Exam 2 lecture 1 Flashcards
Why is glucose so toxic?
oxidation products react irreversibly with proteins to form advanced glycation end products (AGE)
Why is glucose so reactive? In what form is it the most reactive
In its extended aldehyde form. Aldehydes are very reactive
what are some oxidation products of glucose
Glyoxal and methylglyoxal
what do glyoxal and methylglyoxal do?
They react with proteins and degrade them.
What do glyoxal and methylglyoxal bind to?
RAGE (receptor for AGE)
hemoglobin A1C is a measure of
how much glucose there is hanging on hemoglobin protein in RBC.
What is the pro of A1c over BG levels
A1c measures the avg blood glucose level over a period of time, BG is too volatile
RAGE is mostly present on
Leukocytes and endothelial cells, it is a part of MHC superfamily
WHat are CML and CEL
carbomethyl lysine and carboethyl lysine
how are CML and CEL formed
lysine reacting with glyoxal and methylglyoxal
(remember that glyoxal and methylglyoxal degrade proteins to form AGEs)
How do CML and CEL affect our bodies
Since they are AGEs, they bind to RAGE and promote inflammation.
why are different mechanisms taken by glucose in hyperglycemia
When we have a high BG, we shove glucose through metabolic pathways that are normally not used much. (polyol pathway, hexosamine pathway and PKC pathway)
explain the polyol pathway
nerves process glucose to sorbitol and convert to fructose. This is then stored in the nerves.
Why is polyol process a probelm
- If we accumulate sugar alcohols in neurons, this leads to water flooding the neuron, which leads to neuropathies
- the rxn to turn glucose to sorbitol is catalyzed by aldose reductase, which consumes a lot of NADPH, which is needed to protect neurons from oxidative stress. This makes neurons more suseptible.
how is hexosamine pathway activated
glucose is metabolized to fructose-6-phosphate (Rate limiting step). Accumulating a lot of fructose-6-phosphate can activate a lot of hexosamine pathway
Why does accumulating a lot of fructose6-phosphate activate hexosamine pathway
fructose-6-phosphate is reacted on by GFAT, which turns into G-6-P and conjugated with UDP forming UDP-G1CNAC
What is UDP-G1cNAC
a substrate for enzymes that can put glutamines onto OH groups of proteins, changing their function.
In short polyol process summarize
Glucose turned into fructose and stored in neurons cause issues like water in neurons. Also NADPH is consumed when sorbitol is catalyzed making neuron more susceptible for oxidative stress.
hexosamine pathway summarize
Fructose-6 phosphate is accumulated and activates hexosamine pathway. this f-6-p is turned into g-6-p and conjugated with UDP to form UDP-G1cnac
Explain the PKC pathway
hyperglycemia leads toGlyceraldehyde-3-p accumulation, this leads to elevated DAG and activates PKC
link between hyperglycemia and ability to exert vascular relaxation
Methylglyoxal inhibits vasorelaxation stimulated by AcH/nitric oxide
how does methylglyoxal inhibit vasorelaxation
Methylglyoxal can react with arginine and form MG-H1 in endothelial cell of BV. ARG is an important substrate for nitric oxide synthase (which is essential to mediate vascular tone)
Why is insulin important
To use glucose effectively as a fuel
what does no insulin mean
Hyperglycemia and susceptible to ketoacidosis because they are using fatty acid for fuel.
What are the two subunits of the insulin receptor
alpha (a) and beta (b)
roles of a and b subunits of insulin receptor
alpha- regulatory unit of receptor. represses the catalytic activity of beta subunit. Repression is relieved by insulin binding
beta- contains tyrosine kinase catalytic domain for autophosphorylation.
How are alpha and beta subunits alligned
There is an extracellular alpha subunit and an extracellular and intracellular beta subunit.
ligand binding domain is extracellular and tyrosine kinase is inside B subunit
these two tyrosine kinase domains autophosphorylate each other.
how many molecules of insulin does it take to stimulate insulin receptor
1
3 main tissues for insulin action
liver, muscle and fat
How is IRS (insulin receptor substrate) recruited?
Insulin binding insulin receptor, activating intracellular tyrosine kinase domains.
What is IRS
Insulin receptor substrate. This is an important adaptive protein for insulin signaling. It gets phosphorylated and recruits signalling molecules to complex
give an example of how a hexosamine pathway interferes with normal function
Hyperglycemia and activation of hexosamine pathway can result in glucosamine being added to IRS, which interferes with its function.
what happens when IRS is phosphorylated
It recruits PI3K
What does PI3K do?
Phosphorylates PIP2 to PIP3, activating PDK 1
what does phosphorylation of PIP2 to PIP 3 do?
activates PDK 1
What does PDK 1 do once active
activates 2 kinases
What are the names of the 2 kinases activated by PDK 1
aPKC and PKB
What do aPKC and PKB do
increase glycolysis and increase glucose utilization.
What is another use of PDK 1 and subsequent activation of PKB and aPKC
for translocation of GLUT 4 to plasma membrane
GLUT 4 are stimulated by
Insulin
use of GLUT 4 translocation
enables skeletal muscle to take up glucose at a very rapid rate.
PDK and PKB can also stimulate
an increase in glycogen synthesis in liver and decrease in gluconeogenesis
main effect of glucose on fatty acid cells
increase lipogenesis (taking free fatty acid and storing it as lipid)
how is lipogenesis activated by glucose
Activated by Shc protein that gets phosphorylated by insulin which recruits MAPk, leading to lipogenesis or cell growth and proliferation.
insulin effect on liver
Inhibits- glycogenolysis
Ketogenesis
gluconeogenesis
stimulates- glycogen synthesis
triglyceride synthesis
insulin effect on skeletal muscle
Stimulates- glucose transport
aa transport
Adipose tissue
stimulates- triglyceride storage
glucose transport
glucose disposal in fasting state
75% of glucose disposal is non-insulin dependent (liver, GI, brain)
25% is insulin dependent in skeletal muscle. Glucagon is secreted to prevent hypoglycemia
Glucose disposal in fed state
80-85% is insulin dependent in skeletal muscle.
4-5% in adipose tissue
glucagon secretion is inhibited
Insulin inhibits the release of _________from adipose tissue
Free fatty acid (FFA)
how does a decrease in FFA affect the body
enhances insulin action on skeletal muscle, reduces hepatic glucose production.
What is the major role of skeletal muscle in this topic
site of uptake of glucose after a meal.
What are the 4 glucose transporters
GLUT-1 - widely expressed, constitutive (not insulin dependent)
GLUT-2- Constitutive, found in liver and B cell
GLUT-3- found in nervous system, constitutive
GLUT-4- skeletal muscle and adipocytes, insulin dependent
what is the source of insulin secreted in response to glucose
pancreatic B cell
which cells are endocrine in pancrease?
Islets of langerhans, others are exocrine cells.
What do exocrine cells do in pancrease
secrete digestive enzymes into small intestine.
What do endocrine cells in pancrease secrete
Insulin, Amylin, somatostatin and glucagon
What does glucagon do?
stimulates glycogen breakdown and increased BG
What does somatostatin do?
general inhibitor of secretions
What does insulin do?
Stimulates uptake and utilization of glucose
what does Amylin do?
Co-secreted with insulin from B cells. slows gastric emptying and decreases food intake. inhibits glucagon secretion.
insulin is processed from a pro hormone called
pro-insulin
what is pro insulin
a polypeptide that has not been processed to its active form. it is translated into a polypeptide that is processed in secretory granule by enzymes called pro-convertases.
what do pro converatses do?
Cleave cleave pro insulin in two spots to release connecting peptide.
Insulin source
Recombinant human insullin
What separates the types of insulin
Pharmacokinetics
How long to start acting, how long to peak, duration of action.)
What are the different types of insulin
Ultra rapid onset
regular insulin
Intermediate insulin
slow onset
Example of ultra rapid insulin
Lispro (Humalog)
Aspart (novolog)
Glulisine (Apidra)
Example of slow onset insulin
Glargine (lantus)
Detemir (llevemir)
Degludec (tresiba)
how do modified insulin alter the availability and absorption from subQ inj sites. Why do we need to do this?
Delay absorption- prolong onset and duration
increase absorption- decrease time to onset and duration
We want to mimick what happens physiologically when glucose levels are elevated
What are the 2 phases of insulin secretion
Rapid 1st phase- peaks quickly and plateus
plateu 2nd phase- plateu of elevated insulin after 1st peak
How is Zn important in insulin dosing
Zn is important for causing dense concentrations of insulin by forming a complex with insulin (forms a dimer of trimers)
What is the science behind why we use Zn in insulin
Zn binds insulin forming a complex, larger complex size leads to a more prolonged absorption from subQ inj site. Lente family (no longer used) used to use this method)
What is NPH
neutral protamine hagedon. Intermediate insulin. Has a clear peak, slow absorption, long duration of action.
what are the modifications in lispro (humalog) that give it its properties.
Proline and lysine positions are changed , this disrupts dimerization of insulin monomers, keeping them in monomer form. Monomer is rapidly absorbed.
What are modifications in Insulin aspart (novolog) that give it its properties.
Proline 28 is chnaged to aspartate.
immediately before meal
short duration
Insulin glulisine (apidra) modifications to give it its properties
Asn and lys are switched to Lys and Glu.
short duration, injected immediately before meal
short duration
What are modifications that give Insulin glargine (lantus) its properties
Asn 21 on a chain changed to gly
2 ARG residue added to the end of B chain
This changes its solubility.
Why is insulin glargine (lantus) slowly absorbed
Modifications change solubility to PH 4. When released SubQ, it is PH 7 there, it is not soluble in that PH so it precipitate’s and is slowly absorbed overtime.
What modifications give Insulin detemir (levemir) its properties?
Thr is deleted and Lys is myrilated with fatty acid. This fatty acid allows it to bind to serum albumin extensively, creating a sink of insulin.
what modifications give Insulin deglude (tresiba) its properties
Thr 30 b-chaain is replaced by gamma-glu-c16 fatty acid. Allows it to bind serum albumin.
When are fast acting insulins taken?
Before meals
When are long/intermediate insulins taken?
At bedtime or after breakfast
Why are most insulins in a mixture
Give 1 injection and get a rapidly acting compinent and another for prolonged basal activity.
properties of inhaled Insulin? contraindications
Inhaled dry powder, has more rapid onset and shorter duration than Subq inj
contraindicated in asthma and COPD.
drug name is afrezza
routes of administration of insulin
SubQ- all
insulin infusion pump- fast acting (lispro, aspart, glulisine)
IV-regular for severe hypokalemia or ketoacidosis
mode of action of insulin in diabetic
Decrease liver glucose output
increase fat storage
Increase glucose uptake
