L15 Flashcards
what is glucose stored as
glycogen
what is the normal concentration of glucose in the blood
5mM
Insulin and Glucagon are released by the pancreas, in the Islets of Langerhans
True
what are the cell types in the pancreas
α cells (15 – 20%) – produce glucagon
β cells (65 – 80%) – produce insulin and amylin
γ cells (3 – 10%) – produce somatostatin
how many amino acids does insulin have when first secreted
84
where is pro insulin produced from
Golgi
pro insulin is biologically active
no
how is pro insulin activated
by prohormone convertase 1 and 2 remove 33 amino acids (C chain)
what are the chains in the final insulin
A Chain – 21 amino acids
B Chain – 30 amino acids
where is insulin stored
Stored within secretory granules of the
β cells
what else is stored with insulin
some pro-insulin and the C peptide
C peptide is inactive
false
how does Glucose induce insulin secretion
Infusion of glucose to maintain elevated glucose immediately promotes insulin
secretion from β cells
First phase – release of insulin stored within secretory granules
Second phase – synthesis / secretion of new insulin
Very little binding of insulin to plasma proteins – circulates in free form
Insulin degraded by insulinase (mainly liver but also muscle / kidneys)
Plasma half life ~6 min so effects on tissues
rapidly reversible
C chain is more stable – assayed in order to provide an indicator of insulin secretion
when is insulin at maximum concentration
when glucose is at ~9mM
how does glucose level in the blood cause insulin secretion
β cells express a type 2 glucose transport system (GLUT2)
This system is hormone-insensitive and
therefore always active
In the β cells Glucose is phosphorylated to glucose 6-P by glucokinase and metabolised by glycolysis and mitochondrial oxidation to generate ATP / ADP
β cells express a ATP-sensitive K+ channels
These channels are open at normal levels of ATP
High levels of ATP close channel
Since these channels set the membrane potential (Vm) – channel closure causes depolarization
when Vm goes up to -25mV from -65 mV, voltage-gated Ca2+ channels open
Ca 2+ influx leads to insulin secretion
where is pancreatic blood drained into
hepatic portal vein
Liver therefore first organ to be exposed to insulin
Portal circulation transports glucose from gut to liver
what are the features of insulin receptors
Dimeric receptor
Each receptor consists of 2 subunits α and β
Insulin binding promotes receptor
dimerization and activation (see previous lecture)
Once the receptors dimerise, then the 2 subunits phosphorylate each other at multiple tyrosine residues
what happens after insulin binds the receptor
active receptors phosphorylate IRS-1
IRS-1 activates PI3K resulting to cellular response to insulin
IRS-1 also activates MAPK cascade, resulting in stimulating cell growth and survival
how does insulin promote glucose uptake by the liver
through glucose transport system (GLUT4)
In unstimulated cells GLUT4 is mainly found in intracellular membrane vesicles and not in plasma membrane
Plasma membrane therefore has low glucose permeability
Insulin activates PI3K…
…which then activates protein kinase B (PKB)
Which evokes the translocation of
GLUT4 by phosphorylation to the plasma membrane….
…and thus allows glucose uptake into the hepatocyte
what does glycogen synthesis look like normally
active (dephosphorylated) GSK-3 phosphorylates (inactivates) glycogen synthase
no glycogen synthesis
how does insulin promote glycogen synthesis
PKB activated by insulin phosphorylates (inactivates) GSK
leads to dephosphorylation of glycogen synthase
active glycogen synthase promotes glycogen synthesis
in the absence of insulin, Fatty acids are metabolised. and when insulin is present glucose is metabolized
True
which cells can take up glucose independantly of insulin
CNS cells
the brain metabolises fatty acids
False
how is fat released from adipocytes
hormone sensitive lipase separates fatty acids from glycerol
fatty acids are then released to fuel metabolic processes
how does Insulin promote the deposit of fat in adipocytes
glucose enters cell
glucose is metabolised to glycerol
insulin inactivates lipase
fat synthesis
how does Insulin promote the synthesis of new proteins
Insulin receptors activate PI3K
PI3K phosphorylates TORC1 (Central regulator of protein synthesis)
When amino acids are abundant, insulin stimulates their incorporation into protein
summarize the effects of insulin
Promotes uptake and storage of glucose (mainly liver
/ skeletal muscle)
Promotes metabolic utilisation of glucose and so “spares” fatty acid
Promotes storage of fat
Promotes synthesis of new protein
what conditions allow all the insulin effects to take place
hyperglicemia
raised level of amino acids
which transport protein is a target of PKB activity
GLUT4
what are the features of glucagon
single polypeptide chain (29 amino acids)
Synthesized within α cells of pancreatic islets and stored in secretory granuled (like insulin in β cells)
Major factor for glucagon release is
hypoglycaemia
very potent hyperglycaemic
Glucagon is also released during exercise
Glucagon receptor is not present on skeletal muscle cells
Exercise also promotes translocation of GLUT4 to surface of skeletal muscle
Glucagon therefore allows (indirectly) skeletal muscle to metabolise glucose
how is glucagon secreted by Alpha cells
During hypoglycemia, glucose enter Alpha-cells via GLUT1 transporter
Glucose undergoes glycolysis lowering ATP levels (no oxidative phosphorylation)
Low intracellular ATP levels cause closure of K+ sensitive channels
The efflux of K+ is reduced
This induces depolarization and Calcium influx
Glucagon is released
how can Glucagon promote glycogenolysis (glucose release from liver)
Glucagon receptor is a G protein-coupled receptor (7 transmembrane
domains)
Couple to Gs and activates the cAMP / PKA-dependent signalling pathway
Adrenaline can also activate this pathway via β adrenoceptors (provides
alternative way of promoting glucose release from liver and extra-fuel for the nervous system and skeletal muscles)
how do High levels of glucagon release fatty acids from adipose tissue
reduce permeability of glucose
glucagon also activates lipase which breaks fats into glycerol and fatty acids
fatty acids are then released
what happens when you eat a lot of protein
Amino acids raise both insulin and glucagon levels
Following a meal rich in proteins but low in carbohydrates, plasma amino acid level rise, but glucose levels do not change
The rise in amino acids stimulates insulin secretion to promote increase in amino acids update by cells, but also promote a reduction of plasma glucose (inappropriately)
The rise in amino acids also stimulates glucagon secretion which will promote an increase in plasma glucose, compensating the “inappropriate” response to insulin
N.B. Glucagon does no affect amino acid uptake
how is glucagon important during starvation
Once glycogen stores are depleted, glucagon stimulates the formation of glucose from lipids and amino acids
This takes place via complex metabolic processes in liver and kidney-gluconeogenesis
Glucagon will promote lipid and protein degradation to fuel gluconeogenesis in order to maintain glucose for brain metabolism
summarize the effects of glucagon
Promotes glucose release from glycogen stores (mainly liver)
Promotes gluconeogenesis to convert lipids and amino acids in glucose
what conditions allow the effects of glucagon to take place
Hypoglycemia
Vigorous exercise
Raised level of amino acids
