Exam 2 lecture 3 Flashcards
What are the two types of drugs used inT 2 diabetes that have nothing to do with the pancreatic B cell?
a-gluconidase inhibitors
SGLT2 inhibitor
MOA of a-gluconidase inhibitors
Decrease absorption of carbohydrates from intestine.
How do a-gluconidase inhibitors decrease absorption of carbohydrates from the intestine
gluconidase cleaves disaccharides to monosaccharides. Monosacharides are easily aborbed by the body. a-gluconidase inhibitor inhibits this cleavage.
a-gluconidase drugs? difference between the two?
Acarbose- minimally absorbed
Migitol- completely absorbed
they cause a lot of GI effects
How do the two a-gluconidase inhibitors work?
They both bind the active site of the gluconidase but migitol is absorbed so has no liver toxicity. Acarbose may cause liver damage
What does SGLT2 inhibitors do?
Gets rid of glucose without stimulating uptake, it enhances glucose excretion
How do SGLT-2 inhibitors enhance glucose excretion
By artificially reducing the Vmax of the transporter, allowing more glucose to escape to urine. Also increases Na loss which helps HF pts
SGL-2 inhibitors all stem from______
Name some SGLT-2 inhibitors
Empagliflozin, dapagliflozin
SGLT-2 indication? Contraindication? SAR?
Indicated in T 2 diabetes. may lead to increased risk of limb amputation, We have a glucose as a recognition site for transporter, allows binding but not transport
adverse effects of SGLT-2
Increased risk of UTI
increased risk of diabetic ketoacidosis
SGLT-2 qshows benefit is
reducing A1C
(weightloss and even CKD)
What are some agents that reduce insulin resistance
Biguanides
Thiazoladiindeonides
Name a biguanide
Metformin
Name some thiazoladindonide drugs
pioglitazone
Rosiglitazone
T/F There is a key link between FFA (free fatty acid) levels and insulin resistance
True
How is non-obese T 2 diabetes caused
By a mutation causing a problem that leads to either insulin resistance or decreased protein secretion
What is insulin resistance? How is it detected? What are its causes?
Decreased responsiveness to actions of insulin. Can be detected by OGTT. Caused by mutations, obesity (common) and inactivity
Insulin resistance effect on skeletal muscle
Impaired glucose uotake
Insulin resistance effect on adipose tissue
Impaired glucose uptake
impaired inhibition of lipolysis
Insulin resistance effect on liver
Impaired inhibition of glucose output
via gluconeogenesis
how does obesity cause insulin resistance
Increased FFA
Can insulin resistance be caused by polymorphism?
Yes
What mutation causes insulin resistance
Switch of phosphorylation of Tyr to Ser can inhibit signalling
What other two things can also cause insulin resistance
elevated FFA and inflammatory mediators (TNFa)
mechanism of how FFA causes insulin resistance
FFA is elevated and is uptaken into tissue
They activate a kinase called MTOR. (mTOR is the key sensor of nutreint level)
mTOR phosphorylates P7056K
p7056K phosphorylates IRS protein.
phosphorylates not on tyrosines, but on serines, which leads to resistance
quick summary of how elevated FFA can stimulate insulin resistance
activation of MTOR
phosphorylation of IRS proteins that interefere with normal function
increased cytokines can do what?
activate a number of kinases
What are some kinases activated by cytokines
PKC, JNK, NFKB
What do kinases do after activation by cytokines
Phosphorylate both insulin receptor and IRS protein
What does phosphorylation of IRS by kinases do?
recruits PI3k
WHat does PI3K do after phosphorylation of IRS
phosphorylates PIP2 to PIP3
What does PIP3 do?
Activates AKT
What does AKT do?
allows rapid translocation of GLUT-4 to plasma membrane
summarize how cytokines affect IRS protein
Cytokines activate kinases
Kinases phosphorylate both insulin receptor and IRS protein
phosphorylation or IRS causes recruitment of PI3K
P13K phosphorylates PIP2 to PIP3
PIP3 activates AKT
AKT allows rapid translocation of GLUT-4 to pm
What happens when serine phosphorylation inhibits IRS signalling
It interferes with the recruitment of the catalytic subunit (P110), reducing PIP3 accumulation, this interferes with AKT activation.
T/F serine phosphorylation of insulin receptor leads to insulin resistance
True
P110 vs P13K
P110 is catalytic
P13K is regulatory
Is there an increase in inflammatory cytokines in obesity? WHy?
Yes. There is a hypertrophy of adipose tissue and infiltration of M1 macrophages that lead to an increase in inflammatory cytokines. (TNFa)
Who has M1 macrophages? Who has M2 macrophages? What is the difference between the two?
M2 macrophages are in non-obese people
M1 macrophages are in obese people
M2- secrete IL-10 which maintain insulin snsitivity
M1- lead to inflammatory cytokines
Which two drugs can address insulin resistance, without stimulating insulin secretion
Metformin
Thiazoldindiones
What are the pros of metfromin compared to sulfonylureas
Pros- no hypoglycemia, no weight gain, independent of B cells
MOA of metformin
Activates AMP-kinase, increases efficiency or sensitivity to insulin in liver, fat and muscle cells
What does metformin bind?
Complex I
What does metformin do to liver?
Stops export of glucose from liver
How does metformin stop the export of glucose from the liver
-Metformin binds to complex I and inhibits it.
-This lowers energy availability (ADP:ATP and AMP:ATP ratios rise)
-Inhibition of ATP leads to rise in AMP
-Increased AMP inhibits fructose-6-bisphosphate which is required for gluconeogenesis
summary of how metformin works in liver
inhibits gluconeogenesis in liver by inhibiting fructose-1,6- Bisphosphate
How does metformin affect skeletal muscle
Accumulation of AMP leads to increase in translocation of GLUT-4 to plasma membrane and increased uptake of glucose into skeletal muscle
How does metformin cause increased uptake of GLUT-4
AMP accumulates
activates AMP-K
AMP-k phosphorylates a GTP-ase regulator of Rab called TBC1D 1/4
TBC1D 1/4 helps Rab hydrolyze GTP, Rab dissociates and translocation of GLUT-4 occurs
why would metformin cause lactic acidosis
Since it inhibits gluconeogenesis. This pathways is important for the removal of lacyic acid
most common side effect of metfromin
GI side effects (N, V, D)
also decreases B12 absorption
Metformin effect on blood lipid profile
decreases serum triglycerides
Decreases serum LDL
decreases risk of adverse CV events
What do thiazoliedindiones do?
Decrease insulin resistance
target of thiazoldindiones
PPAR-g
What is PPAR-g? what does it do?
It is a transcription factor that enhances adipocyte differentiation
how does PPAR-g affect FFA`
Enhances FFA uptake into subQ, reduces serum FFA.
WHat are some thiazoledindione drugs
Rosiglitazone
pioglitazone
FDA warning for thiazoledindione drugs
Contraindicated in class 3 or 4 HF
How do thiazodindiones affect TNF-a, resistin and adiponectin
Lower TNF-a and resistin (adipokines) and raise adiponectin
What is adiponectin
stimulates insulin dependent glucose uptake
Thiazonedindiones ________FFA levels and ______ adiponectin levels
decrease, stimulate
Why is there an increased risk of fracture with thiazonedindiones
They reduce the differentiation of stem cells to osteoblasts
What is gestational diabetes? what is it caused by?
Hyperglycemia during pregnancy in non-diabetic women. caused by the normal changes in insulin sensitivity and metabolism furing pregnancy
What happens to insulin response in early vs late pregnancy
Early- increased nsulin response
late- reduced insulin sensitivity
Why is there an increased insulin response in early pregnancy
Placenta is not growing, body becomes insulin sensitive to increase maternal fat storage to help placenta grow
Why is there reduced insulin sensitivity in late pregnancy?
Fetus frows and takes all nutrients from mom. Body compensates by increasing insulin secretion
When is gestational diabetes diagnosed? how is it diagnosed?
24-28 weeks with OGTT. This is the rapid growth stage of gestation.
What are some complications in gestational diabetes
Baby could have hypoglycemia when separate
increased risk of developing T2 diabetes in mom and baby
Why is there an increased risk of developing T2 diabetes in gestational diabetes babies
Due to the exposure of fetus to high levels of insulin and glucose from gestation (fetal programming)
Does insulin cross the placenta? Does glucose cross the placenta?
Insulin does not, but glucose does. That means the baby needs to make its own insulin.
placental hormones secreted in gestational DM
CRH-cortisol
Progesterone
Placental GH
Placental lactogens (PL)
What are placental lactogens
Placental hormones secreted by placenta that induce peripheral insulin resistance in mother
why is GDM predictive of T2 diabetes
Because of the inability of mothers pancrease to compensate for resistance by increasing B cell acitivity
what are hormones secreted during pregnancy that increase B cell mass
Prolactin and placental lactogen
What does prolactin do?
Stimulates B cell proliferation
mutations i prolactin receptor are associated with GDM
What does placental lactogen do
Is similar to GH, activates prolactin
Compare the different treatments of GDM
Insulin- gold standard, does not cross placenta, disadvanatge is that it can cause stress
Glyburide- adv- oral, disadvantage, crosses placenta
Metformin- disadvantage- crosses placenta but does not seem to harm it.
TZD not used- teratogenic
metformin target
complex I
Cellular effect of metfromin
Elevates CAMP and activates AMPk
Metformin effect on liver
Reduced glucose export due to inhibition of gluconeogenesis
