Diabetes: Hockerman Flashcards
What are the causes of Type 1 DM? (Obj 1)
autoimmune disruption of normal insulin secretion or function
autoantibodies may be made against insulin, pancreatic islet cells, insulin granule associated proteins
What are the causes of Type 2 DM? (Obj 1)
can be either a decrease in insulin production due to exhaustion of pancreatic cells or by insulin resistance in peripheral tissues
manifestations of diabetes (Obj 1)
three poly’s (polydipsia, polyuria, polyphagia)
unexplained weight loss
glucosuria
Which of the two types of diabetes predisposes individuals to ketoacidosis more? (Obj 2)
type 1
complete lack of endogenous insulin production makes these individuals more likely to excessively oxidize FA for fuel, as they cannot use glucose
Why do type 1 diabetics have to receive exogenous insulin? (Obj 2)
they cannot produce their own insulin due to destruction of beta cells
Which comorbidity is most often associated with T2DM? (Obj 2)
obesity
80% of T2DM population
How does the age of onset of T2DM differ between obese and non-obese individuals? (Obj 2)
Non-obese patients tend to develop T2DM earlier (before 25) than do obese patients (Usually after 35).
What are the 4 possible diagnostic criteria for diabetes? (Obj 1)
(1) Hgb A1C > 6.5%
(2) 2 hr OGTT >200 mg/dL
(3) any BG > 200 mg/dL
(4) FBG > 126 mg/dL
What is the effect of insulin on the liver? (Obj 3)
inhibition of gluconeogenesis, glycogenesis, inhibition of ketone body formation (at lower concentrations than are required for uptake by muscles)
What are the complications of diabetes on other body systems? (Obj 1)
CONNI
cardiovascular - increased blood pressure
ophthalmic - cataracts, glaucoma
neuropathy - damage to peripheral nerves by excessive alcohol production
nephropathy - damage to renal vasculature and glomerular bed
increased susceptibility to infections
There is a sharp increase in risk of retinopathy once fasting glucose levels rise above ____ mg/dL, which corresponsds to an A1C of ____.
110, 5.9
Which metabolic intermediate of glucose metabolism is responsible for inhibition of vasorelaxation? How does it do so?
methylglyoxal, inhibits acetylcholine mediated nitric oxide release
What is the polyol pathway? In what part of the body does this become a problem in diabetics?
metabolic pathway involving the depletion of reducing agents and production of osmotically active, alcohol rich sugars
issue in the nervous system, where nerves swell and are damaged
What are the roles of the alpha and beta subunits of the insulin receptor? (Obj 5)
alpha subunit - regulatory domain: suppresses beta subunit phosphorylation, suppression relieved by insulin
beta subunit - tyrosine catalytic domain
Which tissue is the most important player in lowering BG in response to insulin?
skeletal muscle
How does the disposal of glucose in response to insulin change between fed and fasting states?
In the fed state, 75% of glucose disposal is insulin-independent via the liver, brain, and GI system. The other 25% is done by skeletal muscle and is insulin dependent. after a meal, skeletal muscle becomes much more important in glucose uptake and is responsible for 80% of post-prandial glucose uptake. Another 5% is done in adipose tissue.
What happens to FFA levels in the blood when insulin is released? How does this affect glucose uptake by skeletal muscle?
FFA levels decrease, which enhances skeletal muscle’s ability to uptake glucose.
Which glucose receptor has the highest Km? the lowest?
highest belongs to the liver (GLUT2) and lowest belongs to the brain/neurons (GLUT3)
This makes sense because the NS should always have some constant supply of glucose.
Which hormone secreted with insulin is responsible for slowing gastric emptying and inhibits glucagon secretion?
amylin
What are the metabolic effects of glucagon? (Obj 3)
increase gluconeogenesis, increase glycogenolysis to raise BG
What are the metabolic effects of somatostatin? (Obj 3)
general inhibitor is secretion from alpha and beta cells
What modification has been made to NPH insulin? What effect does this have on absorption and duration of action? (Obj 6)
insulin is complexed with protamine (a protein), which slowly releases it and prolongs the duration of action
What is the appearance of NPH insulin? (Obj 6)
cloudy solution due to proteins
What structural modification is made to insulin lispro? Explain the effect this has on time to onset.
Lysine and Proline at positions 29 and 28, respectively, are switched. This disrupts normal interactions that lead to aggregation of insulin peptides. Because they are no longer interacting, the time to onset is greatly reduced (5-15 mins).
What structural modifications have been made to insulin glargine?
Asparagine 21 is replaced with a glycine and 2 arginine residues are added.
Why is glargine such a slow-releasing formulation of insulin?
The solution is stored at pH 4, but when it is injected and neutralized by the body’s pH, it crystallizes and is slowly released over 24 hours.
How does the modification to insulin aspart affect its duration of action?
Changing proline 28 to aspartate disrupts the interaction between insulin monomers, as with lispro.
What are the unique properties of insulin detemir?
Threonine 30 is deleted and Lysine 29 is myristilated. This allows binding to serum albumin, which serves as a storage pool, releasing insulin slowly over 24 hours or more.
Insulin degludec has a structural modification most similar to that of insulin _______.
detemir
Similar to detemir, degludec binds serum albumin extensively, greatly prolonging its duration of action.
Short acting insulins are usually taken __________ (time) and long acting insulins are usually taken _________ (time).
immediately before meals, before bed (sometimes in the morning as well, if divided doses of basal insulin)
Which insulins are examples of combination products? What insulins do they contain?
Humulin 70/30 and 50/50 (NPH and regular)
Humalog 75/25 and 50/50 (NPL and lispro)
Which formulation of insulin is ALWAYS used intravenously, often for severe ketoacidosis or hyperglycemia?
regular
What are some signs/symptoms of hypoglycemia?
irritability, weakness, tachycardia, diaphoresis, hunger, tremor, blurred vision
What are the general treatment recommendations for T1 and T2DM?
T1-insulin, diet, and exercise
T2-lifestyle modifications, oral anti diabetics, possibly insulin
What are the effects of insulin resistance commonly seen in T2DM on the liver, adipose tissue, glucagon, skeletal muscle, and overall plasma insulin?
liver-increased hepatic glucose production
adipose tissue-increase lipolysis
glucagon-plasma levels increase
skeletal muscle-glucose utilization decreases
plasma insulin-levels drop and increase slower
How are sulfonylureas used in diabetes management?
increase the first phase insulin secretion by binding to the potassium channel of beta cells, depolarizing them and activating calcium channels that promote exocytosis of insulin containing granules
What are the second generation sulfonylureas?
Glyburide, Glipizide, Glimepiride
Starlix
a “glinide” drug that works by blocking the Katp channel, increasing insulin release.
synergistic with metformin, less risk of hypoglycemia than prandin due to shorter half-life
What are the side effects of sulfonylureas?
GI issues, lasting hypoglycemia due to long half-life, weight gain, secondary failure after prolonged use
Which drugs may increase the hypoglycemic effect of sulfonylureas?
high dose salicylates, alcohol
Why does an oral glucose challenge cause a greater release of insulin than dose IV glucose?
When glucose is ingested and absorbed in the GI tract, GLP-1 is released. GLP-1 potentiates the insulin response to glucose (in a glucose dependent manner).
What are some of the effects of GLP-1?
increased insulin release, promotes satiety, slows gastric emptying, increases beta-cell mass, increases insulin sensitivity
Which two drug classes resurrect the blunted GLP-1 response in diabetics?
GLP-1 analogs and DPP-IV inhibitors
What are the benefits of GLP-1 agonists in diabetes therapy?
potential for weight loss, helps prevent hyperglycemia with low risk of hypoglycemia
GLP-1 agonists enhance _____ phase secretion of insulin.
first
GLP-1 analogs can be co-administered in T2DM management with what other drug classes?
metformin, TZDs, and sulfonylureas
For each of the GLP-1 analogs (Exenatide, Liraglutide, Lixisenatide, Dulaglutide), state the frequency of administration.
Dulaglutide-qweekly
Liraglutide-QD
Exenatide-BID or qweekly
Lixisenatide-QD
GLP-1 agonists carry risks of ______ cancer and ________.
thyroid, pancreatitis
Which GLP-1 agonist is conjugated to IgG?
dulaglutide (Trulicity)
What modification has been made to GLP-1 in Victoza? How does this affect the duration of action?
similar to insulin detemir and degludec, a FA chain is attached, allowing binding to albumin and slower release/longer duration of action
most common side effects of GLP-1 agonists
N/V, hypoglycemia if using with insulin
The “gliptins” belong to the drug class _________.
DPP-IV inhibitors
dosing frequency of DPP-IV inhibitors
QD
DPP-IV inhibitors can be co-administered with what drug classes?
metformin and TZDs
This makes sense, as both of these are insulin sensitizers, and DPP-IV inhibitors increase endogenous GLP-1 levels, which increase insulin secretion in a glucose dependent manner. With the combination, you will be both increasing glucose-stimulated insulin release and increasing the sensitivity of the body to that insulin.
side effects of DPP-IV inhibitors
N/V, constipation, HA, severe skin reactions
Because DPP-IV is also found on immune cells, what else must a pharmacist and patient be aware of when using DPP-IV inhibitors?
increased risk of infection due to WBC loss, potential increased risk of cancers
Which peptide hormone, other than GLP-1, can be mimicked in diabetes treatment?
amylin
What are the natural physiological effects of amylin?
slows gastric emptying, inhibits glucagon secretion (useful in T1 diabetics because of glucagon’s unopposed action in the absence of insulin), decreases food intake
mechanism of action of alpha-glucosidase inhibitors
decrease sugar absorption in the gut by inhibiting the enzyme that breaks complex sugars down into monomers
