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TBL 1 > Metabolic Effects of Insulin and Glucagon > Flashcards

Metabolic Effects of Insulin and Glucagon Flashcards

LM 10.1

1
Q

what are the two key regulatory hormones controlling multiple aspects of metabolism?

A

insulin and glucagon

supporting roles: catecholamines (epinephrine and norepinephrine)

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2
Q

what’s the relationship between glucagon and insulin levels?

A

inverse

when one is high the other is low

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3
Q

what are three reasons blood glucose levels can rise?

A
  1. diet
  2. breakdown of glycogen
  3. synthesis of glucose
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4
Q

what’s the response to a rise in blood glucose after a meal?

A

the rise in glucose is detected by the pancreatic B-cells which respond by releasing insulin

insulin increases the uptake and use of glucose by tissues such as skeletal muscle and fat cells

rise in glucose also inhibits the release of glucagon, inhibiting the production of glucose from other sources like glycogen breakdown

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5
Q

what’s the structure of insulin?

A

it’s a 51 AA protein arranged into a polypeptide of 2 chains, an A and a B chain liked through disulfide bonds

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6
Q

how is insulin made?

A
  1. translated as a preprotein in the RER
  2. processed through a series of proteolytic cleaves to remove a signal sequence = proinsulin
  3. once it’s in the Golgi, a C-peptide sequence is removed
  4. insulin is secreted in vesicles along with the C-peptide via exocytosis
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7
Q

what’s the purpose of C-peptide?

A

essential for proper insulin folding

it’s half-life in plasma is longer relative to insulin so C-peptide is a good diagnostic indicator of insulin production and secretion

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8
Q

what 3 things lead to increased insulin secretion?

A
  1. blood glucose levels
  2. AA levels
  3. gastrointestinal peptides: glucagon-like peptide (GLP1) or gastric inhibitory peptide (GIP)
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9
Q

what 3 things lead to decreases in insulin secretion?

A
  1. scarcity of dietary fuels
  2. periods of physiological stress: infection, hypoxia, vigorous stress
  3. contributions of hormone catecholamines like epinephrine and norepinephrine
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10
Q

what are the metabolic effects of insulin?

A

it promotes nutrient storage as glycogen, TAGs, & protein while inhibiting their mobilization

insulin is an ANABOLIC hormone

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11
Q

how does insulin effect glucose uptake?

A

increases it

we want to store glucose when insulin is present

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12
Q

how does insulin effect glycogen synthesis??

A

increases it

insulin promotes anabolic storage of nutrients in the liver and muscle

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13
Q

how does insulin effect the mechanism of changes in glucose uptake?

A

it increases GLUT4 glucose transporter expression in the adipose tissue and muscle

this allows for increased glucose uptake in response to insulin

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14
Q

how does insulin effect glucose production? how?

A

decreases it

insulin signals for glucose storage, not synthesis

glucose production is blocked in the liver through inhibition of glycogenolysis and gluconeogensis

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15
Q

how does insulin effect FA release?

A

decreases it

decreases FA release fro adipose through dephosphorylating and thus inhibiting hormone sensitive lipase

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16
Q

how does insulin effect glucose transport into adipocytes? how?

A

increases it

insulin increases glucose transport and metabolism in fat cells

this will provide the glycerol-3phosphate substrate needed for TAG synthesis

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17
Q

how does insulin effect expression of lipoprotein lipase in adipocytes?

A

increases the expression of lipoprotein lipase in adipose (this enzyme is anchored to endothelial cells)

lipoprotein lipase degrades TAG in chylomicrons and provides FA for esterification to glycerol in adipose

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18
Q

how does insulin effect amino acid entry into cells?

A

increases it

AA enter the cells of most tissues to promote translation of proteins

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19
Q

what is the structure of the insulin receptor? where’s it located?

A

it’s a transmembrane tetramer made up of alph and beta subunits

it’s expressed on cell membranes of most tissues

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20
Q

what’s the cell signaling response inside the cell once insulin binds?

A

once insulin binds to its receptor, there’s a series of cell signaling responses transducer from the cytoplasmic tail of the receptor including signaling through PI3K and IRS = insulin receptor substrates

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21
Q

what does insulin binding to its receptor do to GLUT4?

A

insulin intracellular signaling drives increased glucose transport through increased exocytosis of GLUT4 from intracellular vesicles

the vesicles get transported and fuse with the plasma membrane = exocytosis

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22
Q

is glucose transport always dependent on insulin?

A

no!! only GLUT4 is insulin dependent

there’s insulin in skeletal, cardiac and adipose tissues from insulin-independent mechanisms that occur through other GLUT receptors and this happens in intestinal epithelial cells, renal rubles, erythrocytes, leukocytes, liver and brain + more

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23
Q

what happens to the insulin receptor once insulin binds to it?

A

you don’t want the signal to be on forever, it has to be tightly regulated - this is accomplished through internalization the hormone-bond receptor complex to remove it from the plasma membrane

insulin is degraded in the lysosome and the receptor is mostly recycled back to the membrane or degraded

  1. insulin binding
  2. signaling
  3. internalization/endocytosis of receptor&insulin
  4. recycling or decomposition of reception
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24
Q

what are the kinetics of insulin signaling like?

A

slow and fast

glucose transport takes seconds but changes in enzymatic activity or gene expression occur in hours up to days

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25
Q

where is insulin secreted from?

A

the B-cells of the pancreatic islets of Langerhans

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26
Q

where is glucagon secreted from?

A

the alpha cells of islets of Langerhans

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27
Q

what things oppose the actions of insulin?

A
  • glucagon
  • epinephrine
  • norepinephrine
  • cortisol
  • growth hormones
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28
Q

what 3 things increase glucagon secretion?

A
  1. low blood glucose
  2. AA from protein-rich meals
  3. catecholamine release due to physiological stress
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29
Q

what are the 5 catecholamines?

A
  1. tyrosine
  2. DOPA
  3. dopamine
  4. noradrenaline
  5. adrenaline
  6. epinephrine (adrenal medulla)
  7. norepinephrine (synthetic innervation of pancreases)

essentially override effects of blood glucose levels in anticipation of high glucose use

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30
Q

what decreases glucagon secretion?

A

increased glucose and insulin after a high carb meal

31
Q

what kind of hormone is glucagon?

A

catabolic

32
Q

where does the glucose come from that glucagon mobilized?

A

it increases the degradation of glycogen in the liver

and increases hepatic gluconeogenesis

33
Q

does glucagon promote FA synthesis?

A

no!!

we want catabolism

so glucagon signals to block FA synthesis

34
Q

which major enzyme associated with FA synthesis is inhibited by glucagon? how is it inhibited?

A

acetyl CoA carboxylase (ACC)

phosphorylation inhibits this enzyme!!

DEphosphorylation Decreases glucose so if glucagon levels are high it means we want to increase glucose so phosphorylation would inhibit ACC

35
Q

which associated enzyme is responsible for the phorylation of ACC and its inactivation?

A

AMP-activated kinase

36
Q

what does ACC have to do with FA synthesis?

A

blocking acetyl CoA carboxylase decreases malonyl CoA and removes the inhibition on long chain FA oxidation

these free FA are taken up by the liver and oxidized to acetyl CoA for later ketone synthesis

37
Q

how does glucagon effect blood plasma AA levels?

A

decreases them

38
Q

how does glucagon effect AA uptake in the liver?

A

increases them

39
Q

how does glucagon effect carbon skeletons for gluconeogenesis?

A

increases them

40
Q

how does glucagon work to promote glucose mobilization/synthesis once it binds its receptor?

A
  1. glucagon binds to transmembrane G-protein coupled receptor (GPCR) on the cell surface of hepatocytes
  2. adenylyl cyclase is activated in the plasma membrane which increases cytosolic cAMP
  3. PKA is activated by cAMP and can phosphorylate other target proteins - this drives a signaling cascade of phosphorylation-mediated activation/inactivation of key enzymes that drive glycogen degradation
41
Q

what are the three clinical criteria for hypoglycemia?

A
  1. CNS symptoms (confusion, coma, aberrant behavior)
  2. simultaneous blood glucose < 50-70 mg/ml
  3. symptoms resolved within minutes of glucose administration
42
Q

what do severe cased of hypoglycemia require?

A

glucagon administration

43
Q

what are mild to moderate symptoms of hypoglycemia?

A
  • shaky/jittery
  • sweaty
  • hungry
  • headache
  • blurred vision
  • sleepy
  • dizzy/lightheaded
  • confusion
  • disoriented
  • pale
  • argumentative or combative
  • irritable
  • weak
  • fast or irregular heartbeat
44
Q

what are symptoms of severe hypoglycemia?

A
  • unable to eat or drink
  • seizures or convulsions
  • unconscious
45
Q

what are the two types of hypoglycemia symptoms?

A

adrenergic (neurogenic)

neuroglycopenic

46
Q

what are neurogenic hypoglycemia symptoms?

A

autonomic, adrenergic

symptoms stem from the physiological changes that result in activation of the autonomic nervous system during hypoglycemia

47
Q

what are neuroglycopenic hypoglycemia symptoms?

A

symptoms result from the brain’s deprivation of glucose during hypoglycemia

48
Q

what is normal fasting glucose?

A

70-100 mg/ml

49
Q

at what blood sugar does insulin production decrease?

A

85 mg/mL

50
Q

at what blood glucose does glucagon and epinephrine production increase?

A

70 mg/mL

51
Q

at what blood glucosedoes growth hormone production increase?

A

65 mg/mL

52
Q

at what blood glucose does cortisol production increase?

A

60 mg/mL

53
Q

what symptoms are adrenergic? at what blood sugar level do they start?

A

when blood glucose levels fall ABRUPTLY

symptoms dictated by catecholamine release from the hypothalamus

anxiety, palpitation, remote, sweating

55 mg/mL

54
Q

what symptoms are neuroglycopenic? at what blood sugar level do they start?

A

they show up with impaired delivery of blood glucose to the brain - blood glucose levels SLOWLY drops to 50

symptoms dictated by cortisol and adrenal gland

headache, confusion, slurred speech, seizures, coma, death

50 mg/mL

55
Q

what dictates adrenergic hypoglycemia symptoms?

A

symptoms dictated by catecholamine release from the hypothalamus

56
Q

what dictates neuroglycopenic hypoglycemia symptoms?

A

symptoms dictated by cortisol and adrenal gland

57
Q

what are the symptoms as blood glucose decreases?

A
  1. first is to stop insulin secretion
  2. once <70 mg/mL is reached, glucagon is released- glucagon plays primary role i correction of hypoglycemia by stimulating hectic glucose production via glycogenolysis and gluconeogeneisis while epinephrine has a secondary role
  3. at 65 mg/mL the adrenals release catecholamines (epi) = adrenergic response = sweating, anxiety, palpitations
58
Q

is there an adrenergic response when there are slow declines in blood glucose?

A

no

CNS is deprived of field but an adequate adrenergic response isn’t triggered

59
Q

what are three things the body does to try to correct hypoglycemia?

A
  • increase catecholamines
  • decrease insulin
  • increase glucagon
60
Q

explain glucagon release process when there’s hypoglycemia

A

happens in the alpha cells of the pancreatic islets

glucagon release increases BOTH glycogenolysis and gluconeogenesis

61
Q

what is glycogenolysis?

A

Glycogenolysis is the biochemical breakdown of glycogen to glucose

62
Q

explain catecholamine release process when there’s hypoglycemia

A

happens in the hypothalamus

triggers the release of ACTH and GH

ACTH release increases cortisol synthesis and its release by adrenal

ACTH release also increases GH release by the anterior pituitary

ACTH = adrenocorticotropic hormon
GH = growth hormone
63
Q

what are the 4 types of hypoglycemia?

A
  1. insulin-induced hypoglycemia
  2. postprandial hypoglycemia
  3. fasting hypoglycemia
  4. alcohol-related hypoglycemia
64
Q

what is insulin-induced hypoglycemia?

A

frequent in diabetics trying to achieve tight control of their blood glucose

it’s a response to too much insulin being administered

if it’s mild, eating carbs fixes it but if it’s severe then IM or subQ administration of glucagon is required

65
Q

what is postprandial hypoglycemia?

A

exaggerated insulin release after a meal

it’s accompanies by mild adrenergic symptoms

glucose normalizations occurs normally

66
Q

what is fasting hypoglycemia?

A

leads to neuroglycopenic symptoms

it’s rare to see fasting hypoglycemia due to regulatory mechanisms involving glucagon

causes may include rare pancreatic tumors that produce excess insulin

67
Q

what is alcohol related hypoglycemia?

A

manifested through ethanol metabolism in which gluconeogenic precursors are diverted to alternate pathways which decreases glucose synthesis

individuals with depleted glycogen stores like chronic alcoholics are very susceptible

68
Q

does cortisol increase or decrease blood glucose?

A

increases

69
Q

does epinephrine increase or decrease blood glucose?

A

increase

70
Q

how does insulin decrease blood glucose?

A
  1. decreasing glycogenolysis and gluconeogensis via changes in some enzymes of these processes
  2. increases uptake of blood glucose into myocytes and adipocytes by increasing GLUT4 transporters onto cells
71
Q

what is true for both insulin and glucagon?

A
  1. peptide hormones secreted by pancreatic cells
  2. actions are mediated by binding to a receptor found on the cell membrane of liver cells
  3. effects include alternations in gene expression
  4. secretion is increased by AA
  5. synthesis involves a nonfunctional precursor that gets cleaved to yield a functional molecule
72
Q

where is GLUT4 found?

A

adipose and muscle tissue

insulin dependent!

73
Q

what are characteristics of insulinoma?

A

insulinomas are characterized by constant production of insulin (and therefore C-peptide) by tumor cells

increase in insulin drives glucose uptake by tissues like muscle and adipose that have insulin-dependent glucose transporters = hypoglycemia

insulinomas are characterized by increased blood insulin and decreased blood glucose

insulin would result in weight gain

TBL 1 (5 decks)

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