Flashcards in Block 1 Lecture 2 -- Diabetes II Deck (90):
Normal post-prandial [glucose]
normal fasting [glucose]
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]
Normal bolus insulin [concentration] at mealtime
How is insulin secretion stimulated?
primarily by glucose
-- also GLP-1, GIP
-- cholinergic vagal stimulation
Describe endogenous insulin clearance.
60% hepatic; 40% renal
Describe exogenous insulin clearance
40% hepatic; 60% renal
What is the t1/2 of insulin?
Describe [insulin receptor] on non-responsive cells
Describe [insulin receptor] on responsive cells.
Describe structure of insulin receptor.
2 covalently-linked heterodimers
-- extracellular alpha subunit recognition site
-- beta membrane-spanning TK unit
What are the GLUT isoforms?
Location and fx of GLUT-1:
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:
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?
2) June '14
What is the equivalent mg/mL concentration of 100 units/mL insulin?
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)
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?
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?
Which insulin class is approved for CSII pumps?
Describe onset of Short-acting/regular insulins.
-- 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.
-- ≥ 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
Brand name of intermediate-acting NPA/NPL + rapid (A/L)
What is a usual dosing regimen for patients on intermediate-acting + rapid-acting insulin mix?
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?
What is the important consideration for mixing intermediate + rapid?
NPH + rapid
-- must be mixed ≤ 15 mins prior to inj.
What is the most consistent insulin injection site for absorption?
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?
-- 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?
What are the general insulin regiments?
-- long @ breakfast or qhs
-- bolus @ mealtimes
-- breakfast + dinner mix
-- if dinner doesn't control hyperglycemia @ night, pre-dinner regular + NPH qhs
What is the usual initial insulin dose in T1DM?
What is the usual initial insulin dose during DKA or illness?
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?
-- sweating, palpitations, tremor, anxiety
-- nausea, hunger
What are symptoms of severe hypoglycemia?
-- confusion, weakness, drowsy, dizzy, blurred vision, loss of consciousness
-- convulsions, coma
When do hypoglycemia symptoms start?
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?
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?
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
-- 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