Block 1 Lecture 2 -- Diabetes II Flashcards
Normal post-prandial [glucose]
120-140 mg/dL
normal fasting [glucose]
70-100 mg/dL
Describe the structure of insulin.
51 AA with alpha and beta chain
- 2 disulfides link chains
- 1 addl disulfide on alpha chain
Normal fasting [insulin]
50 pM
Normal bolus insulin [concentration] at mealtime
500 pM
How is insulin secretion stimulated?
primarily by glucose
- also GLP-1, GIP
- cholinergic vagal stimulation
- medications
Describe endogenous insulin clearance.
60% hepatic; 40% renal
Describe exogenous insulin clearance
40% hepatic; 60% renal
What is the t1/2 of insulin?
5 minutes
Describe [insulin receptor] on non-responsive cells
40/cell
Describe [insulin receptor] on responsive cells.
300,000/cell
Describe structure of insulin receptor.
2 covalently-linked heterodimers
- extracellular alpha subunit recognition site
- beta membrane-spanning TK unit
What are the GLUT isoforms?
1-4
Location and fx of GLUT-1:
1) brain
2) transport across BBB
Location and fx of Glut-2:
1) beta cells, liver
2) regulation of insulin release and glucose homeostasis
Location and fx of Glut-3:
1) brain
2) uptake into neurons
Location and fx of GLUT-4:
1) skeletal muscle, adipose
2) insulin-mediated glucose uptake
What is the inhaled insulin on the market, and when was it approved?
1) Afrezza
2) June ‘14
What is the equivalent mg/mL concentration of 100 units/mL insulin?
3.6 mg/mL
What are the rapid acting insulin analogs?
1) Aspart (Novolog)
2) Glulisine (Apidra)
3) Lispro (Humalog)
What are the short-acting insulins?
Regular (Humulin/Novolin R)
What insulin forms come U-500?
Humulin R (lilly)
What are the intermediate-acting analogs?
1) NPH (neutral protamine Hagedorn)
- - also NPA/NPL in mixtures
What insulin products are identical to human insulin?
1) Regular (Humulin/Novolin R)
2) NPH
What are the long-acting insulin analogs?
1) Detemir (Levemir)
2) Glargine (Lantus)
What is the usual dosage of insulin glargine?
once-daily (24h coverage)
What is the usual dosage of insulin detemir?
often BID
What insulins are mixed?
1) intermediate + rapid/short
- - NPH + rapid
- - NPA/NPL + rapid
- - short can be used in place of rapid
2) NPH + regular
What modifications are made in insulin aspart?
Pro replaced with Asp in beta-chain
– reduced aggregation
What modifications are made in insulin glulisine?
Glu and Lys replace AA’s in beta-chain
– reduced aggregation
What modifications are made in insulin lispro?
identical except 2 residues reversed to match IGF-1
- no aggregation
- dissociates into monomers following inj.
Describe onset and duration of rapid-acting analogs.
1) inject ≤ 15 mins before meal
2) duration ≤ 4-5 hrs
Which insulin class has the lowest variability of absorption?
rapid-acting
Which insulin class is approved for CSII pumps?
rapid-acting
Describe onset of Short-acting/regular insulins.
30 minutes
- injected 30 mins prior to meal
- 25% variability in F
Describe the peak and duration of short-acting/regular insulins.
Peak @ 2-3 hours
Duration = 5-8 hours
– bigger dose = longer
How are short-acting/regular insulins supplied?
U-100 or U-500 in clear solution
How are intermediate-acting insulin analogs supplied?
cloudy susp of human insulin + Zn + Protamine in a neutral buffer
What is Protamine?
positively-charged polypeptide that is degraded by proteolytic enzymes SubQ to delay absorption
Describe the onset of intermediate-acting insulin analogs.
2-5 hr onset
– 50% variability in F
Describe duration of intermediate-acting insulin analogs.
4-12 hr duration
– small dose = earlier peak, shorter duration
What modifications are made to insulin detemir?
Thr removed, myristic acid added
- increased aggregation
- binding to albumin in tissue
Describe duration of insulin detemir.
variable duration
- ≥ 0.8 u/kg = 23 hrs
- lower dose = variable, ≤ 12 hours
Which insulins cannot be mixed?
Long-acting (PD changes)
What is the only insulin analog to have modifications in the alpha-chain?
insulin glargine (lantus)
How is insulin glargine supplied?
clear solution of pH 4 for hexamer stabilization
Describe modifications to insulin glargine?
alpha-Gly sub, 2 beta-Arg subs
How does insulin glargine produce long-lasting release?
pH of 4 = hexamers in vial
neutral pH = aggregation in SubQ
Describe absorption and duration of glargine.
- 24 hr prolonged, peakless duration
- - onset not altered by injection site or exercise
What is the issue with insulin glargine?
increased binding to IGF-1 receptor
– cell growth, may increase cancer risk
Brand name of NPH + regular
Humulin/Novolin Mix
Brand name of intermediate-acting NPA/NPL + rapid (A/L)
Humalog/Novolog Mix
What is a usual dosing regimen for patients on intermediate-acting + rapid-acting insulin mix?
breakfast: mix
lunch: rapid
dinner: rapid
hs: intermediate
What is a usual dosing regimen for patients on NPH + regular mix?
breakfast and supper mix
What are common pre-mixed formulation ratios?
50/50, 75/25, 70/30
– first # = longer acting
Why is intermediate-acting mixed with rapid-acting?
to avoid post-prandial glucose peak
What mix proportions are allowed?
any
What is the important consideration for mixing intermediate + rapid?
NPH + rapid
- must be mixed ≤ 15 mins prior to inj.
- unstable
What is the most consistent insulin injection site for absorption?
abdomen
What is the slowest insulin injection site?
arm (30% slower)
What factors affect insulin onset?
1) IM injection more rapid onset
2) increased SubQ blood flow more rapid onset
What is the average dose of insulin in T1DM?
- 7 units/kg/day
- - obese ~ 1-2 units/kg/day
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%
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
What is the usual initial insulin dose in T1DM?
0.3-0.5 units/kg/day
What is the usual initial insulin dose during DKA or illness?
1-1.5 units/kg/day
How does initial insulin dose compare to eventual insulin dose and why?
1) eventual less than initial
glucose toxicity causes IR
What are symptoms of hypoglycemia?
SNS symptoms
– sweating, palpitations, tremor, anxiety
PNS symptoms
– nausea, hunger
What are symptoms of severe hypoglycemia?
neuroglycopenic symptoms
- confusion, weakness, drowsy, dizzy, blurred vision, loss of consciousness
- convulsions, coma
When do hypoglycemia symptoms start?
60-80 mg/dL
When do severe hypoglycemia symptoms start?
less than 60 mg/dL
When do neurons stop signaling?
When glucose less than 10 mg/dL
What is hypoglycemic unawareness?
condition that occurs after prolonged, untreated hypoglycemia
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
How are DKA and hyperglycemic hyperosmolar state treated?
IV insulin
IV fluids
electrolyte replacement
monitoring
What insulins are approved for IV use?
regular and rapid-acting
What insulins are OTC?
R and NPH
How is hypoglycemia counteracted endogenously?
\+++ glycogenolysis (faster) -- ACTH: EPI/NE -- SNS: NE \+ gluconeogenesis (slower) -- SNS: glucagon -- ACTH: cortisol
What causes DKA?
lack of insulin (usually T1)
– unchecked FA/AA breakdown, KB production
Sxs of DKA:
1) blood pH less than 7.3
2) osmotic diuresis
- - dehydration worsens DKA
What are the KB’s in DKA?
acetoacetic acid
beta-HB
What causes the hyperglycemic hyperosomolar state?
reduced insulin (usually T2)
- severe hyperglycemia (600 mg/dL)
- osmotic diuresis
What are Sxs of hyperglycemic hyperosmolar state?
600 mg/dL glucose
osmotic diuresis
– volume depletion
– hemo-concentration = viscosity, thrombosis
[FA] during fasting and post-prandial:
fasting: 400 uM
post-prandial: ≤ 400 uM
How does insulin aggregate?
hexamers, dimers, monomers
What is the fx of basal insulin release?
inhibition of glucose production by liver
insulin effects on adipose:
1) glucose transport
2) glucose –> glycerol for ester
3) inhibition of lipolysis
insulin effects on muscle:
1) glucose transport
2) glycogen + protein synthesis
3) inhibition of protein catabolism
insulin effects on liver:
1) G6K activation - glucose uptake
2) glycogen synthase
3) inhibits glycogenolysis and gluconeogenesis
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)
