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PHS 933 > Block 1 Lecture 2 -- Diabetes II > Flashcards

Block 1 Lecture 2 -- Diabetes II Flashcards

1
Q

Normal post-prandial [glucose]

A

120-140 mg/dL

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2
Q

normal fasting [glucose]

A

70-100 mg/dL

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3
Q

Describe the structure of insulin.

A

51 AA with alpha and beta chain

    • 2 disulfides link chains
    • 1 addl disulfide on alpha chain
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4
Q

Normal fasting [insulin]

A

50 pM

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5
Q

Normal bolus insulin [concentration] at mealtime

A

500 pM

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6
Q

How is insulin secretion stimulated?

A

primarily by glucose

    • also GLP-1, GIP
    • cholinergic vagal stimulation
    • medications
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7
Q

Describe endogenous insulin clearance.

A

60% hepatic; 40% renal

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8
Q

Describe exogenous insulin clearance

A

40% hepatic; 60% renal

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9
Q

What is the t1/2 of insulin?

A

5 minutes

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10
Q

Describe [insulin receptor] on non-responsive cells

A

40/cell

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11
Q

Describe [insulin receptor] on responsive cells.

A

300,000/cell

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12
Q

Describe structure of insulin receptor.

A

2 covalently-linked heterodimers

    • extracellular alpha subunit recognition site
    • beta membrane-spanning TK unit
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13
Q

What are the GLUT isoforms?

A

1-4

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14
Q

Location and fx of GLUT-1:

A

1) brain

2) transport across BBB

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15
Q

Location and fx of Glut-2:

A

1) beta cells, liver

2) regulation of insulin release and glucose homeostasis

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16
Q

Location and fx of Glut-3:

A

1) brain

2) uptake into neurons

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17
Q

Location and fx of GLUT-4:

A

1) skeletal muscle, adipose

2) insulin-mediated glucose uptake

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18
Q

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

A

1) Afrezza

2) June ‘14

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19
Q

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

A

3.6 mg/mL

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20
Q

What are the rapid acting insulin analogs?

A

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

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21
Q

What are the short-acting insulins?

A

Regular (Humulin/Novolin R)

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22
Q

What insulin forms come U-500?

A

Humulin R (lilly)

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23
Q

What are the intermediate-acting analogs?

A

1) NPH (neutral protamine Hagedorn)

- - also NPA/NPL in mixtures

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24
Q

What insulin products are identical to human insulin?

A

1) Regular (Humulin/Novolin R)

2) NPH

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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)

PHS 933 (14 decks)

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