10 Flashcards
Two types of insulin products in current clinical use
Rapid-acting analogues for prandial bolus injection
Basal formulations for one or twice-a-day treatment
Examples of rapid-acting insulin analogues
Insulin lispro (Humalog) Insulin aspart (Novorapid) Insulin glulisine (Apidra)
What mutations are done to the insulin
Amino acid substitution to weaken hexamer and dimer interfaces
What is involved in further attempts to prepare even faster-acting analogues (4)
Further structural analysis of insulin hexamer
Heating of site of injection
Co-injection of hyaluronidase
Micro-injection patches
What are two basal or long-lasting analogues
Insulin glargine (Toujeo Solostar) Insulin detemir (Levemir)
What’s a new basal analogue with 25 hour half-life
Insulin degludec
Ryzodeg is combination with
What is recommended basal–bolus insulin regime for adults with Type 1 diabetes
Twice-daily basal insulin
Rapid-acting insulin analogue injected before meals for mealtime insulin replacement
How do inhaled insulin preparations work
Lung pH causes dissolution of microspheres releasing insulin for rapid absorption in monomeric form
What is the effect of GLP-1 (5)
1) Increased insulin secretion
2) Decreased glucagon secretion
3) Decreased gastric emptying
4) Decreased appetite
5) Decrease B-cell apoptosis
Why does GLP-1 have such a short half-life
It is rapidly inactivated by DPP4 and needs continuous administration
What are 3 strategies to take advantage of incretins
1) Administer GLP-1
2) Give structural analogue of GLP-1 not susceptible to degredation
3) Administer inhibitors of DPP-4
What are 4 ways to prolong GLP-1 receptor agonist half life in vivo
1) Covalent modification with albumin or IgG to retard renal elimination (albiglutide and dulaglutide [Trulicity])
2) Attachment of FA chain confers albumin binding (liraglutide [Saxenda])
3) Coupling to biodegradadable polymer microsphere confers protracted release from subcutaneous tissue
4) Dilution with chemical adjuvants e.g. zinc, delays absorption from subcutaneous tissue (taspoglutide)
MOA of exenatide (Bydureon)
1) Subcutaneous injection of microsphere suspension of exenatide
2) Individual microspheres aggregate and intitial release of exenatide
3) Microsphere degredation and continued release of exenatide
4) Further degradation and metabolism of microsphere polymer for sustained levels of exenatide
What are some examples of DPP4 inhibitors (gliptins)
Alogliptin (Nesina) Linagliptin (Trajenta) Saxagliptin (Onglyza) Sitagliptin (Januvia) Vildagliptin (Galvus)
What causes insulin sensitivity and impairs glucsoe uptake
1) Excess lipid deposition in muscle and inactivation of insulin signaling through IRS1
2) Ceramide effect on PKC reduces Akt2 activation and deceased GLUT4 translocation to membrane and decreased glycogen synthesis
