Metabolic Effects of Insulin and Glucagon Flashcards
LM 10.1
what are the two key regulatory hormones controlling multiple aspects of metabolism?
insulin and glucagon
supporting roles: catecholamines (epinephrine and norepinephrine)
what’s the relationship between glucagon and insulin levels?
inverse
when one is high the other is low
what are three reasons blood glucose levels can rise?
- diet
- breakdown of glycogen
- synthesis of glucose
what’s the response to a rise in blood glucose after a meal?
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
what’s the structure of insulin?
it’s a 51 AA protein arranged into a polypeptide of 2 chains, an A and a B chain liked through disulfide bonds
how is insulin made?
- translated as a preprotein in the RER
- processed through a series of proteolytic cleaves to remove a signal sequence = proinsulin
- once it’s in the Golgi, a C-peptide sequence is removed
- insulin is secreted in vesicles along with the C-peptide via exocytosis
what’s the purpose of C-peptide?
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
what 3 things lead to increased insulin secretion?
- blood glucose levels
- AA levels
- gastrointestinal peptides: glucagon-like peptide (GLP1) or gastric inhibitory peptide (GIP)
what 3 things lead to decreases in insulin secretion?
- scarcity of dietary fuels
- periods of physiological stress: infection, hypoxia, vigorous stress
- contributions of hormone catecholamines like epinephrine and norepinephrine
what are the metabolic effects of insulin?
it promotes nutrient storage as glycogen, TAGs, & protein while inhibiting their mobilization
insulin is an ANABOLIC hormone
how does insulin effect glucose uptake?
increases it
we want to store glucose when insulin is present
how does insulin effect glycogen synthesis??
increases it
insulin promotes anabolic storage of nutrients in the liver and muscle
how does insulin effect the mechanism of changes in glucose uptake?
it increases GLUT4 glucose transporter expression in the adipose tissue and muscle
this allows for increased glucose uptake in response to insulin
how does insulin effect glucose production? how?
decreases it
insulin signals for glucose storage, not synthesis
glucose production is blocked in the liver through inhibition of glycogenolysis and gluconeogensis
how does insulin effect FA release?
decreases it
decreases FA release fro adipose through dephosphorylating and thus inhibiting hormone sensitive lipase
how does insulin effect glucose transport into adipocytes? how?
increases it
insulin increases glucose transport and metabolism in fat cells
this will provide the glycerol-3phosphate substrate needed for TAG synthesis
how does insulin effect expression of lipoprotein lipase in adipocytes?
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
how does insulin effect amino acid entry into cells?
increases it
AA enter the cells of most tissues to promote translation of proteins
what is the structure of the insulin receptor? where’s it located?
it’s a transmembrane tetramer made up of alph and beta subunits
it’s expressed on cell membranes of most tissues
what’s the cell signaling response inside the cell once insulin binds?
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
what does insulin binding to its receptor do to GLUT4?
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
is glucose transport always dependent on insulin?
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
what happens to the insulin receptor once insulin binds to it?
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
- insulin binding
- signaling
- internalization/endocytosis of receptor&insulin
- recycling or decomposition of reception
what are the kinetics of insulin signaling like?
slow and fast
glucose transport takes seconds but changes in enzymatic activity or gene expression occur in hours up to days
where is insulin secreted from?
the B-cells of the pancreatic islets of Langerhans
where is glucagon secreted from?
the alpha cells of islets of Langerhans
what things oppose the actions of insulin?
- glucagon
- epinephrine
- norepinephrine
- cortisol
- growth hormones
what 3 things increase glucagon secretion?
- low blood glucose
- AA from protein-rich meals
- catecholamine release due to physiological stress
what are the 5 catecholamines?
- tyrosine
- DOPA
- dopamine
- noradrenaline
- adrenaline
- epinephrine (adrenal medulla)
- norepinephrine (synthetic innervation of pancreases)
essentially override effects of blood glucose levels in anticipation of high glucose use
what decreases glucagon secretion?
increased glucose and insulin after a high carb meal
what kind of hormone is glucagon?
catabolic
where does the glucose come from that glucagon mobilized?
it increases the degradation of glycogen in the liver
and increases hepatic gluconeogenesis
does glucagon promote FA synthesis?
no!!
we want catabolism
so glucagon signals to block FA synthesis
which major enzyme associated with FA synthesis is inhibited by glucagon? how is it inhibited?
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
which associated enzyme is responsible for the phorylation of ACC and its inactivation?
AMP-activated kinase
what does ACC have to do with FA synthesis?
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
how does glucagon effect blood plasma AA levels?
decreases them
how does glucagon effect AA uptake in the liver?
increases them
how does glucagon effect carbon skeletons for gluconeogenesis?
increases them
how does glucagon work to promote glucose mobilization/synthesis once it binds its receptor?
- glucagon binds to transmembrane G-protein coupled receptor (GPCR) on the cell surface of hepatocytes
- adenylyl cyclase is activated in the plasma membrane which increases cytosolic cAMP
- 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
what are the three clinical criteria for hypoglycemia?
- CNS symptoms (confusion, coma, aberrant behavior)
- simultaneous blood glucose < 50-70 mg/ml
- symptoms resolved within minutes of glucose administration
what do severe cased of hypoglycemia require?
glucagon administration
what are mild to moderate symptoms of hypoglycemia?
- shaky/jittery
- sweaty
- hungry
- headache
- blurred vision
- sleepy
- dizzy/lightheaded
- confusion
- disoriented
- pale
- argumentative or combative
- irritable
- weak
- fast or irregular heartbeat
what are symptoms of severe hypoglycemia?
- unable to eat or drink
- seizures or convulsions
- unconscious
what are the two types of hypoglycemia symptoms?
adrenergic (neurogenic)
neuroglycopenic
what are neurogenic hypoglycemia symptoms?
autonomic, adrenergic
symptoms stem from the physiological changes that result in activation of the autonomic nervous system during hypoglycemia
what are neuroglycopenic hypoglycemia symptoms?
symptoms result from the brain’s deprivation of glucose during hypoglycemia
what is normal fasting glucose?
70-100 mg/ml
at what blood sugar does insulin production decrease?
85 mg/mL
at what blood glucose does glucagon and epinephrine production increase?
70 mg/mL
at what blood glucosedoes growth hormone production increase?
65 mg/mL
at what blood glucose does cortisol production increase?
60 mg/mL
what symptoms are adrenergic? at what blood sugar level do they start?
when blood glucose levels fall ABRUPTLY
symptoms dictated by catecholamine release from the hypothalamus
anxiety, palpitation, remote, sweating
55 mg/mL
what symptoms are neuroglycopenic? at what blood sugar level do they start?
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
what dictates adrenergic hypoglycemia symptoms?
symptoms dictated by catecholamine release from the hypothalamus
what dictates neuroglycopenic hypoglycemia symptoms?
symptoms dictated by cortisol and adrenal gland
what are the symptoms as blood glucose decreases?
- first is to stop insulin secretion
- 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
- at 65 mg/mL the adrenals release catecholamines (epi) = adrenergic response = sweating, anxiety, palpitations
is there an adrenergic response when there are slow declines in blood glucose?
no
CNS is deprived of field but an adequate adrenergic response isn’t triggered
what are three things the body does to try to correct hypoglycemia?
- increase catecholamines
- decrease insulin
- increase glucagon
explain glucagon release process when there’s hypoglycemia
happens in the alpha cells of the pancreatic islets
glucagon release increases BOTH glycogenolysis and gluconeogenesis
what is glycogenolysis?
Glycogenolysis is the biochemical breakdown of glycogen to glucose
explain catecholamine release process when there’s hypoglycemia
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
what are the 4 types of hypoglycemia?
- insulin-induced hypoglycemia
- postprandial hypoglycemia
- fasting hypoglycemia
- alcohol-related hypoglycemia
what is insulin-induced hypoglycemia?
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
what is postprandial hypoglycemia?
exaggerated insulin release after a meal
it’s accompanies by mild adrenergic symptoms
glucose normalizations occurs normally
what is fasting hypoglycemia?
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
what is alcohol related hypoglycemia?
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
does cortisol increase or decrease blood glucose?
increases
does epinephrine increase or decrease blood glucose?
increase
how does insulin decrease blood glucose?
- decreasing glycogenolysis and gluconeogensis via changes in some enzymes of these processes
- increases uptake of blood glucose into myocytes and adipocytes by increasing GLUT4 transporters onto cells
what is true for both insulin and glucagon?
- peptide hormones secreted by pancreatic cells
- actions are mediated by binding to a receptor found on the cell membrane of liver cells
- effects include alternations in gene expression
- secretion is increased by AA
- synthesis involves a nonfunctional precursor that gets cleaved to yield a functional molecule
where is GLUT4 found?
adipose and muscle tissue
insulin dependent!
what are characteristics of insulinoma?
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
