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Bloc E - GI & Metabolism > Feb7 M1,2-Glucoregulatory Hormones > Flashcards

Feb7 M1,2-Glucoregulatory Hormones Flashcards

1
Q

avg 24hr glucose and std in non diabetic, controlled diabetes and uncontrolled diabetes

A
  • non diabetic: 5-6. std less than 1
  • controlled diabetic: 5-8. higher std
  • 10-11. even higher std
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2
Q

glucose sensor cells in the body and associated with what cells and link

A

beta cells of the pancreas (islets) make insulin. mixed with alpha cells that make glucagon. they communicate

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3
Q

1st step of glucose sensing by beta cells

A
  1. glucose in through glut2
  2. glycolysis and oxidative phosphorylation
  3. higher ATP to ADP ratio
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4
Q

2nd step of glucose sensing by beta cells (after higher ATP to ADP ratio)

A
  1. ratio sensing K channel shut down and K+ kept inside
  2. depol of the membrane
  3. voltage dependent Ca channel opens and lets Ca in
  4. Ca activates insulin granules fusion with plasma membrane
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5
Q

Km and V max meaning (MM kinetics)

A

Km is the substrate conc at which an enzyme operates at half its maximal speed (V max over 2)

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6
Q

why beta cell is unique glucose sensor

A
  1. glut2 has Km of 15-20 mM glucose (brain glut1 is only 1-2 mM for ex, won’t sense glucose change)
  2. GK (glucokinase) Km is 8
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7
Q

Km of 15 and glucose conc goes from 4 to 8: how glucose uptake changes by glut2 (beta cells)

A

increases significantly

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8
Q

km of 1 mM (brain glut1) and glucose goes from 4 to 8, how glucose uptake by glut1 varies

A

no significant change (very slight increase)

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9
Q

first enzyme handling glucose in beta cell and what it does

A

GK. makes it glucose 6 P (requires ATP)

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10
Q

how Km reflects affinity of substrate for enzyme

A

lower Km = greater affinity

higher Km = less substrate-enzyme affinity

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11
Q

kinds of mutations in MODY

A
  1. very high Km mutation in GK (less affinity)
  2. normal Km but low catalytic activity mutation in GK
    * some in active site, some outside of it but affect conformation*
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12
Q

subunits in ratio sensing K channels and fcts

A
  • 4 SUR subunits (Sur1 senses ATP with NBD1 and NDB2 (nucleotide, ATP, binding domain)
  • 4 kir6 subunits (K+ channel)
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13
Q

inhibitor of K channel consequences

A

always active and always make insulin. hypoglycemia (bc downstream of glut2 and ATP prod)

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14
Q

2 ratio sensing K channel inhibiting drug classes and act on what

A
  1. sulfonylureas (end with ide): act on reg Sur subunits

2. glitinides (end with inide): act on K channel subunits

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15
Q

sulfonylureas vs glitnides charact

A
  • sulfonylureas: long acting (reg subunit)

- meglitinides: short acting (channel subunit)

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16
Q

mutations in reg or channel subunits of ratio sensing K channels consequence and treatment

A

neonatal diabetes. the channel is unable to close. sulfonylureas would work in mutation in reg domain

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17
Q

2 non glucose stimuli to insulin secretion and how

A

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

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18
Q

long term (chronic) presence of FA consequence on beta cells

A

lipotoxicity. decreased insulin secretion (impairs ability to secrete insulin)

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19
Q

name of category of gut hormones that can stimulate insulin secretion and give 2 hormones

A

incretins. examples: GIP (gastric inhibitory peptide) and GLP-1 (glucagon-like peptide 1)

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20
Q

what cells make GIP and GLP-1

A

GIP: duodenum and jejunum

GLP-1: distal SI and large intestine

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21
Q

type 2 DM: response to GIP and GLP-1

A
  • no response to GIP

- preserved response to GLP-1

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22
Q

GIP and GLP-1 half life in circulation and why

A

cleaved by proteases, especially one called DPP4 sitting on vascular endothelium

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23
Q

GLP-1 how it is produced and this mechanism differs in diff cells

A
  • in intestine from cleavage of proglucagon

- proglucagon cleavage in alpha cells of pancreas is different and makes glucagon

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24
Q

GLP-1: 3 effects on glucose

A
  • stimulates insulin release (but acts only when needed bc released upon eating)
  • slows gut motility (abso more spread out)
  • inhibits glucagon (catabolic)
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25
Q

2 GLP-1 related diabetes therapies

A
  1. gastric bypass (increases glucose delivery to distal SI and endogenous GLP-1 prod)
  2. GLP-1 proteases (dpp-4) inhibitors
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26
Q

2 kinds of protease (DPP-4) resistant (synthetic) GLP-1 therapies

A
  1. exenatide

2. FA attachement to to GLP-1

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27
Q

exenatide how it works

A

GLP-1 variant where there’s a change of second aa (second aa is cleavage site of DPP-4) so doesn’t cleave anymore

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28
Q

FA chain attachement to synthetic GLP-1 how it works

A

FA chain will bind albumin, which will protect the synthetic GLP-1 (normal sequence) from DPP-4

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29
Q

other GLP-1 related therapy for type 2 DM (where no GLP-1 injected)

A

DPP4 protease inhibitors

30
Q

GLP-1 mechanism of action

A

binds GPCR (Gs protein), adenylyl cyclase activated, cAMP made, acts on enzymes to stimulate insulin secretion

31
Q

proinsulin structure and what cleaves it

A

A chain, C peptide (connecting peptide) and B chain. A and B chains connected by disulfur bonds.
proinsulin cleaved by same enzyme cleaving proglucagon

32
Q

C peptide lab test serves for what

A

check if insulin production is endogenous (tumor or wtv) = high C peptide or exogenous (took too much) = low C peptide

33
Q

short acting insulin mode of action

A

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)

34
Q

rapid acting insulin mode of action

A

mutated so not cristals formed. abso rapid. peak at 1-2 hours. max duration 4 hours

35
Q

intermediate acting insulin name and mechanism of action

A

neutral protamine Hagedorn (insulin bound to protamin so much longer to dissolve under the skin). peak 12 hours. duration max 18 hours

36
Q

long actin insulin charact

A

lasts 24 hours. constant and no peaking

37
Q

basal insulin def

A

there’s a minimal insulin amount in the blood at all times

38
Q

1st kind of insulin regimen (less popular)

A

1 long actin at bedtime

3 rapid acting at each meal

39
Q

2nd kind of insulin regimen (more popular)

A

NPH (intermediate) + rapid mix at breakfast and NPH+rapid again at supper

40
Q

what regulates glucagon secretion by alpha cells exactly

A

low levels of insulin secretion from beta cells (NOT glucose levels)

41
Q

stimulators of glucagon secretion (other than low insulin)

A
  1. aa (prevent low glucose in only prot meal)
  2. GIP, CCK
  3. SS
  4. GH, cortisol, NE and E
  5. exercise (need glucose + SS)
42
Q

inhibitors of glucagon (other than high insulin)

A
  • somatostatin (inhibits BOTH glucagon and insulin)
  • GLP-1
  • leptin
43
Q

key glucagon regulators and why

A

insulin, amino acids, exercise, stress (are ways we can work on to control blood glucose)

44
Q

glucagon effect on the liver

A
  • more glycogenolysis
  • more gluconeogenesis
  • FA oxidation to ketones
45
Q

glucagon effect on adipose tissue

A

-stimulate lipolysis

46
Q

glucagon effect on skeletal muscle

A

no effect (no glucagon R on SKM)

47
Q

experience done to antagonize glucagon

A

somatostatin given to diabetic patients on insulin and blood glucose decreased

48
Q

insulin production in type 2 DM (early vs late)

A
  • early: much higher than normal insulin to keep normal glucose
  • late: lower insulin production than in healthy subject
49
Q

DKA (diabetic ketoacidosis) in what disease

A

type 1 DM (not type 2)

50
Q

1st step of insulin signaling

A

-insulin binds RTK which phosphorylates itself (cytoplasmic side). this recruits signaling molecules

51
Q

2nd step of insulin signaling after RTK phopsh

A

IRSs (insulin R substrate proteins) recruited to phosph tyrosine. then recruite PI3 kinase

52
Q

3rd step of insulin signaling (actions of phosphorylated PI3K)

A
  1. PI3K phosph a lipid called PTEN in plasma membrane

2. other molecules are recruited like Akt

53
Q

4th step of insulin signaling (how GLUT4 (muscle, fat) or GLUT2 in liver inserts in membrane)

A

Akt works to insert GLUT2 vesicles on plasma membrane

54
Q

2 potential therapy targets of insulin signaling and why

A

PI3K and Akt because are involved in many other receptors (we could act through these other receptors)

55
Q

main cause of insulin resistance and why

A

obesity.
1. FFAs and TNF alpha in circulation inhibit PI3K activity
2. fat deposition between muscle fibers + droplets INSIDE fibers

56
Q

why high cortisol (high glucocorticoid level) pts need higher level of insulin

A

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

57
Q

main therapy in diabetes and why

A

exercise. stimulates glut4 insertion without insulin presence

58
Q

2 drugs increasing insulin sensitivity

A

metformin

PPARg agonists

59
Q

first line drug to treat diabetes

A

metformin

60
Q

enzyme metformin works on and consequence

A

inhibits the mitochondrial glyceraldehyde-3 phosphate dehydrogenase. (mGPD)

61
Q

consequence of metformin inhibitng glyceraldehyde dehydrogenase (mGPD)

A

glycerol 3 P accum in both mt and cytosol bc mvmt to mt for conversion to DHAP is blocked

62
Q

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)

A

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

63
Q

consequence of high NADH environment (low NAD made) as consequence of metformin effect and glycerol 3 P accum in cytosol

A

highly reduced environment (high NADH) mimicks low O2 conditions. pyruvate made into lactate and no gluconeogenesis in the liver

64
Q

global effect of metformin

A

blocks GNG in hepatocytes

65
Q

PPAR gamma agonists type of molecule and where it acts as a drug

A

steroid. binds the TF PPAR gamma in adipocytes to change gene expression

66
Q

end effect of PPAR gamma agonists

A

adipocytes accum more fat and secrete LESS insulin resist substances in the blood and more substances that decrease insulin resistance

67
Q

example of insulin resistance substance that is less released by adipocytes as effect of PPAR gamma agonists

A

TNF alpha

68
Q

benefits of metformin and PPAR gamma agonists

A

don’t cause hypoglycemia bc act when insulin is present ONLY

69
Q

drug that slows intestinal glucose absorption

A

alpha glucosidase inhibitors (acarbose)

70
Q

drug that inhibits renal glucose reabso

A

SGLT2i in PCT

71
Q

mistake done in hospitals and to avoid with diabetic patients

A

ER: stop insulin

can’t do that bc need basal insulin (otherwise get DKA)

Bloc E - GI & Metabolism (58 decks)

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