Block 1 Lecture 2 -- Diabetes II Flashcards Preview

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Flashcards in Block 1 Lecture 2 -- Diabetes II Deck (90):
1

Normal post-prandial [glucose]

120-140 mg/dL

2

normal fasting [glucose]

70-100 mg/dL

3

Describe the structure of insulin.

51 AA with alpha and beta chain
-- 2 disulfides link chains
-- 1 addl disulfide on alpha chain

4

Normal fasting [insulin]

50 pM

5

Normal bolus insulin [concentration] at mealtime

500 pM

6

How is insulin secretion stimulated?

primarily by glucose
-- also GLP-1, GIP
-- cholinergic vagal stimulation
-- medications

7

Describe endogenous insulin clearance.

60% hepatic; 40% renal

8

Describe exogenous insulin clearance

40% hepatic; 60% renal

9

What is the t1/2 of insulin?

5 minutes

10

Describe [insulin receptor] on non-responsive cells

40/cell

11

Describe [insulin receptor] on responsive cells.

300,000/cell

12

Describe structure of insulin receptor.

2 covalently-linked heterodimers
-- extracellular alpha subunit recognition site
-- beta membrane-spanning TK unit

13

What are the GLUT isoforms?

1-4

14

Location and fx of GLUT-1:

1) brain
2) transport across BBB

15

Location and fx of Glut-2:

1) beta cells, liver
2) regulation of insulin release and glucose homeostasis

16

Location and fx of Glut-3:

1) brain
2) uptake into neurons

17

Location and fx of GLUT-4:

1) skeletal muscle, adipose
2) insulin-mediated glucose uptake

18

What is the inhaled insulin on the market, and when was it approved?

1) Afrezza
2) June '14

19

What is the equivalent mg/mL concentration of 100 units/mL insulin?

3.6 mg/mL

20

What are the rapid acting insulin analogs?

1) Aspart (Novolog)
2) Glulisine (Apidra)
3) Lispro (Humalog)

21

What are the short-acting insulins?

Regular (Humulin/Novolin R)

22

What insulin forms come U-500?

Humulin R (lilly)

23

What are the intermediate-acting analogs?

1) NPH (neutral protamine Hagedorn)
-- also NPA/NPL in mixtures

24

What insulin products are identical to human insulin?

1) Regular (Humulin/Novolin R)
2) NPH

25

What are the long-acting insulin analogs?

1) Detemir (Levemir)
2) Glargine (Lantus)

26

What is the usual dosage of insulin glargine?

once-daily (24h coverage)

27

What is the usual dosage of insulin detemir?

often BID

28

What insulins are mixed?

1) intermediate + rapid/short
-- NPH + rapid
-- NPA/NPL + rapid
-- short can be used in place of rapid
2) NPH + regular

29

What modifications are made in insulin aspart?

Pro replaced with Asp in beta-chain
-- reduced aggregation

30

What modifications are made in insulin glulisine?

Glu and Lys replace AA's in beta-chain
-- reduced aggregation

31

What modifications are made in insulin lispro?

identical except 2 residues reversed to match IGF-1
-- no aggregation
-- dissociates into monomers following inj.

32

Describe onset and duration of rapid-acting analogs.

1) inject ≤ 15 mins before meal
2) duration ≤ 4-5 hrs

33

Which insulin class has the lowest variability of absorption?

rapid-acting

34

Which insulin class is approved for CSII pumps?

rapid-acting

35

Describe onset of Short-acting/regular insulins.

30 minutes
-- injected 30 mins prior to meal
-- 25% variability in F

36

Describe the peak and duration of short-acting/regular insulins.

Peak @ 2-3 hours
Duration = 5-8 hours
-- bigger dose = longer

37

How are short-acting/regular insulins supplied?

U-100 or U-500 in clear solution

38

How are intermediate-acting insulin analogs supplied?

cloudy susp of human insulin + Zn + Protamine in a neutral buffer

39

What is Protamine?

positively-charged polypeptide that is degraded by proteolytic enzymes SubQ to delay absorption

40

Describe the onset of intermediate-acting insulin analogs.

2-5 hr onset
-- 50% variability in F

41

Describe duration of intermediate-acting insulin analogs.

4-12 hr duration
-- small dose = earlier peak, shorter duration

42

What modifications are made to insulin detemir?

Thr removed, myristic acid added
-- increased aggregation
-- binding to albumin in tissue

43

Describe duration of insulin detemir.

variable duration
-- ≥ 0.8 u/kg = 23 hrs
-- lower dose = variable, ≤ 12 hours

44

Which insulins cannot be mixed?

Long-acting (PD changes)

45

What is the only insulin analog to have modifications in the alpha-chain?

insulin glargine (lantus)

46

How is insulin glargine supplied?

clear solution of pH 4 for hexamer stabilization

47

Describe modifications to insulin glargine?

alpha-Gly sub, 2 beta-Arg subs

48

How does insulin glargine produce long-lasting release?

pH of 4 = hexamers in vial
neutral pH = aggregation in SubQ

49

Describe absorption and duration of glargine.

-- 24 hr prolonged, peakless duration
-- onset not altered by injection site or exercise

50

What is the issue with insulin glargine?

increased binding to IGF-1 receptor
-- cell growth, may increase cancer risk

51

Brand name of NPH + regular

Humulin/Novolin Mix

52

Brand name of intermediate-acting NPA/NPL + rapid (A/L)

Humalog/Novolog Mix

53

What is a usual dosing regimen for patients on intermediate-acting + rapid-acting insulin mix?

breakfast: mix
lunch: rapid
dinner: rapid
hs: intermediate

54

What is a usual dosing regimen for patients on NPH + regular mix?

breakfast and supper mix

55

What are common pre-mixed formulation ratios?

50/50, 75/25, 70/30
-- first # = longer acting

56

Why is intermediate-acting mixed with rapid-acting?

to avoid post-prandial glucose peak

57

What mix proportions are allowed?

any

58

What is the important consideration for mixing intermediate + rapid?

NPH + rapid
-- must be mixed ≤ 15 mins prior to inj.
-- unstable

59

What is the most consistent insulin injection site for absorption?

abdomen

60

What is the slowest insulin injection site?

arm (30% slower)

61

What factors affect insulin onset?

1) IM injection more rapid onset
2) increased SubQ blood flow more rapid onset

62

What is the average dose of insulin in T1DM?

0.7 units/kg/day
-- obese ~ 1-2 units/kg/day

63

What proportion of the total daily dose does long-acting basal make up vs. short- or rapid-acting postprandial?

long-acting: 50-75%
short/rapid: 50-25%

64

What are the general insulin regiments?

1) basal/bolus
-- long @ breakfast or qhs
-- bolus @ mealtimes
2) split-mixed
-- breakfast + dinner mix
-- if dinner doesn't control hyperglycemia @ night, pre-dinner regular + NPH qhs

65

What is the usual initial insulin dose in T1DM?

0.3-0.5 units/kg/day

66

What is the usual initial insulin dose during DKA or illness?

1-1.5 units/kg/day

67

How does initial insulin dose compare to eventual insulin dose and why?

1) eventual less than initial
glucose toxicity causes IR

68

What are symptoms of hypoglycemia?

SNS symptoms
-- sweating, palpitations, tremor, anxiety
PNS symptoms
-- nausea, hunger

69

What are symptoms of severe hypoglycemia?

neuroglycopenic symptoms
-- confusion, weakness, drowsy, dizzy, blurred vision, loss of consciousness
-- convulsions, coma

70

When do hypoglycemia symptoms start?

60-80 mg/dL

71

When do severe hypoglycemia symptoms start?

less than 60 mg/dL

72

When do neurons stop signaling?

When glucose less than 10 mg/dL

73

What is hypoglycemic unawareness?

condition that occurs after prolonged, untreated hypoglycemia

74

How is severe hypoglycemia treated?

20-50 mL of 50% glucose IV over 2-3 minutes
-- if unconscious and IV not available, 1 mg SQ/IM glucagon, then dextrose po

75

How are DKA and hyperglycemic hyperosmolar state treated?

IV insulin
IV fluids
electrolyte replacement
monitoring

76

What insulins are approved for IV use?

regular and rapid-acting

77

What insulins are OTC?

R and NPH

78

How is hypoglycemia counteracted endogenously?

+++ glycogenolysis (faster)
-- ACTH: EPI/NE
-- SNS: NE
+ gluconeogenesis (slower)
-- SNS: glucagon
-- ACTH: cortisol

79

What causes DKA?

lack of insulin (usually T1)
-- unchecked FA/AA breakdown, KB production

80

Sxs of DKA:

1) blood pH less than 7.3
2) osmotic diuresis
-- dehydration worsens DKA

81

What are the KB's in DKA?

acetoacetic acid
beta-HB

82

What causes the hyperglycemic hyperosomolar state?

reduced insulin (usually T2)
-- severe hyperglycemia (600 mg/dL)
-- osmotic diuresis

83

What are Sxs of hyperglycemic hyperosmolar state?

600 mg/dL glucose
osmotic diuresis
-- volume depletion
-- hemo-concentration = viscosity, thrombosis

84

[FA] during fasting and post-prandial:

fasting: 400 uM
post-prandial: ≤ 400 uM

85

How does insulin aggregate?

hexamers, dimers, monomers

86

What is the fx of basal insulin release?

inhibition of glucose production by liver

87

insulin effects on adipose:

1) glucose transport
2) glucose --> glycerol for ester
3) inhibition of lipolysis

88

insulin effects on muscle:

1) glucose transport
2) glycogen + protein synthesis
3) inhibition of protein catabolism

89

insulin effects on liver:

1) G6K activation - glucose uptake
2) glycogen synthase
3) inhibits glycogenolysis and gluconeogenesis

90

Common causes of hypoglycemia?

1) large dose
2) mismatch b/w peak and food intake
3) pre-disposition (adrenal/pituitary insufficiency)
4) increased insulin-dependent uptake (exercise)