Feb7 M1,2-Glucoregulatory Hormones Flashcards
avg 24hr glucose and std in non diabetic, controlled diabetes and uncontrolled diabetes
- non diabetic: 5-6. std less than 1
- controlled diabetic: 5-8. higher std
- 10-11. even higher std
glucose sensor cells in the body and associated with what cells and link
beta cells of the pancreas (islets) make insulin. mixed with alpha cells that make glucagon. they communicate
1st step of glucose sensing by beta cells
- glucose in through glut2
- glycolysis and oxidative phosphorylation
- higher ATP to ADP ratio
2nd step of glucose sensing by beta cells (after higher ATP to ADP ratio)
- ratio sensing K channel shut down and K+ kept inside
- depol of the membrane
- voltage dependent Ca channel opens and lets Ca in
- Ca activates insulin granules fusion with plasma membrane
Km and V max meaning (MM kinetics)
Km is the substrate conc at which an enzyme operates at half its maximal speed (V max over 2)
why beta cell is unique glucose sensor
- glut2 has Km of 15-20 mM glucose (brain glut1 is only 1-2 mM for ex, won’t sense glucose change)
- GK (glucokinase) Km is 8
Km of 15 and glucose conc goes from 4 to 8: how glucose uptake changes by glut2 (beta cells)
increases significantly
km of 1 mM (brain glut1) and glucose goes from 4 to 8, how glucose uptake by glut1 varies
no significant change (very slight increase)
first enzyme handling glucose in beta cell and what it does
GK. makes it glucose 6 P (requires ATP)
how Km reflects affinity of substrate for enzyme
lower Km = greater affinity
higher Km = less substrate-enzyme affinity
kinds of mutations in MODY
- very high Km mutation in GK (less affinity)
- normal Km but low catalytic activity mutation in GK
* some in active site, some outside of it but affect conformation*
subunits in ratio sensing K channels and fcts
- 4 SUR subunits (Sur1 senses ATP with NBD1 and NDB2 (nucleotide, ATP, binding domain)
- 4 kir6 subunits (K+ channel)
inhibitor of K channel consequences
always active and always make insulin. hypoglycemia (bc downstream of glut2 and ATP prod)
2 ratio sensing K channel inhibiting drug classes and act on what
- sulfonylureas (end with ide): act on reg Sur subunits
2. glitinides (end with inide): act on K channel subunits
sulfonylureas vs glitnides charact
- sulfonylureas: long acting (reg subunit)
- meglitinides: short acting (channel subunit)
mutations in reg or channel subunits of ratio sensing K channels consequence and treatment
neonatal diabetes. the channel is unable to close. sulfonylureas would work in mutation in reg domain
2 non glucose stimuli to insulin secretion and how
fatty acids: 1. activate FA receptor 2. metab to fatty acyl CoA and DAG, which activates granules fusion
aa: their metab increases ATP to ADP ratio
long term (chronic) presence of FA consequence on beta cells
lipotoxicity. decreased insulin secretion (impairs ability to secrete insulin)
name of category of gut hormones that can stimulate insulin secretion and give 2 hormones
incretins. examples: GIP (gastric inhibitory peptide) and GLP-1 (glucagon-like peptide 1)
what cells make GIP and GLP-1
GIP: duodenum and jejunum
GLP-1: distal SI and large intestine
type 2 DM: response to GIP and GLP-1
- no response to GIP
- preserved response to GLP-1
GIP and GLP-1 half life in circulation and why
cleaved by proteases, especially one called DPP4 sitting on vascular endothelium
GLP-1 how it is produced and this mechanism differs in diff cells
- in intestine from cleavage of proglucagon
- proglucagon cleavage in alpha cells of pancreas is different and makes glucagon
GLP-1: 3 effects on glucose
- stimulates insulin release (but acts only when needed bc released upon eating)
- slows gut motility (abso more spread out)
- inhibits glucagon (catabolic)
2 GLP-1 related diabetes therapies
- gastric bypass (increases glucose delivery to distal SI and endogenous GLP-1 prod)
- GLP-1 proteases (dpp-4) inhibitors
2 kinds of protease (DPP-4) resistant (synthetic) GLP-1 therapies
- exenatide
2. FA attachement to to GLP-1
exenatide how it works
GLP-1 variant where there’s a change of second aa (second aa is cleavage site of DPP-4) so doesn’t cleave anymore
FA chain attachement to synthetic GLP-1 how it works
FA chain will bind albumin, which will protect the synthetic GLP-1 (normal sequence) from DPP-4
other GLP-1 related therapy for type 2 DM (where no GLP-1 injected)
DPP4 protease inhibitors
GLP-1 mechanism of action
binds GPCR (Gs protein), adenylyl cyclase activated, cAMP made, acts on enzymes to stimulate insulin secretion
proinsulin structure and what cleaves it
A chain, C peptide (connecting peptide) and B chain. A and B chains connected by disulfur bonds.
proinsulin cleaved by same enzyme cleaving proglucagon
C peptide lab test serves for what
check if insulin production is endogenous (tumor or wtv) = high C peptide or exogenous (took too much) = low C peptide
short acting insulin mode of action
forms cristals of 6 insulin molecules (hexamers). must dissolve before go in the blood so takes 1 hour to absorb. (2-4 hrs = peak. max duration = 6 hours)
rapid acting insulin mode of action
mutated so not cristals formed. abso rapid. peak at 1-2 hours. max duration 4 hours
intermediate acting insulin name and mechanism of action
neutral protamine Hagedorn (insulin bound to protamin so much longer to dissolve under the skin). peak 12 hours. duration max 18 hours
long actin insulin charact
lasts 24 hours. constant and no peaking
basal insulin def
there’s a minimal insulin amount in the blood at all times
1st kind of insulin regimen (less popular)
1 long actin at bedtime
3 rapid acting at each meal
2nd kind of insulin regimen (more popular)
NPH (intermediate) + rapid mix at breakfast and NPH+rapid again at supper
what regulates glucagon secretion by alpha cells exactly
low levels of insulin secretion from beta cells (NOT glucose levels)
stimulators of glucagon secretion (other than low insulin)
- aa (prevent low glucose in only prot meal)
- GIP, CCK
- SS
- GH, cortisol, NE and E
- exercise (need glucose + SS)
inhibitors of glucagon (other than high insulin)
- somatostatin (inhibits BOTH glucagon and insulin)
- GLP-1
- leptin
key glucagon regulators and why
insulin, amino acids, exercise, stress (are ways we can work on to control blood glucose)
glucagon effect on the liver
- more glycogenolysis
- more gluconeogenesis
- FA oxidation to ketones
glucagon effect on adipose tissue
-stimulate lipolysis
glucagon effect on skeletal muscle
no effect (no glucagon R on SKM)
experience done to antagonize glucagon
somatostatin given to diabetic patients on insulin and blood glucose decreased
insulin production in type 2 DM (early vs late)
- early: much higher than normal insulin to keep normal glucose
- late: lower insulin production than in healthy subject
DKA (diabetic ketoacidosis) in what disease
type 1 DM (not type 2)
1st step of insulin signaling
-insulin binds RTK which phosphorylates itself (cytoplasmic side). this recruits signaling molecules
2nd step of insulin signaling after RTK phopsh
IRSs (insulin R substrate proteins) recruited to phosph tyrosine. then recruite PI3 kinase
3rd step of insulin signaling (actions of phosphorylated PI3K)
- PI3K phosph a lipid called PTEN in plasma membrane
2. other molecules are recruited like Akt
4th step of insulin signaling (how GLUT4 (muscle, fat) or GLUT2 in liver inserts in membrane)
Akt works to insert GLUT2 vesicles on plasma membrane
2 potential therapy targets of insulin signaling and why
PI3K and Akt because are involved in many other receptors (we could act through these other receptors)
main cause of insulin resistance and why
obesity.
1. FFAs and TNF alpha in circulation inhibit PI3K activity
2. fat deposition between muscle fibers + droplets INSIDE fibers
why high cortisol (high glucocorticoid level) pts need higher level of insulin
glucocorticoids turn on p85 subunit and makes lot of free p85 subunits. p85 binds IRS-1 and competes with other enzymes binding it. IRS-1 and PI3K decoupling
main therapy in diabetes and why
exercise. stimulates glut4 insertion without insulin presence
2 drugs increasing insulin sensitivity
metformin
PPARg agonists
first line drug to treat diabetes
metformin
enzyme metformin works on and consequence
inhibits the mitochondrial glyceraldehyde-3 phosphate dehydrogenase. (mGPD)
consequence of metformin inhibitng glyceraldehyde dehydrogenase (mGPD)
glycerol 3 P accum in both mt and cytosol bc mvmt to mt for conversion to DHAP is blocked
consequence of high conc of glycerol 3 phosphate in the cytosol (bc doesn’t move to mt bc high conc in mt bc not made into DHAP)
rx converting DHAP to glycerol 3 P in cytosol doesn’t occur. this rx uses NADH and yields NAD. less NAD is yielded. HIGH NADH environment
consequence of high NADH environment (low NAD made) as consequence of metformin effect and glycerol 3 P accum in cytosol
highly reduced environment (high NADH) mimicks low O2 conditions. pyruvate made into lactate and no gluconeogenesis in the liver
global effect of metformin
blocks GNG in hepatocytes
PPAR gamma agonists type of molecule and where it acts as a drug
steroid. binds the TF PPAR gamma in adipocytes to change gene expression
end effect of PPAR gamma agonists
adipocytes accum more fat and secrete LESS insulin resist substances in the blood and more substances that decrease insulin resistance
example of insulin resistance substance that is less released by adipocytes as effect of PPAR gamma agonists
TNF alpha
benefits of metformin and PPAR gamma agonists
don’t cause hypoglycemia bc act when insulin is present ONLY
drug that slows intestinal glucose absorption
alpha glucosidase inhibitors (acarbose)
drug that inhibits renal glucose reabso
SGLT2i in PCT
mistake done in hospitals and to avoid with diabetic patients
ER: stop insulin
can’t do that bc need basal insulin (otherwise get DKA)
