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Therapeutics P2 > Exam 2 lecture 3 > Flashcards

Exam 2 lecture 3 Flashcards

1
Q

What are the two types of drugs used inT 2 diabetes that have nothing to do with the pancreatic B cell?

A

a-gluconidase inhibitors
SGLT2 inhibitor

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2
Q

MOA of a-gluconidase inhibitors

A

Decrease absorption of carbohydrates from intestine.

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3
Q

How do a-gluconidase inhibitors decrease absorption of carbohydrates from the intestine

A

gluconidase cleaves disaccharides to monosaccharides. Monosacharides are easily aborbed by the body. a-gluconidase inhibitor inhibits this cleavage.

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4
Q

a-gluconidase drugs? difference between the two?

A

Acarbose- minimally absorbed
Migitol- completely absorbed
they cause a lot of GI effects

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5
Q

How do the two a-gluconidase inhibitors work?

A

They both bind the active site of the gluconidase but migitol is absorbed so has no liver toxicity. Acarbose may cause liver damage

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6
Q

What does SGLT2 inhibitors do?

A

Gets rid of glucose without stimulating uptake, it enhances glucose excretion

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7
Q

How do SGLT-2 inhibitors enhance glucose excretion

A

By artificially reducing the Vmax of the transporter, allowing more glucose to escape to urine. Also increases Na loss which helps HF pts

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8
Q

SGL-2 inhibitors all stem from______
Name some SGLT-2 inhibitors

A

Empagliflozin, dapagliflozin

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9
Q

SGLT-2 indication? Contraindication? SAR?

A

Indicated in T 2 diabetes. may lead to increased risk of limb amputation, We have a glucose as a recognition site for transporter, allows binding but not transport

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10
Q

adverse effects of SGLT-2

A

Increased risk of UTI
increased risk of diabetic ketoacidosis

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11
Q

SGLT-2 qshows benefit is

A

reducing A1C
(weightloss and even CKD)

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12
Q

What are some agents that reduce insulin resistance

A

Biguanides
Thiazoladiindeonides

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13
Q

Name a biguanide

A

Metformin

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14
Q

Name some thiazoladindonide drugs

A

pioglitazone
Rosiglitazone

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15
Q

T/F There is a key link between FFA (free fatty acid) levels and insulin resistance

A

True

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16
Q

How is non-obese T 2 diabetes caused

A

By a mutation causing a problem that leads to either insulin resistance or decreased protein secretion

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17
Q

What is insulin resistance? How is it detected? What are its causes?

A

Decreased responsiveness to actions of insulin. Can be detected by OGTT. Caused by mutations, obesity (common) and inactivity

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18
Q

Insulin resistance effect on skeletal muscle

A

Impaired glucose uotake

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19
Q

Insulin resistance effect on adipose tissue

A

Impaired glucose uptake
impaired inhibition of lipolysis

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20
Q

Insulin resistance effect on liver

A

Impaired inhibition of glucose output
via gluconeogenesis

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21
Q

how does obesity cause insulin resistance

A

Increased FFA

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22
Q

Can insulin resistance be caused by polymorphism?

A

Yes

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23
Q

What mutation causes insulin resistance

A

Switch of phosphorylation of Tyr to Ser can inhibit signalling

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24
Q

What other two things can also cause insulin resistance

A

elevated FFA and inflammatory mediators (TNFa)

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25
Q

mechanism of how FFA causes insulin resistance

A

FFA is elevated and is uptaken into tissue
They activate a kinase called MTOR. (mTOR is the key sensor of nutreint level)
mTOR phosphorylates P7056K
p7056K phosphorylates IRS protein.
phosphorylates not on tyrosines, but on serines, which leads to resistance

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26
Q

quick summary of how elevated FFA can stimulate insulin resistance

A

activation of MTOR
phosphorylation of IRS proteins that interefere with normal function

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27
Q

increased cytokines can do what?

A

activate a number of kinases

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28
Q

What are some kinases activated by cytokines

A

PKC, JNK, NFKB

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29
Q

What do kinases do after activation by cytokines

A

Phosphorylate both insulin receptor and IRS protein

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30
Q

What does phosphorylation of IRS by kinases do?

A

recruits PI3k

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31
Q

WHat does PI3K do after phosphorylation of IRS

A

phosphorylates PIP2 to PIP3

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32
Q

What does PIP3 do?

A

Activates AKT

33
Q

What does AKT do?

A

allows rapid translocation of GLUT-4 to plasma membrane

34
Q

summarize how cytokines affect IRS protein

A

Cytokines activate kinases
Kinases phosphorylate both insulin receptor and IRS protein
phosphorylation or IRS causes recruitment of PI3K
P13K phosphorylates PIP2 to PIP3
PIP3 activates AKT
AKT allows rapid translocation of GLUT-4 to pm

35
Q

What happens when serine phosphorylation inhibits IRS signalling

A

It interferes with the recruitment of the catalytic subunit (P110), reducing PIP3 accumulation, this interferes with AKT activation.

36
Q

T/F serine phosphorylation of insulin receptor leads to insulin resistance

A

True

37
Q

P110 vs P13K

A

P110 is catalytic
P13K is regulatory

38
Q

Is there an increase in inflammatory cytokines in obesity? WHy?

A

Yes. There is a hypertrophy of adipose tissue and infiltration of M1 macrophages that lead to an increase in inflammatory cytokines. (TNFa)

39
Q

Who has M1 macrophages? Who has M2 macrophages? What is the difference between the two?

A

M2 macrophages are in non-obese people
M1 macrophages are in obese people

M2- secrete IL-10 which maintain insulin snsitivity
M1- lead to inflammatory cytokines

40
Q

Which two drugs can address insulin resistance, without stimulating insulin secretion

A

Metformin
Thiazoldindiones

41
Q

What are the pros of metfromin compared to sulfonylureas

A

Pros- no hypoglycemia, no weight gain, independent of B cells

42
Q

MOA of metformin

A

Activates AMP-kinase, increases efficiency or sensitivity to insulin in liver, fat and muscle cells

42
Q

What does metformin bind?

A

Complex I

43
Q

What does metformin do to liver?

A

Stops export of glucose from liver

43
Q

How does metformin stop the export of glucose from the liver

A

-Metformin binds to complex I and inhibits it.
-This lowers energy availability (ADP:ATP and AMP:ATP ratios rise)
-Inhibition of ATP leads to rise in AMP
-Increased AMP inhibits fructose-6-bisphosphate which is required for gluconeogenesis

44
Q

summary of how metformin works in liver

A

inhibits gluconeogenesis in liver by inhibiting fructose-1,6- Bisphosphate

45
Q

How does metformin affect skeletal muscle

A

Accumulation of AMP leads to increase in translocation of GLUT-4 to plasma membrane and increased uptake of glucose into skeletal muscle

46
Q

How does metformin cause increased uptake of GLUT-4

A

AMP accumulates
activates AMP-K
AMP-k phosphorylates a GTP-ase regulator of Rab called TBC1D 1/4
TBC1D 1/4 helps Rab hydrolyze GTP, Rab dissociates and translocation of GLUT-4 occurs

47
Q

why would metformin cause lactic acidosis

A

Since it inhibits gluconeogenesis. This pathways is important for the removal of lacyic acid

48
Q

most common side effect of metfromin

A

GI side effects (N, V, D)
also decreases B12 absorption

49
Q

Metformin effect on blood lipid profile

A

decreases serum triglycerides
Decreases serum LDL
decreases risk of adverse CV events

50
Q

What do thiazoliedindiones do?

A

Decrease insulin resistance

51
Q

target of thiazoldindiones

A

PPAR-g

52
Q

What is PPAR-g? what does it do?

A

It is a transcription factor that enhances adipocyte differentiation

53
Q

how does PPAR-g affect FFA`

A

Enhances FFA uptake into subQ, reduces serum FFA.

54
Q

WHat are some thiazoledindione drugs

A

Rosiglitazone
pioglitazone

55
Q

FDA warning for thiazoledindione drugs

A

Contraindicated in class 3 or 4 HF

56
Q

How do thiazodindiones affect TNF-a, resistin and adiponectin

A

Lower TNF-a and resistin (adipokines) and raise adiponectin

57
Q

What is adiponectin

A

stimulates insulin dependent glucose uptake

58
Q

Thiazonedindiones ________FFA levels and ______ adiponectin levels

A

decrease, stimulate

59
Q

Why is there an increased risk of fracture with thiazonedindiones

A

They reduce the differentiation of stem cells to osteoblasts

60
Q

What is gestational diabetes? what is it caused by?

A

Hyperglycemia during pregnancy in non-diabetic women. caused by the normal changes in insulin sensitivity and metabolism furing pregnancy

61
Q

What happens to insulin response in early vs late pregnancy

A

Early- increased nsulin response
late- reduced insulin sensitivity

62
Q

Why is there an increased insulin response in early pregnancy

A

Placenta is not growing, body becomes insulin sensitive to increase maternal fat storage to help placenta grow

63
Q

Why is there reduced insulin sensitivity in late pregnancy?

A

Fetus frows and takes all nutrients from mom. Body compensates by increasing insulin secretion

64
Q

When is gestational diabetes diagnosed? how is it diagnosed?

A

24-28 weeks with OGTT. This is the rapid growth stage of gestation.

65
Q

What are some complications in gestational diabetes

A

Baby could have hypoglycemia when separate
increased risk of developing T2 diabetes in mom and baby

66
Q

Why is there an increased risk of developing T2 diabetes in gestational diabetes babies

A

Due to the exposure of fetus to high levels of insulin and glucose from gestation (fetal programming)

67
Q

Does insulin cross the placenta? Does glucose cross the placenta?

A

Insulin does not, but glucose does. That means the baby needs to make its own insulin.

68
Q

placental hormones secreted in gestational DM

A

CRH-cortisol
Progesterone
Placental GH
Placental lactogens (PL)

69
Q

What are placental lactogens

A

Placental hormones secreted by placenta that induce peripheral insulin resistance in mother

70
Q

why is GDM predictive of T2 diabetes

A

Because of the inability of mothers pancrease to compensate for resistance by increasing B cell acitivity

71
Q

what are hormones secreted during pregnancy that increase B cell mass

A

Prolactin and placental lactogen

72
Q

What does prolactin do?

A

Stimulates B cell proliferation
mutations i prolactin receptor are associated with GDM

73
Q

What does placental lactogen do

A

Is similar to GH, activates prolactin

74
Q

Compare the different treatments of GDM

A

Insulin- gold standard, does not cross placenta, disadvanatge is that it can cause stress
Glyburide- adv- oral, disadvantage, crosses placenta
Metformin- disadvantage- crosses placenta but does not seem to harm it.
TZD not used- teratogenic

75
Q

metformin target

A

complex I

76
Q

Cellular effect of metfromin

A

Elevates CAMP and activates AMPk

77
Q

Metformin effect on liver

A

Reduced glucose export due to inhibition of gluconeogenesis

Therapeutics P2 (41 decks)

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