Exam 2 Lecture 2 Flashcards
Hypoglycemia
BG less than 60
Modification on insulin detemir
Fatty acid added to peptide to prolong action
signs of hypoglycemia
Weakness, sweating, hunger, tachycardia, increased irritability, tremor, blurred vision, seizures (neurologic symotoms)
Why are signs of hypoglycemia neurologic symptoms
low BG leads to increased sympathetic outout
Why does low BG cause increased sympathetic output
It is the brains way of bringing BG back up by mobilizing glucose from liver, which can cause these symptoms
Preferred fuel in nervous symptom
glucose
What are some drugs that can increase BG levels in diabetes
catecholamines
glucocorticoid
somatotropin (leads to insulin resistance)
How do catecholamine, glucocorticoids and somatotropin increase BG levels in diabetics
They have a pro-sympathetic effect on the liver and interfere with trying to keep BG levels down by stimulating release of glucose from liver
Agents with increased risk of hypoglycemia
ETHANOL
ACE inhibitor
B blocker
Fluoxetine
How does Ethanol increase the risk of hypoglycemia
Inhibits gluconeogenesis (which is one of the two ways that liver can export glucose into bloodstream and bring levels up.)
How do ACE inhibitors, B blockers and fluoxetine cause hypoglycemia
Inhibit enhanced sympathetic output from brain
What are adverse effects of insulin with regard to lipids
Lipodystrophy- changes in fat at over used inj site
Lipohypertrophy- accumulation of fat in SUbQ tissue
What was the mechanism for insulin glargine
It is soluble at acidic PH and insoluble at physiologic PH. Percipitates at site of inj
Which insulin preparation is not genetically modified?
NPH (only complexed with protamine) (has action peak)
2 Phases of normal insulin secretion
1st- high peak, quick onset
2nd- elevated for long time
Type 2 diabetes is a combination of
Insulin resistance and reduced insulin secretion
Why does the decline in glucose utilization in skeletal muscles in T2 diabetics have a big effect on oateint
Skeletal muscle accounts for a large percentage of the glucose uptake stimulated by insulin after a meal
How does insulin affect the liver
Inhibits glucose output from liver by inhibiting breakdown of glycogen and inhibiting gluconeogenesis
What happens to glucose export in non diabetic patients when insulin is secreted
Steep drop
T/F The ability of insulin to shut off exprt of glucose from liver is going to be compromised
True
What do pancreatic islet cells do? how does insulin affect this? how is this affected by diabetes
They secrete glucagon. Insulin inhibits glucagon secretion. This inhibition is blunted in diabetes T2
How does insulin affect lipolysis. How is this affected in diabetics
Insulin suppresses lipolysis. . This is blunted in diabetes
What are the drugs that have the ability to directly stimulate insulin secretion from pancreatic B cell.
Sulfonylurea- prolonged duration of action
meglitinides- rapid onset and short duration
Examples of sulfonylureas
Tolbutamide, Glipizide, Tolazemide
Examples of meglitinides
Nateglinide, Repaglinide
What is the predominant glucose transporter in pancreatic B cells?
GLUT-2
What is sepcial about GLUT-2
It has a high KM
What does high Km for GLUT-2 entail?
We need a high blood glucose to start uptake into pancreatic B cell
What happens after GLUT-2 uptakes glucose into blood stream
Glucose is phosphorylated to G-6-P, producing ATP
What happens after ATP is produced from G-6-P
There is a big swing in ratio of ATP to ADP, ADP decreases and ATP increases
When does K-ATP channel close? How many subunits of K-ATP?
Closes when bound to ATP, 2 subunits
What happens when K-ATP channel is closed?
membrane potential starts to go up
What happens when ATP binds K channel?
It closes it and reduces the efflux of potassium from cell. This causes membrane depolarization.
What happens when membrane is depolarized?
Opens voltage gated calcium channels. When voltage gated calcium channels open, calcium comes into the cell and stimulates release of insulin
What happens when calcium channels open?
Ca stimulates release of insulin
Why do we have low efflux of glucose when glucose levels are low?
GLUT-2 has a very high Km
What effect does GLUT-2 not uptaking glucose have during low blood glucose
There will be more ADP than ATP, ADP bunds KATP channel
During low glucose, when ADP binds K-ATP, what happenss
ADP causes the K-ATP channel to remain open and maintain negative resting potential
What is the K-ATP channel?
The key sensor of metabolic activity that regulates electric activity that determines insulin secretion
K_ATP channel is made up of how many subunits
2 subunits
KIR 6.2- pore forming
SUR 1
both have 4 subunits
where do sulfonylureas bind
Between KIR 6.2 and SUR 1 subunits in K-ATP channel
What are some sulfonylurea drug names
Tolbutamide
Glyburide
Gluclazide
Recognize the sulfonyl urea structure
.
Sulfonylurea mechanism
Act like B cell. They bind K-ATP and block it. Causing membrane depolarization
Which sulfonylurea has a faster effect? why?
Tolbutamide, it does not have to be metabolized
which are the 1st gen sulfonylureas
tolbutamide- lowest potency and duration
Chlorpropramide- longest duration
What differentiates 1st gen from second gen sulfonylureas
Potency, second is much more potent
second gen sulfonyurea drugs
Glipizide
glyburide
glimepride
difference between sulfonylureas and meglitinides
same function (blocking k-atp) different structure.
Meglitinides have repaglinide instead of sulfonylurea
Name two meglitinides
Nateglinides, prandin
DIfferentiate between nateglinide and prandin
Nateglinide is very specific for KATP channels in pancrease compared to CV
Nateglinide also has a shorter half life
Adverse effects of sulfonylureas
Prolonged HYPOGLYCEMIA due to long t1/2 especially in 2nd gen (glipizide, glimepride)
risk of CV events
GI problems
Why do sulfonylureas lead to loss of B cell mass
They stimulate persistent insulin secretion. This can be stressful on B cells leading to loss of BCM
Drugs that may enhance the action of sulfonylureas and risk of hypoglyccemia
Salicylates, sulfonamides
Drugs that cause hyperglycemia that may oppose sulfonylureas
OC
epinephrine
thiazide diuretics
corticosteroids
What is the incretin effect?
Oral glucose elicits higher response that IV glucose
Why does oral glucose stimulate larger insulin response than IV glucose
Small intestine increases the hormones called incretins in response to absorption of glucose. They incremetally increase the secretion of insulin and increase glucose utilization.
Name 2 incretin hormones
GLP-1
GIP
Difference between the two incretins
GLP-1 is secreted from the ileum and is stimulated by the uptake of glucose from the lumen
GIP- is secreted from duodenum
Most important effect of incretins
Acutely increase insulin secretion through C-AMP stimulation in pancrease cell
How does incretin increase insulin secretion
stimulate c-AMP in B cell in response to glucose
How do incretins affect BCM
protect and maintain B cells
What is DPP-IV
a protease that degrades GIP and GLP-1
What inhibits DPP-IV? What effect does this have?
DPP-IV inhibitor . Helps raise levels of incretin
Besides stimulating insulin production, what else do incretins do?
Suppress glucagon secretion
slow gastric emptying
decrease food intake
increase BCM
enhance glucose disposal and improves insulin sensitivity
Is incretin glucose dependent or independent?
Dependent
Why do incretins have a lower risk of hypoglycemia compared to sulfonylureas?
If there is no glucose around to depolarize the membrane potential, incretins will not stimulate insulin secretion. Sulfonyl ureas persistently stimulate insulin secretion
does GLP-1 byitself stimulate insulin secretion?
No, it can amplify the ability of glucose to stimulate insulin secretion.
Does GLP-1 stimulate membrane depolarization?
No, it increases CAMP inside the cell. This amplifies the effective membrane depolarization. causing more insulin to be secreted in response to glucose
Incretins in Type 2 diabetes?
Incretin effect is diminished in t2 diabetes
2 startegies to increase the incretin effect in t 2 DM
provide GLP analog
prevent degradation of endogenous GLP-1
What are some GLP -1 analogs
Exenatide
Liraglutide (Victoza)
Dulaglutide (trulicity)
Lixisenatide (adlyxin)
Semaglutide (ozempic)
mounjaro (tirzepatide)
warning for all GLP-1 analogs
Nausea, vomiting, pancreatitis
Contraindication to all GLP-1 analogs
contraindicated in pts with FH of medullary thyroid cancer
Liraglutide (victoza) modifications
Fatty acid added to enhance duration of action by binding serum albumin
Dulaglutide (trulicity) modifications
GLP-1 peptides slowly released from IgG Fc domain by reduction of disulfide bonds.
Can be injected once a week due to ability to circulate for long periods
Modifications of Lixisenatide (Adlyxin)
Not a derivative of GLP-1 sequence. It is a derivative of exenatide with a polylysine tail. Inj daily.
No fatty acid, no serum binding
Which position is most susceptible to proteolysis
Position next to histidine
Ozempic (semaglutide) half life?
1 week, binds serum albumin
semaglutide (ozempic) modification
Has an artificial aa next to histidine, reducing susceptibility to cleavage. Has a hydrophobic spacer and fatty acid.
How does semaglutide (ozempic) affect appetite
They have receptors in CNS that affect appetite, reducing food intake
Only GLP-analog that is orally active
Semaglutide (rybelsus), poor oral bioavailability.
semaglutide (rybellus) modifications
unnatural aa after histidine, hydrophobic spacer and fatty acid called salcaprozate (makes it absorbable from GI tract)
What is salcaprozate
fatty acid in semaglutide (rybella) that makes it absorbable from GI tract
How does mounjaro (tirzepatide work)
Reduces internalization (desensitization) of GLP-1 receptor to maintain effect.
How does moounjaro affect GIP and GLP-1
Full agonist for GIP
biased agonist for GLP-1
How does mounjaro reduce desensitization
activates CAMP over b-arrestin, b arrestin causes desensitization
What is DPP-IV and what does DPP-IV inhibitor do?
DPP-IV cleaves hormones on luminal side of capillary. The inhibitor allow greater release of GLP-1 and GIP after a meal because we inhibit their breakdown
What is amylin? main action?
A peptide secreted from B cell along with insulin that regulates the absorption of nutrients from the GI tract. main action- inhibits glucagon secretion
Amylin drug
pramlintide(symlin)
What does pramlintide do?
Blunts post prandial rise in BG
