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Therapeutics P2 > Exam 2 lecture 1 > Flashcards

Exam 2 lecture 1 Flashcards

1
Q

Why is glucose so toxic?

A

oxidation products react irreversibly with proteins to form advanced glycation end products (AGE)

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2
Q

Why is glucose so reactive? In what form is it the most reactive

A

In its extended aldehyde form. Aldehydes are very reactive

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3
Q

what are some oxidation products of glucose

A

Glyoxal and methylglyoxal

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4
Q

what do glyoxal and methylglyoxal do?

A

They react with proteins and degrade them.

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5
Q

What do glyoxal and methylglyoxal bind to?

A

RAGE (receptor for AGE)

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6
Q

hemoglobin A1C is a measure of

A

how much glucose there is hanging on hemoglobin protein in RBC.

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7
Q

What is the pro of A1c over BG levels

A

A1c measures the avg blood glucose level over a period of time, BG is too volatile

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8
Q

RAGE is mostly present on

A

Leukocytes and endothelial cells, it is a part of MHC superfamily

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9
Q

WHat are CML and CEL

A

carbomethyl lysine and carboethyl lysine

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10
Q

how are CML and CEL formed

A

lysine reacting with glyoxal and methylglyoxal
(remember that glyoxal and methylglyoxal degrade proteins to form AGEs)

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11
Q

How do CML and CEL affect our bodies

A

Since they are AGEs, they bind to RAGE and promote inflammation.

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12
Q

why are different mechanisms taken by glucose in hyperglycemia

A

When we have a high BG, we shove glucose through metabolic pathways that are normally not used much. (polyol pathway, hexosamine pathway and PKC pathway)

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13
Q

explain the polyol pathway

A

nerves process glucose to sorbitol and convert to fructose. This is then stored in the nerves.

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14
Q

Why is polyol process a probelm

A
  1. If we accumulate sugar alcohols in neurons, this leads to water flooding the neuron, which leads to neuropathies
  2. the rxn to turn glucose to sorbitol is catalyzed by aldose reductase, which consumes a lot of NADPH, which is needed to protect neurons from oxidative stress. This makes neurons more suseptible.
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15
Q

how is hexosamine pathway activated

A

glucose is metabolized to fructose-6-phosphate (Rate limiting step). Accumulating a lot of fructose-6-phosphate can activate a lot of hexosamine pathway

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16
Q

Why does accumulating a lot of fructose6-phosphate activate hexosamine pathway

A

fructose-6-phosphate is reacted on by GFAT, which turns into G-6-P and conjugated with UDP forming UDP-G1CNAC

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17
Q

What is UDP-G1cNAC

A

a substrate for enzymes that can put glutamines onto OH groups of proteins, changing their function.

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18
Q

In short polyol process summarize

A

Glucose turned into fructose and stored in neurons cause issues like water in neurons. Also NADPH is consumed when sorbitol is catalyzed making neuron more susceptible for oxidative stress.

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19
Q

hexosamine pathway summarize

A

Fructose-6 phosphate is accumulated and activates hexosamine pathway. this f-6-p is turned into g-6-p and conjugated with UDP to form UDP-G1cnac

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20
Q

Explain the PKC pathway

A

hyperglycemia leads toGlyceraldehyde-3-p accumulation, this leads to elevated DAG and activates PKC

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21
Q

link between hyperglycemia and ability to exert vascular relaxation

A

Methylglyoxal inhibits vasorelaxation stimulated by AcH/nitric oxide

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22
Q

how does methylglyoxal inhibit vasorelaxation

A

Methylglyoxal can react with arginine and form MG-H1 in endothelial cell of BV. ARG is an important substrate for nitric oxide synthase (which is essential to mediate vascular tone)

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23
Q

Why is insulin important

A

To use glucose effectively as a fuel

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24
Q

what does no insulin mean

A

Hyperglycemia and susceptible to ketoacidosis because they are using fatty acid for fuel.

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25
Q

What are the two subunits of the insulin receptor

A

alpha (a) and beta (b)

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26
Q

roles of a and b subunits of insulin receptor

A

alpha- regulatory unit of receptor. represses the catalytic activity of beta subunit. Repression is relieved by insulin binding

beta- contains tyrosine kinase catalytic domain for autophosphorylation.

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27
Q

How are alpha and beta subunits alligned

A

There is an extracellular alpha subunit and an extracellular and intracellular beta subunit.

ligand binding domain is extracellular and tyrosine kinase is inside B subunit

these two tyrosine kinase domains autophosphorylate each other.

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28
Q

how many molecules of insulin does it take to stimulate insulin receptor

A

1

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29
Q

3 main tissues for insulin action

A

liver, muscle and fat

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30
Q

How is IRS (insulin receptor substrate) recruited?

A

Insulin binding insulin receptor, activating intracellular tyrosine kinase domains.

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31
Q

What is IRS

A

Insulin receptor substrate. This is an important adaptive protein for insulin signaling. It gets phosphorylated and recruits signalling molecules to complex

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32
Q

give an example of how a hexosamine pathway interferes with normal function

A

Hyperglycemia and activation of hexosamine pathway can result in glucosamine being added to IRS, which interferes with its function.

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33
Q

what happens when IRS is phosphorylated

A

It recruits PI3K

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34
Q

What does PI3K do?

A

Phosphorylates PIP2 to PIP3, activating PDK 1

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35
Q

what does phosphorylation of PIP2 to PIP 3 do?

A

activates PDK 1

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36
Q

What does PDK 1 do once active

A

activates 2 kinases

37
Q

What are the names of the 2 kinases activated by PDK 1

A

aPKC and PKB

38
Q

What do aPKC and PKB do

A

increase glycolysis and increase glucose utilization.

39
Q

What is another use of PDK 1 and subsequent activation of PKB and aPKC

A

for translocation of GLUT 4 to plasma membrane

40
Q

GLUT 4 are stimulated by

A

Insulin

41
Q

use of GLUT 4 translocation

A

enables skeletal muscle to take up glucose at a very rapid rate.

42
Q

PDK and PKB can also stimulate

A

an increase in glycogen synthesis in liver and decrease in gluconeogenesis

43
Q

main effect of glucose on fatty acid cells

A

increase lipogenesis (taking free fatty acid and storing it as lipid)

44
Q

how is lipogenesis activated by glucose

A

Activated by Shc protein that gets phosphorylated by insulin which recruits MAPk, leading to lipogenesis or cell growth and proliferation.

45
Q

insulin effect on liver

A

Inhibits- glycogenolysis
Ketogenesis
gluconeogenesis

stimulates- glycogen synthesis
triglyceride synthesis

46
Q

insulin effect on skeletal muscle

A

Stimulates- glucose transport
aa transport

47
Q

Adipose tissue

A

stimulates- triglyceride storage
glucose transport

48
Q

glucose disposal in fasting state

A

75% of glucose disposal is non-insulin dependent (liver, GI, brain)
25% is insulin dependent in skeletal muscle. Glucagon is secreted to prevent hypoglycemia

49
Q

Glucose disposal in fed state

A

80-85% is insulin dependent in skeletal muscle.
4-5% in adipose tissue
glucagon secretion is inhibited

50
Q

Insulin inhibits the release of _________from adipose tissue

A

Free fatty acid (FFA)

51
Q

how does a decrease in FFA affect the body

A

enhances insulin action on skeletal muscle, reduces hepatic glucose production.

52
Q

What is the major role of skeletal muscle in this topic

A

site of uptake of glucose after a meal.

53
Q

What are the 4 glucose transporters

A

GLUT-1 - widely expressed, constitutive (not insulin dependent)
GLUT-2- Constitutive, found in liver and B cell
GLUT-3- found in nervous system, constitutive
GLUT-4- skeletal muscle and adipocytes, insulin dependent

54
Q

what is the source of insulin secreted in response to glucose

A

pancreatic B cell

55
Q

which cells are endocrine in pancrease?

A

Islets of langerhans, others are exocrine cells.

56
Q

What do exocrine cells do in pancrease

A

secrete digestive enzymes into small intestine.

57
Q

What do endocrine cells in pancrease secrete

A

Insulin, Amylin, somatostatin and glucagon

58
Q

What does glucagon do?

A

stimulates glycogen breakdown and increased BG

59
Q

What does somatostatin do?

A

general inhibitor of secretions

60
Q

What does insulin do?

A

Stimulates uptake and utilization of glucose

61
Q

what does Amylin do?

A

Co-secreted with insulin from B cells. slows gastric emptying and decreases food intake. inhibits glucagon secretion.

62
Q

insulin is processed from a pro hormone called

A

pro-insulin

63
Q

what is pro insulin

A

a polypeptide that has not been processed to its active form. it is translated into a polypeptide that is processed in secretory granule by enzymes called pro-convertases.

64
Q

what do pro converatses do?

A

Cleave cleave pro insulin in two spots to release connecting peptide.

65
Q

Insulin source

A

Recombinant human insullin

66
Q

What separates the types of insulin

A

Pharmacokinetics
How long to start acting, how long to peak, duration of action.)

67
Q

What are the different types of insulin

A

Ultra rapid onset
regular insulin
Intermediate insulin
slow onset

68
Q

Example of ultra rapid insulin

A

Lispro (Humalog)
Aspart (novolog)
Glulisine (Apidra)

69
Q

Example of slow onset insulin

A

Glargine (lantus)
Detemir (llevemir)
Degludec (tresiba)

70
Q

how do modified insulin alter the availability and absorption from subQ inj sites. Why do we need to do this?

A

Delay absorption- prolong onset and duration
increase absorption- decrease time to onset and duration

We want to mimick what happens physiologically when glucose levels are elevated

71
Q

What are the 2 phases of insulin secretion

A

Rapid 1st phase- peaks quickly and plateus
plateu 2nd phase- plateu of elevated insulin after 1st peak

72
Q

How is Zn important in insulin dosing

A

Zn is important for causing dense concentrations of insulin by forming a complex with insulin (forms a dimer of trimers)

73
Q

What is the science behind why we use Zn in insulin

A

Zn binds insulin forming a complex, larger complex size leads to a more prolonged absorption from subQ inj site. Lente family (no longer used) used to use this method)

74
Q

What is NPH

A

neutral protamine hagedon. Intermediate insulin. Has a clear peak, slow absorption, long duration of action.

75
Q

what are the modifications in lispro (humalog) that give it its properties.

A

Proline and lysine positions are changed , this disrupts dimerization of insulin monomers, keeping them in monomer form. Monomer is rapidly absorbed.

76
Q

What are modifications in Insulin aspart (novolog) that give it its properties.

A

Proline 28 is chnaged to aspartate.
immediately before meal
short duration

77
Q

Insulin glulisine (apidra) modifications to give it its properties

A

Asn and lys are switched to Lys and Glu.
short duration, injected immediately before meal
short duration

78
Q

What are modifications that give Insulin glargine (lantus) its properties

A

Asn 21 on a chain changed to gly
2 ARG residue added to the end of B chain

This changes its solubility.

79
Q

Why is insulin glargine (lantus) slowly absorbed

A

Modifications change solubility to PH 4. When released SubQ, it is PH 7 there, it is not soluble in that PH so it precipitate’s and is slowly absorbed overtime.

80
Q

What modifications give Insulin detemir (levemir) its properties?

A

Thr is deleted and Lys is myrilated with fatty acid. This fatty acid allows it to bind to serum albumin extensively, creating a sink of insulin.

81
Q

what modifications give Insulin deglude (tresiba) its properties

A

Thr 30 b-chaain is replaced by gamma-glu-c16 fatty acid. Allows it to bind serum albumin.

82
Q

When are fast acting insulins taken?

A

Before meals

83
Q

When are long/intermediate insulins taken?

A

At bedtime or after breakfast

84
Q

Why are most insulins in a mixture

A

Give 1 injection and get a rapidly acting compinent and another for prolonged basal activity.

85
Q

properties of inhaled Insulin? contraindications

A

Inhaled dry powder, has more rapid onset and shorter duration than Subq inj
contraindicated in asthma and COPD.
drug name is afrezza

86
Q

routes of administration of insulin

A

SubQ- all
insulin infusion pump- fast acting (lispro, aspart, glulisine)
IV-regular for severe hypokalemia or ketoacidosis

87
Q

mode of action of insulin in diabetic

A

Decrease liver glucose output
increase fat storage
Increase glucose uptake

88
Q
A

Therapeutics P2 (41 decks)

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