Flashcards in Pharma of Insulin Deck (23)
What is proinsulin?
Proinsulin is comprised of a connecting or C peptide and active insulin
Describe the life course of proinsulin
Proinsulin is packaged in golgi of the pancreatic beta cell and undergoes proteolytic cleavage into C peptide and insulin. Zinc is added forming crystalline insulin (hexamer)
-->insulin is packaged as a hexamer, but it must be broken down into a monomer to cross capillary membranes and have any physiologic effect
What is the most impt stimulant for insulin sec?
Glucose (some others=fat protein, ANS, GLP1, GIP
What happens once insulin is produced and secreted?
Insulin binds IGF-1 receptors and insulin receptors. This initiates a phosphorylation cascade that results in Glut4 transporters being translocated to the cell surface in order to take up glucose
Describe insulin metabolism
Primarily occurs in the liver. 60% of endogenous insulin is degraded by the first pass effect (beta cell-->portal vein-->liver, portal concentration is 3x blood), remaining 40% degraded in the kidneys
Exogenous insulin is degraded 60% kidneys and 40% liver (SubQ-->blood-->kidney (60%)-->liver (40%)
What are the anabolic actions of insulin?
Adipose: promotes TG synth and storage, glucose uptake; inhibits lipolysis
Muscle: promotes glycogen synth, AA uptake, protein synth
Liver: promotes glycogen synth, FA synth; inhibits glucose output and ketogenesis
What are the indications for insulin treatment?
-Inadequately controlled T2D
-Temporary use for: Hospitalizations, pregnancy, renal disease, to initially gain glycemic control in pts with severe T2D, to overcome glucose tox and re-regulate decompensated patients
Describe Human Synthetic Insulin
-All packaged at neutral pH (pH 7.4) except Glargine (pH4)
-Standardized concentration of U-100 except for pts who are VERY insulin resistant who get U-500 (regular human insulin)
-Short-acting regular in crystalline zinc complex
-Long-acting: glargine, detemir, NPH
What is bolus insulin used for?
Used for fast acting coverage of food intake or correction of hyperglycemia
-Regular: short acting
-Rapid acting: Aspart, Lispro, Glulisine
What are Aspart, Lispro and Glulisine
Rapid acting insulins that are different from regular human insulin due to a single amino acid change that disrupts the formation of insulin hexamers, leading to more rapid dissociation to the monomer form and more rapid absorption after sub Q injection.
Compare aspart and lispro to regular human insulin
Compared to regular human insulin, these have same glucose lowering effects, same affinity for insulin receptor, similar bioavailability, but they have 2x faster absorption, 2x higher peak concentration, faster onset of action (5-15 min post injection) and shorter duration of action (3-5 hours), peak=1-2 hrs
REgular: onset 30-60 min, peak 2-4 hours, duration 6-10 hrs
What is used to maintain euglycemia?
Euglycemia: basal insulin
-Intermediate and long acting insulins are used to maintain euglycemia in the fasting state
List an intermediate insulin
NPH (dosed 1-2x daily)
List a long acting insulin
Glargine (1x daily) Detemir (1-2x daily)
What is special about glargine and detemir
No peak! and can work up to 24 hours
What is NPH duration of action
10-12 hrs (intermediate)
What is an advantage and disadvantage of NPH
Adv: Can be combined with other insulins
Disadv: peak in action inc risk of hypoglycemia
What is detemir?
A soluble, long acting basal insulin analog with a relatively flat action profile
How is insulin administered?
Sub Q or IV
-IV: hospital only, rapid on/off
See dosing slides
see dosing slides
Intensive/Mult daily injections
Preferred over conventional dosing methods because it allows for tighter glycemic control and more closely matches normal physiology.
Can have mult injections or continuous insulin infusion using a pump
What do you take into account when deciding how much insulin to give a pt?
Pts weight, blood glucose, insulin sensitivity, carb intake, phys activity