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PMCOL 344 > diabetes-3 > Flashcards

diabetes-3 Flashcards

1
Q

what is T1DM

A

chronic disorder resulting from autoimmune destruction of beta cells

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2
Q

what relates to the complications of hyperglycemia

A

the degree and length of duration

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3
Q

what part of the body is most vulnerable to hyperglycemia

A

capillary endothelium

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4
Q

what are 3 alterations to cell metabolism that happen in T1DM

A
  • imbalance glucose and FA oxidation
  • ER stress, accumulation lipids, NADPH depletion
  • increased free radicals
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5
Q

what causes glycosuria

A

overcome renal glucose resorption

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6
Q

what can happen to protein metabolism in T1DM

A

it is dysfunctional, leads to protein wasting

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7
Q

what is ketoacidosis

A

limited ability to take up glucose and subsequent lack of glycogen stores means that fats converted to acetyl-CoA to acetoacetate, beta hydroxybutyeate and acetone

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8
Q

what are the goals in T1DM treatment

A

tight regulation of plasma glucose to alleviate symptoms related to hyperglycemia and prevent chronic complications

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9
Q

what are 2 main regiments in T1DM

A

regular monitoring of glucose and insulin replacement therapy

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10
Q

what is used in insulin replacement therapy

A

human recombinant insulin

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11
Q

can you give insulin orally and why

A

no, destroyed in GI tract

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12
Q

what is the half life of insulin

A

10 mins

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13
Q

what are 2 major differences when it comes to injected insulin and normal human made

A
  • absorption kinetics do not reproduce rapid rise and fall of endogenous insulin in response to food
  • enters peripheral rather than portal circulation so may alter effects on hepatic metabolic processes
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14
Q

what are the 2 main preparations of insulin

A

soluble and protamine NPH insulin

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15
Q

what is soluble insulin route and timing

A

rapid acting, short duration of action, IV or IM

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16
Q

what is protamine NPH insulin

A

insulin complexed with zine and protamine, relatively insoluble crystals injected as a suspension

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17
Q

what is protamine NPH insulin route and timing

A

IM or SC, slower absorption and longer duration of action (once or twice a day)

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18
Q

what are 2 types of insulin analogues

A

insulin lispro and glargine

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19
Q

what is insulin lispro structure

A

lysine and proline residues at position 28 and 29 switched (on B chain)

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20
Q

what is duration of insulin lispro and why

A

reduces tendency of molecules to self associate, so act rapidly for shorter time, inject immediately before eating

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21
Q

what is insulin glargine structure

A

asparagine substituted for glycine at position 21 on A chain and B chain, lengthened by adding 2 arginines

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22
Q

what is the duration of insulin glardine and why

A

long acting, reduced solubility at pH7.4 so precipitates in sub-cutaneous tissue and slowerly released (mimic basal release)

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23
Q

which insulin is made to mimic basal release

A

insulin glargine

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24
Q

which insulin is made to mimic rapid release

A

insulin lispro

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25
Q

what are some side effects of insulin

A

hypoglycemia, can cause brain damage and sudden cardiac death

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26
Q

what characterizes T2DM

A

insulin resistance and insulin deficiency

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27
Q

what happens to glucagon in T2DM

A

increased levels

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28
Q

what happens to GLP-1 in T2DM

A

reduced levels/ actions

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29
Q

what does insulin resistance do to liver

A

inadequate suppression of glucose output after meals

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30
Q

what does insulin resistance do to glucose utilization and uptake

A

decrease

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31
Q

what does insulin resistance do to lipolysis and fatty acid release

A

increase

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32
Q

what usually happens with insulin receptor activation

A

tyrosine phosphorylation

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33
Q

what happens with tyrosine phosphorylation

A

P13K/Akt activation, GLUT4 translocaction

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34
Q

why may obesity be linked to T2DM

A

because lipid accumulation leads to PKC activation (DAG elevated by increased free fatty acid), phosphorylation of insulin receptor, inhibits normal receptor signalling, inflammatory

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35
Q

what are the goals in the treatment of T2DM

A

improve beta cell function and sensitivity to insulin to alleviate symptoms and prevent chronic complications

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36
Q

what are the 3 main groups of drugs for T2DM

A

insulin sensitizers, drugs targeting beta-cell dysfunction, incretin based therapies

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37
Q

what are 2 drugs used as insulin sensitizers

A

metformin and thiazoladinediones

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38
Q

what are 1 drug used as drugs targeting beta-cell dysfunction (drug and class)

A

sulfonylureas, glibenclamide

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39
Q

what are 2 drugs used as incretin based therapies

A

exenatide and sitagliptin

40
Q

generally, what do metformin and thiazoladinediones do

A

insulin sensitizers

41
Q

generally, what do sulfonylureas, glibenclamide do

A

drugs used as drugs targeting beta-cell dysfunction

42
Q

generally, what does exenatide do

A

GLP-1 mimetic

43
Q

generally, what does sitagliptin do

A

DDP-4 inhibitor

44
Q

how do you ingest metformin

A

oral

45
Q

how do you ingest thiazoladinediones

A

oral

46
Q

what drug class is thiazoladinediones

A

glitazone

47
Q

what are 2 main effects of metformin

A

decrease glucose output, increase glucose uptake due to increase GLUT4 expression

48
Q

how does metformin increase glucose uptake

A

increased GLUT4 expression

49
Q

what is the mechanism of action of metformin

A

activates AMPK, which enhances insulin sensitivity

50
Q

what does AMPK activation lead to

A

decrease glucose output, increase glucose uptake due to increase GLUT4 expression

51
Q

what does metformin do to glucose output

A

decrease

52
Q

what does metformin do to glucose uptake

A

increase

53
Q

what is the mechanism of action of thiazoladinediones

A

activates PPAR gamma ligands

54
Q

what happens once PPAR gamma ligands are activated

A

they alter transcription of enzymes involved in metabolism and proteins involved in insulin response

55
Q

what do thiazoladinediones do to liver

A

decrease glucose output

56
Q

what do thiazoladinediones do to muscle

A

increase glucose uptake

57
Q

what do metformin do to liver

A

decrease glucose output

58
Q

what do metformin do to muscle

A

increase glucose uptake due to increase GLUT4 expression

59
Q

what 2 things can thiazoladinediones do (besides the PPAR gamma)

A

increase transcription of lipoprotein lipase (LPL) and GLUT-4

60
Q

what can thiazoladinediones do to weight + how

A

cause weight gain, differentiation of adipocytes, increased lipogenesis, reduced leptin

61
Q

what can thiazoladinediones do to blood pressure + how

A

lower, vasodilation

62
Q

what do sulfonylureas and gibenclamide come from

A

antibiotic derivaties

63
Q

what is the mechanism of action of sulfonylureas and gibenclamide

A

block pancreatic B-cell KATP channel by binding to SUR subunit, depolarization, increased, calcium channels, then release of insulin

64
Q

does sulfonylureas insulin secretion depend on glucose levels

A

no

65
Q

which kind of people would sulfonylureas not work for

A

patients that dont have beta cell function

66
Q

how is sulfonylureas often prescribed

A

with metformin or glitazones

67
Q

what kind of side effects come with sulfonylureas and why

A

cardiovascular cause there are KATP channels in the heart

68
Q

what are a couple of drug interactions with sulfonylureas

A

NSAIDS, alcohol, MAO inhibitors, antibiotics

69
Q

why does sulfonylureas have drug interactions

A

competition for metabolizing enzymes, interference with plasma protein binding or excretion

70
Q

what % of secreted insulin in healthy individuals are caused by incretins

A

50%

71
Q

what are 2 examples of incretins

A

GLP-1 and GIP

72
Q

what is the mechanism of incretins

A

bind to GPCR, Gs, cAMP

73
Q

what does cAMP do to beta cells

A
  • phosphorylate SUR1 to inhibit KATP
  • inhibit delayed rectifier Kv channel
  • cells depolarize longer
  • mobilize Ca++ From intracellular stores
  • increase ATP (more KATP inhibition)
74
Q

what does ATP to do KATP channel

A

inhibit

75
Q

what does SUR1 phosphorylation cause

A

inhibition of KATP channels

76
Q

what does incretins do to glucagon

A

inhibit secretion

77
Q

what does incretins do to appetite

A

decrease

78
Q

what does incretins do to gastric emptying

A

slow - feel full longer, slows sugar absorption

79
Q

how is exenatide administered

A

sc in sustained release capsules

80
Q

what is exenatide

A

synthetic GLP-1

81
Q

what makes exenatide special

A

it is not broken down by DPP-4

82
Q

what does DPP-4 do

A

breaks down GLP-1 and other incretins (serine protease)

83
Q

what drugs is exenatide used with

A

sulfonylureas (synergism) and metformin (additive)

84
Q

what is the duration of exenatide and why

A

longer, 12-14 hours so take twice daily

because it is not broken down by DPP-4

85
Q

what is sitagliptin

A

DPP-4 inhibitor

86
Q

what is the half life of sitagliptin

A

about 2 mins

87
Q

what is the absorption of sitagliptin

A

less than 25% leaves the gut, 40-50% degraded in liver, 10-15% reaches systemic circulation

88
Q

what is the mechanism of sitagliptin

A

prevents breakdown of endogenous incretins, so potentiates actions of GLP-1

89
Q

why does barely any sitagliptin get into the systemic circulation

A

not much leaves the gut and lots of it degraded in liver

90
Q

what does alpha-glucosidase do

A

releases glucose from more complex carbohydrates in intestine (like starch)

91
Q

what does alpha-glucosidase blocker do

A

slows absorption of glucose, prevents initial glucose spike

92
Q

what is another thing that alpha-glucosidase inhibitors do

A

increase GLP-1 secretion

93
Q

what are some side effects of alpha-glucosidase inhibitors

A

fart, weight loss, diarrhea

94
Q

what do a majority of T2DM patients require at some point + why

A

exogenous insulin because beta cell function declines

95
Q

what is first line therapy

A

metformin + sitagliptin is smart to add

PMCOL 344 (27 decks)

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