Cell Signaling, Insulin Flashcards
what is the major metabolic fuel?
glucose
how are circulating levels of glucose tightly regulated>
opposing actions of insulin and glucagon
insulin
glucagon
lowers blood glucose levels
raises blood glucose levels
glycogenesis
converts smaller carbon molecules such as pyruvate into G6P to glucose to glycogen
where is glucose derived from?
material ingested in the diet
carbohydrates exist in nature as (3)
polysaccharides (starch, glycogen)
disaccharides (sucrose, maltose, lactose)
monosaccharides (galactose, glucose, fructose)
starch represents about –% of carbohydrate intake for westerners (–% sucrose, –% lactose)
60%
20%, 10%
carbohydrates are broken down into — in the gut
hexoses
hexoses cannot pass freely though the cell membrane, so they are absorbed via
glucose transporters like GLUT4
the mammalian brain depends upon glucose as it is the primary/major source of energy. the brain uses –% of all glucose derived energy
20%
when glucose levels drop, the brain still uses up all the glucose at the expense of other cells
regulation of high blood glucose levels
the pancreas secretes insulin from the beta islet cells
glucose is converted to glycogen in the liver, glucose is converted to glycogen in the muscle, and glucose + 3 FA are converted to triglycerides in the adipose tissue
achieve normal blood glucose levels
regulation of low blood glucose levels
the pancreas releases glucagon from alpha islet cells
glycogen is converted to glucose in the liver, glycogen is converted to glucose in the muscle, and triglycerides are converted to glucose + 3 FA in adipose tissue
achieve normal blood glucose levels
what does phosphorylation do to an enzyme or receptor?
can either reversibly turn an enzyme or receptor on or off
reversible phosphorylation results in a conformational change in the structure of enzymes and receptors, causing them to become (2)
activated or deactivated
what type of bond is a protein-phosphate bond?
high energy
which specific side chains of enzymes or receptors does phosphorylation occur? (4)
serine
threonine
tyrosine
histidine
phosphorylation of glycogen synthase kinase-3 by AKT in the insulin pathway
inactivates
some proteins require phosphorylation in order to be recognized by ubiquitin ligases which designate or mark proteins for
proteosomal degradation
kinase
enzyme catalyzing a phosphorylation reaction
kinases utilize a…
high energy source of phosphate, most commonly ATP
phosphatase
enzyme that removes phosphate residues (dephosphorylation)
a conformational change results in
activation or inhibition
how insulin and glucagon regulate glucose/glycogen metabolism
release of insulin in the blood stream activates protein phosphatase which dephosphorylates glycogen synthase, activating it to produce glycogen. insulin also activates protein phosphatase to dephosphorylate glycogen phosphorylase, inhibiting it from producing G1P
release of glucagon/epinephrine in the blood activates cAMP which activates phorphorylase kinase to phosphorylate glycogen phosphorylase which activates it to produce G1P. glucagon/epinephrine activate cAMP which activates protein kinase A to phosphorylate glycogen synthase, inhibiting it from producing glycogen
initial form of insulin
proinsulin
insulin biosynthesis
initially made as proinsulin from beta cells of the pancreas. proinsulin is bigger than the active form of insulin. 2 different prohormone convertases (1 &2) cleave insulin at two different sites to form active insulin and C peptide
where else have we seen prohormone covertase 2?
prohormone convertase 2 actives SCREB 1 and 2 proteins by cleaving them into their active form
insulin synthesis release by the pancreas
insulin is stored inside granules in the beta cells for immediate release of insulin when it is needed. when glucose levels are high, insulin is released. glucose is transported via GLUT2 transporter into the cell, glucose is then converted into ATP through glycolysis. as ATP:ADP ratio increases, that causes the closing of a K+ ATP channel. when that channel closes, that causes the membrane to depolarize. depolarization of the membrane opens up a voltage gated channel. Ca+ acts to stimulate exocytosis of the stored insulin granules, insulin granules move to the membrane, fuse and dump their insulin. a the same time, Ca+ activates insulin gene expression via CREB
CREB
calcium responsive element binding protein
exocytosis is —
CREB to stimulate insulin gene expression is —
rapid
slow
exocytosis of stored insulin is rapid because
the insulin is already stored in vesicles in the cell
normal fasting blood glucose
70-130 mg/dL
kinetics of insulin release
initial fast response phase is followed by a more prolonged phase requiring new synthesis of insulin for the duration of the glucose spike
what is the insulin receptor?
a transmembrane receptor composed of an alpha and beta chain that is activated by insulin, IGF1 (insulin growth factor 1), and IGF2 (insulin growth factor 2)
the insulin receptor belongs to a class of
tyrosine kinase receptors
binding of ligand (IGF2 or insulin) to the alpha chains of the ectosomain induces a structural change (conformational change) in the receptor, leading to
autophosphorylation of tyrosine residues within the intracellular TK domains of the beta chain
these changes recruit (cause the binding of) specific adapter. proteins (IRS, SHC, etc) to the receptor. this facilitates specific changes in
glucose homeostasis
ex. glycogen synthesis
peptide receptors are always
transmembrane
where can IGF2 bind?
IGFR or insulin receptor if there is a high concentration of insulin
activation of the receptor results in
downstream signaling with intracellular 2nd messenger cascades
how many glucose transporters are there?
13
what are the main glucose transporters?
GLUT1-5
glucose can either be transported through (2)
facilitated (passive) diffusion or active transport
GLUT1 tissue distribution (4)
brain, erythrocytes, placenta, fetal tissue
GLU2 tissue distribution (4)
liver
kidney
intestine
pancreatic beta-cells
GLUT3 tissue distribution
brain
GLUT4 tissue distribution (2)
muscle
adipose tissue
GLUT5 tissue distribution
jejunum
Km is the concentration of glucose at which there is
a half maximal rate of transport
Km is inversely proportional to the affinity of glucose for the
transport proteins
mechanical model for Na+ coupled sugar transport
Na+ binds to the channel protein, resulting in a conformational change which allows the binding of glucose which results in another conformational change. close and Na+ are then both transported into the cell
insulin increases the translocation of — to the cell membrane
GLUT4
how does insulin increase the translocation of GLUT4 to the cell membrane?
insulin binds to the receptor which results in a signal transduction cascade so that vesicles containing GLUT4 (GLUT4 secretory vesicles - GSV) are exocytosed to fuse with the membrane so GLUT4 transporters integrate into the membrane, allowing glucose to enter the cell
what does SGLT1 mediate?
intestinal absorption of glucose from the diet on the luminal side of the intestinal enterocyte
SGLT1
sodium-glucose co-transporter 1
GLUT2 is important in the basolateral efflux of glucose into the
blood stream
SGLT1 is also important in the glucose-mediated secretion of — hormones
incretin
incretin hormones (2)
GIP
GLP1
gut transport of glucose
glucose and transported into the enterocyte via SGLT1. this results in a high conc of glucose and Na+ inside the enterocyte. GLUT2 on the basolateral membrane can move glucose down its conc gradient into the blood stream. Na+ is moved out of the cell via a Na+/K+ ATPase on the basolateral membrane
transport of glucose is coupled to the energetically favorable inward transport of …
Na+ from the lumen into the blood
what are incretin hormones?
gut hormones which are released after that stimulate the secretion of insulin by beta cells of the pancreas
major incretins (2)
GIP (gastric inhibitory peptide)
GLP1 (glucagon like peptide 1)
how are GLP1 and GIP inactivated?
the enzyme dipeptidyl peptidase 4 (DPP-4), which is released from endothelial cells of blood vessels
what is a DPP4 inhibitor?
serine protease
inhibition of DPP4 leads to
increased insulin secretion and decreased glucagon levels and consequently improvement in hyperglycemia
the first DPP4 inhibitor approved by the FDA in 2006 was
sitagliptin
mechanism of action of GLP-1RAs and DPP-4 inhibitors
glucose is taken up by the gut, as it increases in the blood supply, incretin hormones are secreted. they bind to a receptor on the beta and alpha cell of the pancreas and stimulate insulin/inhibit glucagon. GLP1 and GIP want to reduce these levels. DPP4 inhibitors allow for the stimulation of insulin
insulin
hormone lower blood glucose by stimulating cellular uptake and glycogen synthesis
ex. humalin R
metaformin
works on the liver to reduce release of glucose in type 2 diabetes. not applicable to type 1 diabetics
ex. metformin HCl, glucaphage
acarbose
by inhibition of intestinal alpha glucosidases, it delays carbohydrate digestion, prolongs overall carbohydrate digestion, reducing the rate of glucose absorption
ex. precose
sulphonylureas
increase insulin release by pancreas
ex. amaryl
GLP1 receptor agonists
incretin receptor agonists
ex. trulicity
DPP4 inhibitors
increase incretin levels
thiazolidinediones
reduces fatty acid oxidation and thereby increases use of glucose as a fuel
ex. rosiglitazone
SGLT2 inhibitors
sodium glucose cotransporter inhibitor. blocks reabsorption of glucose by the kidney
ex. farxiga
in addition to glucose metabolism, insulin regulates key steps affecting
lipolysis (lipid metabolism)
how does insulin regulate lipolysis?
beta cell binds to an insulin receptor on the adipocyte which stimulates a protein kinase cascade which leads to the stimulation/activation of phosphodiesterase 3B which converts cAMP to AMP. AMP stimulates lipase which is important in converting triglycerides into free FA. when you have high circulating levels of glucose, you dont want FA dumped into the blood. so you inhibit adipocyte release of free FA through this signaling cascade
as the concentration of insulin increases, lipolysis – and glucose uptake –
decreases
increases
acetyl coA carboxylase (ACC) regulating FA metabolism
acetyl coA is converted to malonyl coA (via ACC). malonyl coA shuts down beta-oxidation of FA by blocking a transporter which moves free FA from the cytoplasm into the mitochondria
1st committed step of FA metabolism
acetyl coA to malonyl coA via ACC
high levels of malonyl coA blocks
mitochondrial beta-oxidation because you no longer have substrate for beta-oxidation to take place
ACC is regulated by
insulin and glucagon
when blood glucose levels are high,
insulin increases, which actives a phosphates which activates ACC to convert acetyl coA to malonyl coA
insulin stimulates production of acetyl coA and malonyl coA which are the two building blocks needed for FA synthesis
when blood glucose levels are low,
glucagon increases, which phosphorylates ACC to inhibit it, therefore you dont inhibit FA transport into the mitochondria, so they can move through the mitochondria to form energy
insulin increases the rate of which two storage pathways?
lipogenesis
glycogenesis
insulin stimulates lipogenesis by acting on which two targets?
pyruvate dehydrogenase which forms acetyl coA and acetyl coA carboxylase (ACC) which forms malonyl coA from acetyl coA (two major control points)
insulin stimulates the activity of
pyruvate dehydrogenase phosphatase
pyruvate dehydrogenase phosphatase mechanism
removes phosphate from pyruvate dehydrogenase allowing for the conversion of pyruvate to acetyl coA
this mechanism leads to the increased rate of catalysis of this enzyme and increases the levels of acetyl coA. increase acetyl coA will increase the flux through not only the fat synthesis pathway but also the CAC
malonyl coA is an inhibitor of
FA transport and oxidation by mitochondria
insulin leads to dephosphorylation of ACC which
activates the enzyme
glucagon increases phosphorylation of ACC which
inhibits ACC and slows FA synthesis
ATP generation linked to beta-oxidation of FA demands more oxygen than glucose, thereby enhancing the risk for neurons to become
hypoxic
beta-oxidation of FA generates
superoxide
superoxide taken together with poor antioxidative defense in neurons causes
severe oxidative stress
the rate of ATP generation based on adipose tissue derived DA is — than that using blood glucose as fuel
slower
in periods of extended continuous and rapid neuronal firing, FA oxidation cannot guarantee
rapid ATP generation in neurons
