Pancreatic drugs Flashcards
Insulin
- small protein
- protein contains 8 mg or ~200 units of insulin
- proinsulin is processed within the golgi of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C peptide –> insulin and C peptide are secreted in equimolar amounts in response to all insulin stimulants, a small amount of pro-insulin is also released
- pro insulin may have mild hypoglycemic effects, but c peptide has none –> used as a marker to see if insulin is being produced (has a longer half life than insulin)
Insulin secretion
Insulin regulates blood glucose concentration in basal, fasting and fed states - the stimulus for insulin secretion is elevation of blood glucose levels
- GLUT2 in the cell membrane of the pancreatic beta cells increase glucose concentration in beta cells
- in response to elevated glucose levels, metabolism of glucose increases ATP concentrations in beta cells –> increased ATP closes ATP dependent K channels = decreased efflux of K = depolarization of cell –> influx of calcium
- increased calcium triggers insulin secretion
Insulin receptor
- insulin receptor consists of 2 covalently linked heterodimers - each subunit has an alpha and beta subunit
- insulin binds to alpha subunit
- beta subunit contains TK domain
- binding of insulin to the alpha subunits activates the receptor - causes a conformational change that brings the catalytic loops of the opposing beta subunits into closer proximity - facilitates mutual phosphorylation of tyrosine residues on the subunits and TK activity directed at cytoplasmic proteins –> initiates phosphorylation cascade
- many effects of phosphorylation cascade
- –> translocation of GLUT4 to cell membrane with a resultant increase in glucose uptake
- –> increased glycogen synthase activity and increased glycogen formation
- –> multpile effects on protein synthesis, lipolysis and lipogenesis
Insulin receptor is internalized and degraded after its activated –> limits the duration of action of insulin
Effects of insulin on targets
Glucose transporters
- GLUT2 = regulates insulin release in response to blood glucose
- GLUT4 = inserted into the membrane of muscles and adipose cells from intracellular storage vesicles in response to insulin
Liver - increase storage of glucose as glycogen
Muscle
- promotes protein synthesis
- increases glycogen storage
Adipose tissue
- reduce circulating FFAs
- promote TG storage in adipocytes
Insulin preparations
Insulin is required for the treatment of type 1 diabetes - the important objective is to maintain glucose levels as close to normal as possible without producing hypoglycemia
- want insulin supplementation to mimic physiologic insulin –> normally secreted at a basal level at all times then increased upon taking in a glucose load
- administer long acting insulin to simulate basal insulin levels
- short acting insulin given right before meals
Various preparations depending on desired outcome of insulin
- duration of action –> ultra short acting (very rapid onset) to long acting (slow onset of action)
- species –> human and bovine
- purity –> conventional formulations contain less than 50 ppm proinsulin
- concentration –> standard concentration is 100 units/mL, 500 units/mL is available for patients who are insulin resistant
- insulin analopgs
- –> insulin lispro = has effect as soon as its injected; no lag
- –> glargine = long acting insulin; half life = 24 hours
Insulin delivery systems
- portable pen injectors –> replaceable cartridges of insulin + retractable needles
- continuous subcutaneous insulin infusion devices –> insulin pumps; recommended for people who have difficulty obtaining target control on multiple injections
- inhaled insulin –> currently in clinical trials to provide a short term release
Complications of insulin therapy
Hypoglycemia
- can occur with physical exertion, delay in taking a meal, too high a dose of insulin
- hypoglycemia is particularly problematic in children because they are extremely sensitive to hypoglycemia –> would rather be slightly hyper than hypoglycemic
Insulin allergy
- occurs with non-insulin protein contaminants - purified insulin is better
- species change
Lipodystrophy at injection site
- hypertrophy of subcutaneous fat tissue
- multiple injections at the same site
- liposuction can correct this
Anti-diabetic drugs - hypoglycemic vs. anti-hyperglycemic drugs
Hypoglycemic drugs = lower blood gluocose regardless of blood glucose levels –>could cause dangerous hypoglycemia in people with normal blood glucose (e.g. insulin)
Anti-hyperglycemic drugs = lower elevated blood glucose –> no effect on people with normal blood glucose (e.g. metformin)
Oral anti-diabetic drugs
Insulin secretagogues - sulfonylureas - meglitinides Biguanides - metformin Thiazolidinedones Alpha-glucosidase inhibitors Glucagon like polypeptide 1 (GLP1) receptor agonists Dipeptidyl peptidase 4 (DPP4) inhibitors Sodium glucose cotransporter 2 (SGLT-2) inhibitors
Insulin secretagogues - sulfonylureas
- mechanism of action
Mechanism
- stimulate insulin release from pancreatic B cells –> require viable B cells (can’t use for type 1 or late type 2)
- potentiation of insulin action on target tissue
- reduction of serum glucagon concentration
Failure to maintain good sugar control with sulfonylureas
- inability to maintain dietary compliance
- B cells become refractory to sulfonylureas
- progressive decrease in B cell mass in chronic type 2 DM renders these drugs ineffective
Sulfonylureas
- first and second generation drugs
First generation
- tolbutamide
- chlorpropamide
- tolazamide
- acetohexamide
Second generation - more potent, more likely to cause hypoglycemia
- glyburide
- glipizide
- glimepiride
Insulin secretagogues - meglitinides
Repaglinide
Mechanism –> similar to sulfonylureas
- main difference is its rapid onset and short duration of action
- taken just before meals for the purpose of controlling postprandial glucose conc
Use cautiously in hepatic impairment
No sulfur in the structure - can be used when allergic to sulfur or sulfonylureas
Insulin sensitizers - Biguanides
- mechanism
Metformin
Blood glucose lowering ability - does not depend on functioning B cells
- glucose is not lowered in normal subjects
Mechanism of action - not completely understood
- direct stimulation of glycolysis in tissues with increased glucose removal from blood
- reduced hepatic gluconeogenesis
- slowing of glucose absorption from GI tract with increased glucose to lactate conversion by enterocytes
- reduction of plasma glucagon levels
Biguanides
- clinical use
- first line therapy for type 2 DM–> preferred over insulin or sulfonylureas because does not increase body weight or provoke hypoglycemia
- for patients with refractory obesity whose hyperglycemia is due to insulin resistance –> insulin sparing agent = causes the tissues to respond to lower levels of insulin
- can be used with sulfonylureas
- shown to be useful in the prevention of type 2 DM in obese persons with impaired glucose tolerance and fasting hyperglycemia
- may reduce risk of some cancers
- sometimes used for lowering insulin and blood sugar levels in women with PCOS – helps regulate menstrual cycles, start ovulation and lower the risk of miscarriage
Biguanides - side effects and contraindications
Side effects
- most commonly GI related
- anorexia, nausea, vomiting, abdominal discomfort and diarrhea
- –> dose related and transient
- –> persistent diarrhea is small minority may lead to discontinuation
- absorption of B12 may be impaired –> annual serum B12 level monitoring
Contraindicated in patients with renal, hepatic disease, alcoholism or conditions predisposing to tissue anorexia (chronic cardiopulmonary dysfunction)
- increased risk of lactic acidosis induced by biguanides
