In diabetic patients taking metformin, why should metformin be held prior to a contrast CT scan?
Hole metformin due to risk of acute renal failure
Which formulation of insulin is 'cloudy'?
Which is the only insulin available for IV use?
Why is NPH insulin 'cloudy'?
NPH consists of normal insulin aggregated with protamine and zinc. The time involved in breaking down these aggregates contributes to the longer time-of-action of NPH versus regular insulin.
Why do lispro insulin and insulin aspart act faster than regular insulin?
What is the structural difference of each versus regular insulin?
Regular insulin tends to form non-covalent hexamers in solution, delaying entry into system circulation (too fat for the capillary fenestrations). Lispro and aspart more readily form monomers, meaning they enter circulation faster following injection.
Lispro: proB28-lysB29 -> lysB28-proB29
Aspart: proB28 -> aspB28
Compare the structure of insulin glargine to regular insulin. Why is this significant?
aspA21 -> glyA21; two arginines added to C-terminus of B-chain
This makes glargine poorly soluble at pH = 7. Glargine diffuses into the blood very slowly, making this the longest-acting insulin analog. Also, it has no real 'peak' concentration, making it useful for establishing a baseline insulin level in insulin therapy.
What accounts for the long-acting characteristics of insulin detemir?
What structural characteristics account for this?
It self-associates at subQ injection sites (somewhat like regular insulin) and binds albumin. Both prolong its duration of action.
Omits ThrB30 and attaches a 14-carbon fatty acid to position B29
Which insulin(s) have the shortest onset?
Which insulin(s) have the shortest half life?
Which insulin(s) have the longest half life?
Which insulin has no apparent 'peak' action?
Lispro, aspart, glulisine
Lispro, aspart, glulisine
Glargine (24-36h) and detemir (~24h)
As a part of a comprehensive insulin therapy strategy, what is the purpose of:
What is a "Basal-Bolus" strategy?
Short-acting: pre-prandial. Mimic nutrient-stimulated insulin secretion.
Long-acting: Mimic basal insulin secretion.
Basal-bolus: rapid-acting insulins at regular intervals throughout the day (meals?) combined with a baseline glargine injection at the end of the day
Insulin therapy has to be highly individualized. Still, what are some basic goals for glycemic control?
- Fasting and pre-prandial glucoses 70-130mg%
- Post-prandial glucosis two hours after meal <180mg%
- Hemoglobin A1C < 7%
Among other reasons, what is one advantage of an automated insulin pump?
A programmed insulin pump can continuously infuse a basal level of insulin, which can also be programmed to vary throughout the day (closer to normal behavior of baseline insulin secretion in normal patients)
What is the most common side-effect of insulin therapy?
Give a few others
Most common: hypoglycemia
- Insulin allergy
- Insulin edema (patients new to insulin therapy can get swelling in the legs and ankles)
- "Weight gain"
- Atherosclerosis (maybe - high doses required)
- Increased cancer risk (maybe - higher doses required?)
What is the mechanism of action of sulfonylurea agents? Name (3).
Name one other drug that's not technically a sulfonylurea but has basically the same mechanism of action.
Mechanism of action: stimulate insulin secreation by the pancreas by binding potassium transporters on beta-cells in the pancreas. Blocking potassium efflux raises the cell membrane potential, allowing entry of calcium. Calcium efflux triggers exocytosis of insulin-containing vesicles, increasing overall insulin secretion from the pancreas.
Non sulfonylurea (but same mechanism): meglitinide
Give two common and two relatively rare side effects of sulfonylurea therapy
- Rashes / GI upset / drug interactions
- Disulfiram-like reaction
What does metformin do?
What are the most common side effects?
What major side effects can occur?
What is the biggest contraindication? Name some others.
Reduces insulin resistance
Common AE's: abdominal discomfort, diarrhea
Major: Lactic acidosis (potentially fatal), caused by renal insufficiency
CI: renal insufficiency, >80y.o., CHF, acute illness, binge drinking, liver dysfunction
What class of medications sensitizes peripheral tissues (fat, muscle) to insulin?
What is the mechanism of action?
What are the major side effects and contraindications?
Which is most commonly used?
Thiazolidinediones (rosiglitazone, pioglitazone)
Activates PPRA (peroxisome proliferator-activated receptor) - sensitizes muscle and fat to insulin
Major side effects: liver toxicity, weight gain, fluid retention.
Contraindications: Advanced heart failure: Rosiglitazone may also increase cardiac ischemic events
Pioglitazone is most commonly used
What is the mechanism of action of acarbose?
What about the side effects of this drug might make people not want to take it?
Glucosidase inhibitor - inhibits enteric enzymes that break down complex carbohydrates, resulting in partial malabsorption of carbohydrates. Reduces post-prandial hyperglycemia.
Major side effects: bloating, abdominal discomfort, diarrhea, and flatulence. No surprise that it's not commonly used in the US.
Explain the mechanism of action of exenatide and liraglutide. Name some side effects.
Name another drug with the same effect but slightly different mechanism of action
GLP-1 analogs: GLP-1 augments insulin secretion, increases beta-cell mass, inhibits glucagon secretion, and promotes (some) weight loss.
AE's: nausea, emesis, diarrhea, headaches, and pancreatitis (possibly)
Sitagliptin: oral DPP-4 inhibitor. DPP-4 is responsible for the breakdown of GLP-1, so inhibiting this enzyme prolongs the action of GLP-1
What is SGTP-2?
What drug(s) might we use to block it?
What are some adverse effects of using this drug?
Sodium-glucose transport protein 2 - found in the PCT of the kidney nephron. Responsible for glucose reabsorption.
canagliflozin, dapagliflozin, empaglifozin -> block the action of SGTP-2, causing glucose loss in the urine (decrease serum glucose to control hyperglycemia)
AE's: genital yeast infections (organisms chow down on the free sugar), dehydration (modest osmotic diuresis)
Rank the following drugs in order of efficacy (greatest to least) in reducing glucose A1C levels in diabetics:
DPP-4 inhibitors (sitagliptin)
SGPT-2 inhibitors (cacgiflozin)
(1.5%) sulfonylureas = metformin = thiazolidinediones > (0.75%) acarbose = DPP-4 inhibitors = SGPT-2 inhibitors
Describe combination therapy for T2DM therapy
Combining medications to (1) increase insulin and (2) increase sensitivity to insulin
- Pick one drug that increases insulin
- Pick one drug that improves insulin sensitivity