyric acid and acetone.

These two substances, along with the acetoacetic acid, are called ketone bodies, and their presence in large quantities in the body fluids is called ketosis.

This can lead to to sever acidosis and coma in people w/sever diabetes.

Front 151

151. Insulin and protein metabolism

Back 151

Insulin promotes protein synthesis and storage. It does this by:

1. Stimulating transport of many of the AA's into the cells
2. Increasing the translation of mRNA, thus forming new proteins
3. Increasing the rate of transcription of selected DNA genetic sequences, yielding more protein synthesis
4. Inhibiting the catabolism of proteins
5. Depressing the rate of gluconeogenesis in the liver (conserves the AA's in the protein stores of the body)

Front 152

152. Insulin deficiency and proteins

Back 152

Insulin lack causes protein depletion and increased plasma amino acids.

The catoblism of proteins increases, protein synthesisi stops, and large quantities of AAs are dumped into the plasma. These excess AAs are then used for energy or as substrates of gluconeogenesis.

This degradation of AAs also leads to enhanced urea excretion in the urine.

In sum, it leads to protein wasting.

Front 153

153. Insulin and growth hormone

Back 153

They act synergistically to promote growth. Exogenous admin of either one individually promotes some growth, but admin of both together causes dramatic growth.

Perhaps a small part of this necessity for both hormones results from the fact that each promotes cellular uptake of a different selection of AA's.

Front 154

154. Glucose transporters (GLUT-2)

Back 154

The beta cells have a large number of GLUT-2 that permit a rate of glucose influx that is proportional to the blood concentration int eh physiological range.

Front 155

155. What happens to glucose once it is inside the cells?

Back 155

It is phosphorylated to glucose-6-phosphate by glucokinase.

This step appears to be the rate limiting for glucose metabolism in the beta cell and is considered the major mechanism for glucose sensing and adjustment of the amt of secreted insulin to the blood glucose levels.

Front 156

156. What happens to the glucose-6-phosphate?

Back 156

It is subsequently oxidized to form ATP, which inhibits ATP sensitive K+ channels of the cell.

Closure of these channels depolarizes the cell membrane, thereby opening voltage-gated Ca channels, which are sensitive to membrane voltage changes. This produces an influx of Ca that stimulates fusion of the docked insulin-containing vesicles w/the cell membrane and secretion of insulin into the ECF via exocytosis.

Front 157

157. What hormones inhibit exocytosis of insulin?

Back 157

Somatostatin and norepinephrine

Front 158

158. What hormones stimulate insulin secretion?

Back 158

Glucagon and gastric inhibitory peptide, as well as acetylcholine

Front 159

159. Sulfonylurea drugs

Back 159

They stimulate insulin secretion by binding to the ATP-sensitive K+ channels and blocking their activity.

This results in a depolarizing effect that triggers insulin secretion, making these drugs very useful in stimulating insulin secretion in patients with type II diabetes.

Front 160

160. Blood glucose levels and insulin secretion

Back 160

At the normal fasting level of blood glucose of 80-90 mg/100 mL, the rate of insulin secretion is minimal.

If the blood glucose is suddenly increased to a level 23x normal and kept at this high level, insulin secretion increased markedly in two stages.

Front 161

161. Two stages of insulin secretion in response to increased blood glucose levels

Back 161

1. Plasma insulin concentration increase almost 10x w/in 3-5 min after the acute elevation of the blood glucose
-this results from immediate dumping of preformed insulin from the β cells of the islets. However, this increased rate is not maintained, instead the insulin concentration decreases about halfway back toward normal in another 5-10 min.

2. Beginning at about 15 min, insulin secretion rises a second time and reaches a new plateau in 2-3 hours, this time usually at a rate of secretion even greater than that in the initial phase.
-This secretion results both from additional release of preformed insulin and from activation of the enzyme system that synthesizes and releases new insulin from the cells.

Front 162

162. Amino acids and insulin secretion

Back 162

Arginine and lysine strongly potentiate the glucose stimulus for insulin secretion.

Front 163

163. GI hormones and insulin secretion

Back 163

Gastrin, secretin, cholecystokinin, and gastric inhibitory peptide (which seems to be the most potent) causes a moderate increase in insulin secretion.

They almost double the rate of insulin secretion as the blood glucose rises.

Front 164

164. Other hormones that potentiate the glucose stimulus for insulin secretion

Back 164

Glucagon, growth homrone, cortisol, and to a lesser extent, progesterone and estrogen.

Prolonged secretion of any one of these hormones can lead to exhaustion of the β cells of the islets and thereby increase the risk for developing DM.

Front 165

165. What four other hormones play important roles in switching between carb and lipid metabolism?

Back 165

Growth hormone from the anterior pituitary gland, cortisol from the adrenal cortex, epinephrine from the adrenal medulla, and glucagon from the alpha cells of the islets.

Front 166

166. Growth hormone and cortisol secretion

Back 166

Both are secreted in response to hypoglycemia, and both inhibit cellular utilization of glucose while promoting fat utilization.

However, the effects of both of these hormones develop slowly, usually requiring many hours for maximal expression.

Front 167

167. Epinephrine secretion

Back 167

Especially important in increasing plasma glucose concentration during periods of stress.

However, epinephrine acts differently from the other hormones in that it increases the plasma FA concentration at the same time.

Front 168

168. In what two ways does epinephrine act differently?

Back 168

1. It has the potent effect of causing glycogenolysis in the liver, thus releasing within minutes large quantities of glucose into the blood.

2. It also has a direct lipolytic effect on the adipose cells b/c it activates adipose tissue hormone-sensitive lipase, thus greatly enhancing the blood concentration of FA's as well.

Quantitatively, the enhancement of FA's is far greater than the enhancement of blood glucose. Thus, epinephrine especially enhances the utilization of fat in such stressful states as exercise, circulatory shock, and anxiety.

Front 169

169. Glucagon

Back 169

AKA the "hyperglycemic hormone"

Secreted by the alpha cells of the islets when the blood glucose concentration falls.

Most important function is to increase the blood glucose concentration, an effect that is exactly the opposite that of insulin.

Front 170

170. What are the two major effects of glucagon on glucose metabolism?

Back 170

1. Breakdown of liver glycogen (glycogenolysis)
2. Increased gluconeogenesis in the liver

Both of these effects enhance the availability of glucose to the other organs of the body.

Front 171

171. How does glucagon cause glycogenolysis in the liver?

*8 steps here*

Back 171

1. Glucagon activates adenylyl cyclase in the hepatic cell membrane,
2. Which causes the formation of cAMP,
3. Which activates protein kinase regulator protein,
4. Which activates protein kinase,
5. Which activates phosphorylase b kinase,
6. Which convertes phosphorylase b into phosphorylase a,
7. Which promotes the degradation of glycogen into glucose-1-phosphate,
8. Which then is dephosphorylated; and the glucose is released from the liver cells.

Front 172

172. Why is the previous sequence of events important?

Back 172

1. This is one of the most thoroughly studies of all the second messenger functions of cAMP.
2. It demonstrates a cascade system in which each succeeding product is produced in greater quantity than the preceding product; it is an amplifying mechanism
-this explains how only a few micrograms of glucagon can cause the blood glucose level to double or increase even more within a few minutes.

Front 173

173. How does glucagon increase gluconeogenesis?

Back 173

Results from the effect of glucagon to increase the rate of AA uptake by the liver cells and then the conversion of many of the AAs to glucose by glucoenogenesis.

This is achieved by activating multiple enzymes that are required for AA transport and gluconeogenesis, especially activation fo the enzyme system for converting pyruvate to phosphoenolpyruvate, a rate limiting step in gluconeogenesis.

Front 174

174. What are some other effects of glucagon?

Back 174

Most other effects of glucagon occur only when its concentration rises well above the maximum normally found int eh blood.

It activates adipose cell lipase, making increased quantities of FAs available to the energy systems of the body.

It also inhibits the storage of TAGs in the liver, which prevents the liver from removing FAs from the blood.

Front 175

175. What are some other effects of glucagon at high concentrations?

Back 175

1. Enhances the strength of the heart
2. Increases blood flow in some tissues, especially in the kidneys
3. Enhances bile secretion
4. Inhibits gastric acid secretion

Front 176

176. Increased blood glucose and glucagon secretion

Back 176

The blood glucose conentration is by far the most potent factor that controls glucagon secretion.

Increase blood glucose inhibits glucagon secretion.

Front 177

177. Blood amino acids and glucagon secretion

Back 177

High AA concentrations, especially alanine and arginine, stimulate the secretion of glucagon.

*This is the same effect that AAs have in stimulating insulin secretion. Thus, in this instance, the glucagon and insulin responses are not opposites.

The important thing here is that the glucagon then promotes rapid conversion of the AAs to glucose, thus making even more glucose available to the tissues.

Front 178

178. Exercise and glucagon secretion

Back 178

In exhaustive exercise, the blood concentration of glucagon often increase 4-5x normal.

A beneficial effect of the glucagon is that it prevents a decrease in blood glucose.

Front 179

179. Somatostatin

Back 179

Secreted by the delta cells of the islets.

Has an extremely short half life of only 3 min.

Inhibits glucagon and insulin secretion.

Front 180

180. Somatostatin secretion

Back 180

Almost all factors related to the ingestion of food stimulate somatostatin secretion.

The include:
1. Increased blood glucose
2. Increased AA's
3. Increased FA's
4. Increased concentrations of several of the GI hormones released from the upper GI tract in response to food intake.

Front 181

181. What are the three inhibitory effects of somatostatin?

Back 181

1. Acts locally within the islets themselves to depress the secretion of both insulin and glucagon

2. Decreases the motility of the stomach, duodenum, and gallbladder

3. Decreases both secretion and absorption in the GI tract.

Front 182

182. Summary of somatostatin's role

Back 182

In sum, it is suggested that its principal role is to extend the period of time over which the food nutrients are assimilated in the blood.

At the same time, it decreases the utilization of the absorbed nutrients by the tissues, thus preventing rapid exhaustion of the food and therefore making it available over a longer period of time.

Front 183

183. Somatostatin and growth hormone inhibitory hormone

Back 183

Somatostatin is the same chemical substance as growth hormone inhibitory hormone, which is secreted in the hypothalamus and suppresses anterior pituitary gland growth hormone secretion.

Front 184

184. What are the four reasons why it is important not to let the blood glucose concentration rise too high?

Back 184

1. Glucose can exert a large amount of osmotic pressure in the extracellular fluid, and if the glucose concentration rises to excessive values, this can cause considerable cellular dehydration
2. An excessively high level of blood glucose concentration causes loss of glucose in the urine
3. Loss of glucose in the urine also causes osmotic diuresis by the kidneys, which can deplete the body of its fluids and electrolytes
4. Long-term increases in blood glucose may cause damage to many tissues, esp to blood vessels and cause vascular injury.

Front 185

185. Diabetes mellitus

Back 185

Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin.

Front 186

186. What are the two different types of diabetes?

Back 186

1. Type I diabetes, also called insulin dependent diabetes mellitus (IDDM), is caused by lack of insulin secretion.

2. Type II diabetes, also called non–insulin-dependent diabetes mellitus (NIDDM), is caused by decreased sensitivity of target tissues to the metabolic effect of insulin. This reduced sensitivity to insulin is often called insulin resistance.

Front 187

187. Diabetes and metabolism

Back 187

In both types of diabetes mellitus, metabolism of all the main foodstuffs is altered.

The basic effect of insulin lack or insulin resistance on glucose metabolism is to prevent the efficient uptake and utilization of glucose by most cells of the body, except those of the brain.

As a result, blood glucose concentration increases, cell utilization of glucose falls increasingly lower, and utilization of fats and proteins increases.

Front 188

188. Causes of type I diabetes

Back 188

Injury to the beta cells of the pancrease or diseases that impair insulin production can ead to type I diabetes.

Viral infections or autoimmune disorders may be involved in the destruction of beta cells, although heredity also plays a major role in determining the susceptibility of the beta cells to destruction by these insults.

In some instances, there may be a hereditary tendency for beta cell degeneration even without viral infections or autoimmune disorders.

Front 189

189. What is the usual age of onset for DM type I?

Back 189

Occurs at about 14 years of age in the US, and for this reason it is often called juvenile diabetes mellitus.

Front 190

190. What are the three principal sequelae in DM type I?

Back 190

1. Increased blood glucose
2. Increased utilization of fats for energy and for formation of cholesterol by the liver
3. Depletion of the body's proteins.

Front 191

191. What are the three P's of diabetes?

Back 191

1. Polyuria
2. Polyphagia
3. Polydipsia

Front 192

192. Blood glucose concentration and diabetes

Back 192

Glucose levels rise very high in diabetics

The lack of insulin decreases the efficiency of peripheral glucose utilization and augments glucose production, raising plasma glucose to 300 to 1200 mg/dL.

Front 193

192. Increased blood glucose levels and urinary excretion of glucose

Back 193

The high blood glucose causes more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine.

This normally occurs when the blood glucose concentration rises above 180 mg/dL, a level that is called the blood "threshold" for the appearance of glucose in the urine.

Front 194

193. Increased blood glucose levels and dehydration

Back 194

The very high levels of blood glucose can cause severe cell dehydration throughout the body. This occurs partly b/c glucose does not diffuse easily thru the pores of the cell membrane, and the increased osmotic pressure in the ECF causes osmotic transfer of water out of the cells.

In addition, the loss of glucose in the urine causes osmotic diuresis. Thus, polyuria, intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes.

Front 195

194. Chronic high glucose levels and tissue injury

Back 195

When blood glucose is poorly controlled over long periods in diabetes mellitus, blood vessels in multiple tissues throughout the body begin to function abnormally and undergo structural changes that results in inadequate blood supply. This in turn leads to increased risk for heart attack, stroke, end-stage kidney disease, retinopathy and blindness, and ischemia and gangrene of the limbs.

Front 196

195. Other injuries caused by chronic high glucose concentrations

Back 196

Peripheral neuropathy, which is abnormal function of peripheral nerves, and autonomic nervous system dysfunction are frequent complications.

Front 197

196. Type II DM

Back 197

Resistance to the metabolic effects of insulin.

Far more common than type I, the onset is after age 30, and the disease develops gradually. Therefore, this is AKA adult-onset diabetes.

Obesity is the most important risk factor for type II DM in children as well as adults.

Front 198

197. What usually precedes development of type II DM?

Back 198

1. Obesity
2. Insulin resistance
3. Metabolic syndrome.

Front 199

198. What causes most of the insulin resistance?

Back 199

Caused by abnormalities of the signaling pathways that link receptor activation w/multiple cellular effects.

Impaired insulin signaling appears to be closely related to toxic effects of lipid accumulation in tissues such as skeletal muscle and liver secondary to excess weight gain.

Front 200

199. What are the five features of metabolic syndrome?

Back 200

1. Obesity, especially accumulation of abdominal fat
2. Insulin resistance
3. Fasting hyperglycemia
4. Lipid abnormalities such as increased TAGs and decreased HDLs
5. Hyeprtension

Front 201

200. What is the major adverse consequence of metabolic syndrome?

Back 201

Cardiovascular disease, including atherosclerosis and injury to various organs throughout the body.

Also yields a high risk for developing Type II DM

Front 202

201. What are some other factors that can cause insulin resistance and type II DM?

Back 202

1. Polycystic ovary syndrome (PCOS)
2. Excess formation of glucocorticoids (Cushing syndrome)
3. Excess formation of growth hormone (acromegaly)

Front 203

202. Polycystic ovary syndrome (PCOS)

Back 203

Associated w/marked increases in ovarian androgen production and insulin resistance and is one of the most common endocrine disorders in women.

Insulin resistance and hyperinsulinemia are found in approx 80% of affected women.

The long term consequences include increased risk for DM, increased blood lipids, and cardiovascular disease.

Front 204

203. Early stages of prolonged and severe insulin resistance

Back 204

The increased levels of insulin are not sufficient to maintain normal glucose regulation.

As a result moderate hyperglycemia occurs after ingestion of carbs in the early stages of the disease.

Front 205

204. Later stages of prolonged and severe insulin resistance

Back 205

The pancreatic beta cells become exhausted and are unable to produce enough insulin to prevent more severe hyperglycemia, especially after the person ingests a carb-rich meal.

Front 206

205. Treatment and prevention of type II DM

Back 206

Can be effectively treated, at least in the early stages, with exercise, caloric restriction, and weight reduction and no exogenous insulin admin is required.

Drugs that increase insulin sensitivity, such as thiazolidinediones and metformin, or drugs that cause additional release of insulin by the pancreas, such as sulfonylureas, may also be used.

Front 207

206. Fasting blood glucose and insulin levels

Back 207

The fasting glucose level in the early morning is normally 80-90 mg/dL and 110 mg/dL is considered to be the upper limit of normal.

Above this value often indicates DM or at least marked insulin resistance.

Front 208

207. Fasting levels and Types I and II

Back 208

In type I DM, plasma insulin levels are very low or undetectable during fasting and ever after a meal.

In type II DM, plasma insulin concentration may be several fold higher than normal and usually increases to a greater extent after ingestion of a standard glucose load during a glucose tolerance test.

Front 209

208. Glucose tolerance test

Back 209

In a normal person, the blood glucose levels rises with ingestion of glucose and falls back to normal in about two hours.

In a person w/diabetes, upon ingestion of glucose, these people exhibit a much greater than normal rise in the blood glucose level, and the level falls back to the control value only after 4-6 hours; therefore, it fails to fall below the control levels.

Front 210

210. Dx of diabetes

Back 210

Any one of the three criteria:

1. Random glucose level at or over 200 mg/dL, with classical signs and symptoms
2. Fasting glucose level at or over 126 mg/dL
3. Abnormal oral glucose tolerance test, in which the glucose level is at or over 200 mg/dL 2 hours after a standard carbohydrate load

Front 211

211. Metabolic and mitogenic actions of insulin are mediated by the hormone binding to...?

Back 211

The tetrameric insulin receptor, with consequent activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI-3K) signaling pathways

Front 212

212. Pathogenesis of Type I DM

Back 212

This form of diabetes results froma severe lack fo insulin caused by an autoimmune destruction of the islet beta cells.

Type I DM most commonly develops in childhood, becomes manifest at puberty, and is progressive with age.

Front 213

213. What three general mechanisms cause β-cell destruction?

Back 213

1. T-lymphocytes react against β-cell antigens and cause cell damage.
2. Locally produced cytokines damage β-cells.
3. Autoantibodies against islet cells and insulin are also detected in the blood of 70-80% of patients.

Front 214

214. What T-lymphocytes are involved in β-cell destruction?

Back 214

1. CD4+ cells of the TH1 subset causing tissue injury by activating macrophages, with the macrophages causing damage in a characteristic delayed-type hypersensitivity response

2. CD8+ cytotoxic T lymphocytes that directly kill β-cells and also secrete cytokines that activate macrophages

Front 215

215. What cytokines are involved in β-cell destruction?

Where do they come from?

Back 215

IFN-γ, produced by T cells

TNF and IL-1, produced by macrophages that are activated during the immune reaction.

Front 216

216. What about the autoantibodies involved in β-cell destruction?

Back 216

The autoantibodies are reactive w/a variety of β-cell antigens, including the enzyme glutamic acid decarboxylase (GAD).

In susceptible children who have not developed diabetes, the present of antibodies against islet cells is predictive of the development of Type I DM

Front 217

217. Genetic susceptibility of DM type I

Back 217

Has a complex pattern of genetic associations, with at lest 20 genetic loci potentially contributing to the altered host immune tolerance that eventually results in autoimmunity.

By far the most important genetic association is with the class II MHC complex HLA locus.

Between 90-95% of whites w/type I DM have HLA-DR3 or DR4 haplotypes. Certain alleles within these haplotypes, such as DQβ*0302, demonstrate an every greater degree of association with Type I DM.

Front 218

218. DQβ*0602 allele

Back 218

May actually confer some protection in preventing Type I DM.

Front 219

219. What the the non-MHC genes associated with Type I DM disease susceptibility?

Back 219

1. The insulin gene itself
2. The gene encoding the T-cell inhibitory receptor CTLA-4

Front 220

220. What are some environmental factors associated with the development of type I DM?

Back 220

Several viral agents, including:
a. coxsakieviruses
b. mumps
c. measles
d. cytomegalovirus
e. rubella
f. infection mononucleosis

One postulate is that the viruses produce proteins that mimic self antigens, and the immune response to the viral protein cross-reacts w/the self-tissue (molecular mimicry)

Front 221

221. What are the two main metabolic defects that characterize Type II DM?

Back 221

1. Insulin resistance
2. β-cell dysfunction

Front 222

222. Insulin resistance

Back 222

Functional studies in individuals w/insulin resistance demonstrate quantitative and qualitative abnormalities of the insulin signaling pathway, including down-regulation of the insulin receptor, decreased insulin receptor phosphorylation and tyrosine kinase activity, and reduced levels of active intermediaries in the insulin signaling pathway.

Front 223

223. Obesity and insulin resistance

Back 223

Obesity has the strongest association.

Possible factors influencing insulin resistance in obesity include high circulating and intracellular levels of free FAs that can interfere with insulin formation (lipotoxicity) and a variety of cytokines released by adipose tissue (adipokines), including leptin, adiponectin, and resistin.

Front 224

225. Peroxisome proliferator-activated receptor gamma (PPAR-γ)

Back 224

Is an adipocyte nuclear recptor activated by a new class of antidiabetic agents called thiazolidinediones.

It can modulate gene expression in adipocytes, eventually leading to reduction of insulin resistance.

Front 225

226. β-cell dysfunction

Back 225

Manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. β-cell dysfunction is both qualitative (loss in the normal pulsatile, oscillating pattern of insulin secretion and attenuation of the rapid first phase of insulin secretion triggered by elevation in plasma glucose) as well as quantitative (decreased β-cell mass, islet degeneration, and deposition of islet amyloid).

Front 226

227. Maturity-onset diabetes of the young (MODY)

Back 226

MODY is a primary defect in β-cell function that occurs without β-cell loss, affecting either β-cell mass or insulin transcription.

Six distinct genetic defects have been identified thus far.

Front 227

228. MODY characteristics

Back 227

1. Autosomal dominant inheritance as a monogenic defect, with high penetrance.
2. Early onset, usually before age 25, as opposed to after age 40 for most patients w/type II DM.
3. Absence of obesity.
4. Lack of islet cell autoantibodies and insulin resistance syndrome.

Front 228

229. Mitochondrial diabetes

Back 228

Diabetes is rarely (<1% cases) associated w/point mutations in mitochondrial tRNA gene, tRNA ^Leu(UUR)

Front 229

230. Insulin gene or insulin receptor mutations

Back 229

Mutations that affect insulin processing from its precursor (proinsulin), or those that affect insulin structure and binding to its receptor are a rare cause of diabetes.

Insulin receptor mutations that affect receptor synthesis, insulin binding, or receptor tyrosine kinase activity can result in mild to sever insulin resistance and type II DM.

Front 230

231. Diabetic ketoacidosis

Back 230

Occurs almost always in type I diabetes as a result of severe insulin deficiency and absolute or relative increases in glucagon: excessive release of free FAs from adipose tissue and hepatic oxidation generates ketone bodies.

Ketonemia and ketonuria, with dehydration, can cause life-threatening systemic metabolic ketoacidosis.

Front 231

232. Nonketotic hyperosmolar coma

Back 231

Usually develops in type II diabetics in the setting of severe dehydration (from sustained hyperglycemic diuresis) and an inability to drink water.

Front 232

233. Long term complication of diabetes

Back 232

Involves:
1. Macrovascular disease
2. Microvascular disease
3. Accelerated atherosclerosis
4. Diabetic retinopathy, nephropathy, and neuropathy

Front 233

234. Non-enzymatic glycosylation

Back 233

Glucose chemically attaches to amino groups of proteins, reflected in glycated Hb (HbA1c) blood levels.

With glycation of collagens and other long-lived proteins, irreversible advanced glycation end products (AGE) accumulate over the lifetime of blood vessel walls.

Front 234

235. AGE formation of proteins, lipids, and nucleic acids leads to what three things?

Back 234

1. Protein cross-linking, trapping plasma lipoproteins in vessel walls
2. Reduction in normal proteolysis
3. AGE binding to cell receptors, inducing a variety of undesired biologic activities.

Front 235

236. Intracellular hyperglycemia w/disturbances in polyol pathways

Back 235

Some tissues (nerve, lens, kidney, blood vessels) do not require insulin for glucose uptake and thus accumulate increased intracellular glucose by mass action.

This glucose is then metabolized to sorbitol and then fructose, so that an equilibrium with extracellular solute is not achieved.

The accompanying osmotic load leads to influx of water and osmotic cell injury.

Sorbitol also decreases phosphoinositide metabolism and signal transduction.

Front 236

237. Activation of protein kinase C (PKC) and hyperglycemia

Back 236

Activation of intracellular PKC by calcium ions and the second messenger diacylglycerol (DAG) is an important signal transduction pathway in many cellular systems.

Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence activates PKC.

Front 237

238. What are the three downstream effects of PCK activation?

Back 237

1. Production of the pro-angiogenic molecule vascular endothelial growth factor (VEGF), implicated in the neovascularization characterizing diabetic retinopathy.
2. Increased deposition of ECM and basement membrane material.
3. Production of the pro-coagulant molecule plasminogen activator inhibitor-1 (PAI-1), leading to reduced fibrinolysis and possible vascular occlusive episodes.

Front 238

239. Morphological changes in the pancreas in diabetes

Back 238

1. There is a reduction in number and size of islets (especially type I DM).
2. Insulitis (a heavy lymphocytic infiltrate within and about islets) in newly symptomatic type I diabetics.
3. β-cell degranulation and fibrosis of islets.
4. Deposition of extracellular amyloid (amylin protein), especially in long standing type II diabetics.

Front 239

240. Diabetic macrovascular disease

Back 239

Accelerated atherosclerosis in the aorta and large and medium-sized arteries increases the risk for MI, cerebral stroke, aortic aneurysms, and gangrene of the lower extremities.

Front 240

241. Hyaline ateriolosclerosis

Back 240

Vascular lesion associated w/hypertension

More prevalent and more severe in diabetics.

Front 241

242. Diabetic microangiopathy

Back 241

One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes.

The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla.

It may affect nonvascular structures, such as renal tubules, Bowman capsule, peripheral nerves and placenta.

Front 242

243.Are diabetic capillaries more or less likely to leak proteins?

Back 242

Despite the increase in the thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma proteins.

The microangiopathy underlies this development of diabetic nephropathy, retinopathy and some forms of neuropathy.

Front 243

244. Diabetic nephropathy

Back 243

The kidneys are the most severely damaged organ in diabetics, and renal failure is a major cause of death.

Front 244

245. Glomerular involvement in diabetic nephropathy

Back 244

Diffuse mesangial sclerosis, nodular glomerulosclerosis (Kimmelstiel-Wilson lesion), or exudative lesions, resulting in progressive proteinuria and chronic renal failure.

Front 245

246. Vascular effects of diabetic nephropathy

Infections associated with diabetic nephropathy?

Back 245

Arteriosclerosis, including benign nephrosclerosis with hypertension.

Infections:
UTIs, with pyelonephritis and sometimes necrotizing papillitis.

Front 246

247. Diabetic retinopathy

What are the two types?

Back 246

Affects the majority of diabetics. Non-proliferative retinopathy consists of intraretinal and preretinal hemorrhages, exudates, edema, thickening of retinal capillaries, and microaneurysms.

Proliferative retinopathy is the process of neovascularization and fibrosis of the retina, which has a high propensity to cause blindness.

Front 247

248. Diabetic neuropathy

Back 247

A symmetric peripheral neuropathy affecting motor and sensory nerves of the lower extremities is attributable to Schwann cell injury, myelin degeneration, and axonal dmage.

Autonomic neuropathy may lead to sexual impotence and bowel and bladder dysfunction.

Focal neurologic impairment (diabetic mononeuropathy) is most likely due to microangiopathy.

Front 248

249. Pancreatic endocrine neoplasms (PENs)

Back 248

AKA islet cell tumors, are rare compared with tumors of the exocrine pancreas.

PENs may be hormonally functional or nonfunctional, single or multiple, benign or malignant.

Front 249

250. What are the three unequivocal criteria for malignancy?

Back 249

1. Metastases to regional lymph nodes or distant organs (including the liver0
2. Agioinvasion
3. Gross invasion of adjacent viscera.

Front 250

251. β-cell tumors (insulinomas)

Back 250

Most common PEN subtype; tumors may elaborate sufficient insulin to cause hypoglycemia; symptomatic attacks occur w/serum glucose below 50 mg/dL.

Front 251

252. Morphology of β-cell tumors (insulinomas)

Back 251

Most are solitary lesions, although multiple tumors or tumors ectopic to the pancreas may be encountered.

Bona fide carcinomas are diagnosed on the basic of criteria for malignancy.

β-cell tumors are usually less than 2 cm in diameter, usually encapsulated, firm, yellow brown nodules composed of cords and nests of well differentiated β-cells with typical β-cell granules by electron microscopy.

Front 252

253. Clinical features of β-cell tumors (insulinomas)

Back 252

Symptoms of β-cell tumors (insulinomas) include hypoglycemia induced confusion, stupor, and loss of consciousness.

Attacks are promptly relieved by glucose feeding or infusion.

Most commonly seen in infants secondary to maternal diabetes, Beckwith-Wiedemann syndrome, and rare metabolic disorders.

Front 253

254. Maternal diabetes and insulinomas

Back 253

In the infant, insulinomas are caused by diffuse hyperplasia of the islets.

This change is usually encountered in neonates and infants. In maternal diabetes, the fetus, long exposed to the hyperglycemia of maternal blood, responds by an increase in the size and number of its islets.

In the postnatal period, these hyperactive islets may be responsible for serious episodes of hypoglycemia.

Front 254

255. Zollinger-Ellison syndrome (grastrinomas)

Back 254

Comprises a triad of recalcitrant peptic ulcer disease, gastric hypersecretion and an endocrine cell tumor elaborating gastrin.

Front 255

256. Morphology of Zollinger-Ellison syndrome

Back 255

Grastinomas are just as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas.

In approx 25% of patients, gastrinomas arise in conjunction with other endocrine tumors, thus conforming to the MEN-1 syndrome.

Front 256

257. MEN-1 gastrinomas

Back 256

MEN-1 associated gastrinomas are frequently multifocal, while sporadic gastrinomas are usually single.

The histologic and ultrastructral features are similar to normal intestinal and gastric G cells.

Front 257

258. Clinical features of Zollinger-Ellison syndrome

Back 257

The duodenal and gastric ulcers are often multiple; although they are identical to those found in the general population, they are often intractable to usual modalities of therapy.

In addition, ulcers may also occur in unusual locations such as the jejunum- when this happens, Zollinger-Ellison syndrome should be considered.

More than 50% of patients have diarrhea; in 30% it is the presenting symptom.

60% of gastrinomas are malignant; recurrence is very likely post surgical removal

Front 258

259. α-cell tumors (Glucagonomas)

Back 258

α-cell tumors (Glucagonomas) are associated w/increased serum levels of glucagon and a syndrome consisting of mild DM, sin rash, and anemia; they occur most frequently in peri- and post-menopausal women and are characterized by extremely high plasma glucagon levels.

Front 259

260. δ-cell tumors (Somatostatinomas)

Back 259

δ-cell tumors (Somatostatinomas) are associated w/diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria.

Front 260

261. VIPoma (diarrheogenic islet cell tumor)

Back 260

Causes watery diarrhea, hypokalemia, achlorhydria; associated w/neural crest tumors

Front 261

262. Pancreatic carcinoid tumors and pancreatic polypeptide-secreting islet cell tumors

Back 261

Both are very rare

Pancreatic carcinoid tumors are serotonin producing.

Pancreatic polypeptide-secreting islet cell tumors are asymptomatic

Front 262

263. α-Glucosidase inhibitors

What are they?

Back 262

These are carbohydrate analogues that bind 1,000x more avidly than dietary carbohydrates to intestinal brush border α-glucosidase enzymes.

They act by delaying the digestion of carbs, thereby decreasing glucose absorption.

These drugs are taken at the beginning of meals, but are not effective at other times.

Front 263

264. How do α-glucosidase inhibitors work?

Back 263

Glucosidases - maltase, isomaltase, sucrase, and glucoamylase - aid absorption by cleaving complex carbohydrates to yield glucose.

By reversibly inhibiting these enzymes, α-glucosidase inhibitors increase the time required for absorption of carbs such as starch, dextrin, and disaccharides.

Front 264

265. What other effects do α-glucosidase inhibitors have on glucose levels?

Back 264

These drugs also increase the intestinal surface area for absorption b/c carbs that would have been absorbed in the upper intestine are absorbed instead - in smaller quantities - throughout the length of the small intestine.

Therefore, these drugs help reduce the postprandial peak in blood sugar.

Front 265

266. What are the three α-glucosidase inhibitors?

Back 265

1. Acarbose
2. Miglitol
3. Voglibose

Front 266

267. What are the therapeutic uses for α-glucosidase inhibitors?

Back 266

Type 2 diabetes

Front 267

268. Acarbose and miglitol

What are they and in what type of patients are they most useful?

Back 267

These two drugs are similarly effective. When used as monotheapy, these agents reduce fasting blood glucose by 25-30mg/dL, postprandial blood glucose by 40-50 mg/dL, and HbA1c by 0.7 to 0.9%, and they pose no risk of hypoglycemia (Unlike other oral hypoglycemic agents, these drugs do not stimulate insulin release, no do they increase insulin action in target tissues).

These drugs are most useful for patients w/predominantly postprandial hyperglycemia, and for new-onset patients with mild hyperglycemia.

Front 268

269. Pharmacokinetics of acarbose and miglitol

Back 268

Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, and some of the metabolites are abosrbed and excreted into the urine.

On the other hand, miglitol is very well absorbed but has not systemic effects. It is excreted unchanged by the kidney.

They decrease the bioavailability of metformin; concurrent use should be avoided.

Front 269

270. Adverse effects of acarbose and miglitol

Back 269

Flatulence, bloating, abdominal discomfort, and diarrhea are common adverse effects, all of which result form gas released by bacteria acting on undigested carbs that reach the large intestine.

The GI distress usually diminishes w/continued use, but these agents are contraindicated for patients w/inflammatory bowel disease.

Also, elevated ALT levels, and elevated TAGs are common adverse effects

Front 270

271. Contraindications of acarbose and miglitol

Back 270

1. Cirrhosis
2. Diabetic ketoacidosis
3. Severe digestive problems
4. Inflammatory bowel disease
5. Bowel obstruction

Front 271

272. Exogenous insulin

Back 271

Insulin is the only treatmetn for patients w/type I DM.

It is also used for patieitns with type II DM if diet and other therapies are not sufficiently effective at controlling the hyperglycemia.

Insulin preparations are classified according to onset of action, duration of action, and species of origin.

Front 272

273. How is exogenous insulin administered?

Back 272

B/c insulin is a protein that is subject to rapid degradation in the GI tract, it is not effective as an oral agent.

Instead, insulin is administered parenterally, typically by subcutaneous injection that creates a small depot of insulin at the site of injection.

The rate at which this depot of insulin is absorbed depends on a variety of factors, including the solubility of the insulin preparation and the local circulation.

Front 273

274. What are the four categories of exogenous insulin preparations?

Back 273

1. Ultrarapid-acting
-Lispro

2. Short-acting
-Regular insulin
-Semilente

3. Intermediate-acting
-NPH
-Lente

4. Long acting
-Ultralente
-Glargine

Front 274

275. Regular insulin

Back 274

This is a short and rapid acting preparation and is structurally identical to endogenous insulin, but zinc ions are added for stability.

It rapidly lower the blood sugar, and can be used safely in pregnancy only if clearly needed.

Regular insulin tends to aggregate into hexamers, and dissociation of the hexamers to monomers is the rate limiting step for absorption.

Front 275

276. Lispro insulin

Back 275

This is an ultra-rapid acting insulin. It was designed to keep the molecule in a monomeric form in order to speed absorption.

It is structurally similar to regular insulin, except that a sequence of two AAs (proline and lysin) near the carboxy terminus of the B-chain has been switched.

Lispro offers flexibility and convenience for patients b/c it can be injected minutes before a meal, whereas the proper use of longer-acting insulins requires a time lag between insulin injection and the consumption of a meal.

Front 276

277. Neutral protamine Hagedorn (NPH) insulin

Back 276

This is an intermediate-acting preparation.

Insulin is combined w/protamine at neutral pH. Protamine is a protein isolated from rainbow trout sperm - in a zinc suspension.

Protamine prolongs the time required for absorption of insulin b/c it remains complexed w/insulin until proteolytic enzymes cleave the protamine from the insulin. Thus, it provides basal insulin and overnight coverage.

Should only be given subcutaneously (never via IV), and is useful in treating all forms of diabetes except diabetic ketoacidosis or emergency hyperglycemia.

Front 277

278. Ultralente insulin

Back 277

A long acting preparation that is sometimes referred to as extended zinc insulin.

It is a crystalline suspension of insulin and zinc in an acetate buffer. This formulation delays the onset of action of insulin, resulting in a long-lasting hypoglycemic effect.

Also provides basal insulin and overnight coverage.

Front 278

279. Semilente insulin

Back 278

This is semicrystalline, or "amorphous", and is short-acting.

Used for meals or for acute hyperglycemia

Front 279

280. Lente insulin

Back 279

This is a combination of crystalline (i.e. ultralente) and semicrystalline (i.e. semilente) insulin and zine suspended in an acetate buffer.

This formulation is slower acting than semilente but faster acting than ultralente, and is therefore in the intermediate acting category.

Also provides basal insulin and overnight coverage.

Not suitable for IV administration

Front 280

281. Glargine insulin

Back 280

This is regular insulin in which a glycine replaces an asparagine on the A-chain and two additional arginines are added at the carboxy terminus of the B-chain.

These modifications makes the pKa of the insulin more neutral, thus slwoing its absorption into the neutral environment of the blood.

Glargine has the advantages of long duration of action and steady release w/o a peak (mimicking so-called "basal" insulin secretion"

Must be given subcutaneously.

Front 281

282. What is the major danger associated with insulin therapy?

Back 281

Administration of insulin in the absence of adequate carbohydrate intake can result in hypoglycemia.

Thus, patients, both type I and type II diabetics, must be cautioned not to take too much insulin.

Front 282

283. What are the two categories of insulin secretagogues?

Back 282

1. Sulfonylureas
2. Meglitinides

Front 283

284. Sulfonylureas

How do they work?

Back 283

They have been the major oral agents available in the US for the treatment of Type II diabetes.

Sulfonylureas stimulate insulin release from pancreatic beta cells, thereby increasing circulating insulin to levels sufficient to overcome the insulin resistance.

Front 284

285. Mechanisms of action of the sulfonylureas

Back 284

1. Stimulation of insulin release from the beta cells of the pancreas by blocking the ATP-sensitive K+ channels at the SUR1 subunit, resulting in depolarization of calcium influx.
2. Reduction of serum glucagon levels.
3. Increasing binding of insulin to target tissues and receptors.

Front 285

286. At the molecular level, how do sulfonylureas act?

Back 285

They act by inhibiting the beta cell K+/ATP channel at the SUR1 subunit. (The SUR subunit was so named b/c it is the "SUlfonylurea Receptor")

Sulfonylureas may act by displacing endogenous Mg2+-ADP, which bind to SUR1 and activates the channel.

The sulfonylureas used to treat type II diabetes bind w/a higher affinity to SUR1 than to SUR2 isoforms, accounting for their relative beta cell specificity.

Front 286

287. Pharacokinetics of sulfonylureas

Back 286

Given orally, these drugs bind to serum proteins, are metabolized by the liver, and are excreted by the liver or kidney.

Front 287

288. Adverse effects of sulfonylureas

Back 287

Major adverse effects:
1. Hypoglycemia resulting from oversecretion of insulin
2. Weight gain secondary to increased insulin activity on adipose tissue (not a good choice for the obese!)
3. Hyperinsulinemia
4. Rash
5. Diarrhea
6. Dizziness
7. Nausea

Front 288

289. Sulfonylureas contraindications

Back 288

1. Diabetic ketoacidosis
2. Patients w/hepatic or renal insufficiency
3. Pregnancy (the sulfonylureas can traverse the placenta and can deplete insulin from the fetal pancreas)

Front 289

290. What are the two classes of sulfonylureas?

Back 289

First generation:
1. Acetohexamide
2. Chlorpropamide
3. Tolazamide
4. Tolbutamide

Second generation
1. Glimepiride
2. Glipizide
3. Glibenclamide (Glyburide)
4. Gliclazide
5. Gliquidone

Front 290

291. What is the main difference between the first and second generation sulfonylureas?

Back 290

Because first generation sulfonylureas bind w/lower affinity to SUR1 than second-generation agents do, first generation agents must be administered in higher doses to achieve the same degree of glucose lowering.

Also, tolbutamide (1st gen) has the shortest duration of action (6-12 hours), whereas the 2nd gen agents last about 24 hours.

Front 291

292. Meglitinides

Back 291

As with sulfonylureas, meglitinides stimulate insulin release by binding to SUR1 and inhibiting the beta cell K+/ATP channel.

Although both sulfonylureas and meglitinides act on the SUR1 subunit, these two classes of drugs bind to distinct regions of the SUR1 molecule. (They have a more rapid onset and a shorter duration of action when compared to sulfonylureas)

The absorption, metabolism, and adverse effect profiles of meglitinides are similar to those of sulfonylureas

Front 292

293. What are the meglitinide analogues?

Back 292

1. Nateglinide
2. Repaglinide

Front 293

294. Adverse effects of meglitinides

Back 293

1. Hypoglycemia
2. Diarrhea
3. Nausea
4. Upper respiratory infection

Front 294

295. Contraindications for meglitinides

Back 294

1. Diabetic ketoacidosis
2. Type I DM

*Drugs that inhibit CYP3A4 (i.e. ketoconazole, fluconazole, erythromycin) may enhance the glucose lowering effect of repaglinide, whereas drugs that increase levels of this enzyme, such as barbiturates, carbamazepine, may have the opposite effect.

Front 295

296. What are the two classes of insulin sensitizers?

Back 295

1. Thiazolidinediones
2. Biguanides

Front 296

298. Thiazolidinediones (TZD)

Back 296

These drugs are a relatively new class of oral medicaction for Type II diabetes; the two currently avialable in the US is rosiglitazone and pioglitazone.

The TZDs do not affect insulin secretion, but rather enhance the action of insulin at target tissues.

Front 297

299. How do TZDs work?

Back 297

TZDs are agonists for nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ)



This can improve insulin sensitivity in not only adipocytes but also in muscle and liver cells.

Front 298

300. PPARγ

Back 298

PPARγ functions as a heterodimer with the retinoid X receptor to activate transcription of a subset of genes involved in glucose and lipid metabolism.

PPARγ is expressed primarily in adipose tissue and is involved in adipocyte differentiation.

Studies show that cells made to overexpress PPARγ accumulate TAG and acquire other adipocyte markers when treated with TZDs.

Front 299

301. How do TZDs help type II diabetics?

Back 299

Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.

Hyperglycemia, hyperinsulinemia, hypertriacyglycerolemia and elevated HbA1c levels are improved.

Front 300

302. What are the therapeutic uses for TZDs?

Back 300

1. Type II diabetes mellitus
2. Polycystic ovarian syndrome

Front 301

303. Adverse effects of TZDs

Back 301

1. Heart failure
2. Cholestatic hepatitis
3. Hepatic toxicity
4. Diabetic macular edema
5. Edema
6. Weight gain
7. Increased HDL and LDL
8. Decreased circulating TAGs and free FAs

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304. Contraindications of TZDs

Back 302

Hypersensitivity to pioglitazone or rosiglitazone

Women taking oral contraceptives and TZDs may become pregnant, because the latter have been shown to reduce plasma concentrations of the estrogen containing contraceptives.

*Newer TZDs appear to have less hepatotoxicity

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305. Biguanides

Back 303

Like TZDs, biguanides act by increasing insulin sensitivity.

The molecular target of the biguanides appears to be the AMP-dependent protein kinase (AMPPK).

Biguanides activate AMPPK to block the breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis.

Secondary effects include increased insulin signaling as well as increased metabolic responsiveness by the liver and skeletal muscle to insulin.

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306. What is the only currently available biguanide?

Back 304

Metformin

It increases glucose uptake and utilization by target tissues, which essentially reduces hepatic glucose output.

Like the sulfonylureas, metformin requires insulin for its action, but it differs from the sulfonylureas int hat it does not promote insulin secretion.

Front 305

307. Therapeutic uses for metformin

Back 305

1. Type 2 diabetes
2. Polycystic ovarian syndrome

Front 306

308. Adverse effects of metformin

Back 306

1. Lactic acidosis
2. Diarrhea
3. Dyspepsia
4. Flatulence
5. Nausea
6. Vomiting
7. Cobalamin deficiency

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309. Metformin contraindications

Back 307

1. Heart failure
2. Septicemia
3. EtOH abuse
4. Hepatic disease
5. Respiratory disease
6. Renal impairment
7. Iodinated contrast media if acute alteration of renal function is suspected, as this may result in lactic acidosis

Front 308

310. Misc metformin facts

Back 308

1. GI distress associated w/metformin use is usually transient and can be minimized by slow titration of the dose
2. Incidence of lactic acidosis is low and predictable; lactic acidosis typically occurs with metformin use in patients who have other conditions that predispose to metabolic acidosis
3. Does not induce hypoglycemia
4. Lowers serum lipids and decreases weight

Front 309

311. GLP-1 agonists and mimetics

Back 309

Glucagon like peptide-1 (GLP-1) receptor agonist that enhances glucose dependent insulin secretion, inhibits glucagon secretion, delays gastric emptying, and decreases appetite.

Front 310

312. What are the two GLP-1 agonists and mimetics?

Back 310

1. Exenatide
2. Sitaglipin

Front 311

313. Exenatide

Back 311

It apparently mediates its effects thru the GLP-1 receptor, and it not only improves insulin secretion but also slows gastric emptying time, decreases food intake, increases glucose suppression of glucagon secretion, and promotes beta cell regeneration or decreased apoptosis

Front 312

314. Adverse effects of exenatide

Back 312

1. Hypoglycemia
2. Nausea
3. Vomiting
4. Diarrhea
5. Nervousness
6. Dizziness
7. Headache

Front 313

315. Contraindications for exenatide

Back 313

1. Type I DM
2. Diabetic ketoacidosis

Front 314

316. Misc facts for exenatide

Back 314

1. It is not orally available and must be injected
2. Typically used in combination with metformin or a sulfonylurea to improve glucose control

Front 315

317. Sitagliptin

Back 315

This is a selective inhibitor of DPP-IV, the plasma enzyme that rapidly inactivates circulating incretin hormones such as GLP-1.

Sitagliptin threapy increase circulating GLP-1 and insulin concentrations, decreased glucagon concentration, and increased the responsiveness of insulin release to an oral glucose load in patients with type II DM.

It can be used as monotherapy or in combo with a TZD or metformin

Front 316

318. Adverse effects of sitagliptin

Back 316

1. Upper respiratory tract infection
2. Nasopharyngitis
3. Headache
4. Nausea
5. Diarrhea
6. Mild increase in serum creatinine level

Front 317

319. Contraindications for sitagliptin

Back 317

1. Type I DM
2. Diabetic ketoacidosis

Front 318

320. Misc facts for sitagliptin

Back 318

1. Dose adjustment is necessary in patients with moderate or severe kidney disease
2. May cause hypoglycemia in combination with sulfonylureas and insulin
3. Digoxin levels should be monitored in patients receiving digoxin and sitagliptin.

Front 319

321. Diazoxide

Back 319

Binds to SUR1 subunit of K+/ATP channels in pancreatic beta cells and stabilizes the ATP bound (open) state of the channel so that the beta cells remain hyperpolarized; this decreases insulin secretion by the cells.

Front 320

322. Therapeutic uses for diazoxide

Back 320

1. Hypoglycemia due to hyperinsulinism
2. Malignant hypertension

Front 321

323. Adverse effects of diazoxide

Back 321

1. Heart failure
2. Fluid retention
3. Diabetic ketoacidosis
4. Hypernatremia
5. Bowel obstruction
6. pancreatitis
7. Neutropenia
8. Thrombocytopenia
9. Angina
10. Hypotension
11. Tachyarrhythmia
12. Hirsutism
13. Hyperglycemia
14. Glycosuria

Front 322

324. Contraindications for diazoxide

Back 322

Hypersensitivity to diazoxide

Front 323

325. Misc facts about diazoxide

Back 323

Diazoxide also hyperpolarizes SUR2-containing channels in cardiac and smooth muscle cells, and can be used to decrease blood pressure in hypertensive emergencies.

Front 324

326. Octreotide

Back 324

Inhibits GHRH release

Is a somatostatin analogue that is longer acting than endogenous somatostatin.

As with somatostatin, this agent blocks hormone release from endocrine secreting tumors, such as insulinomas, glucagonomas, and thyrotropin-secreting pituitary adenomas.

Front 325

327. Glucagon

Back 325

Used to treat severe hypoglycemia when oral or IV glucose administration is not possible.

As with insulin, it is administered by subcutaneous injection.

The hyperglycemic action of glucagon is transient, and it requires a sufficient hepatic store of glycogen.

Glucagon is also used as an intestinal relaxant before radiographic or MRI imaging of the GI tract.

*Should not be used in those patients with known pheochromocytoma (neuroendocrine tumor of the medulla of the adrenal glands)