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Pancreas

Hormonal regulation of glucose metabolism:


Increase in plasma glucose stimulates Beta cells to produce insulin
(non glucose secretagogues decrease insulin)
Insulin suppresses liver glucose production (and causes glycogen
synth)
The brain and live has insulin independent glc uptake
Skeletal muscle and fat have insulin dependent glc uptake
Insulin stimulates fat cells to take up free fatty acids and to produce
DHAP through glycolysis
Insulin inhibits lipolysis
Glucagon stimulates the liver to produce glc (glycogen breakdown and
gluconeogen)

Glucose metabolism following a meal


Insulin independent uptake of gluc in liver followed by glycogen
synthesis and lipogenesis (glycogen breakdown and gluconeogen
inhibited)
Insulin dependent uptake in skeletal muscle followed by glycogen
synth or usage of the glucose through metabolic pathways
Free Fatty acid up take via VLDL pathway from lipogenesis in liver by
adipose and lipogenesis in the adipose
Insulin dependent uptake in adipose to make acetyl coA for lipogenesis
and to make glycerol P
Insulin independent uptake of glc by the brain

Glucose metabolism during a fast


Liver increases glycogenolysis and gluconegenesis increasing hepatic
glucose output (glucagon)
Production of ketone bodies
Lipolysis in adipose
Glucose uptake in brain
Ketone bodies (from liver)/ fatty acids ( from adipose) used as
substrates for energy in muscle
Protein in muscle broken down into amino acids to be converted and
used as gluconeogenic precurosrs in liver gluconegenesis

Anatomy of endocrine pancreas


Islets of langerhans
Alpha cells- glucagon
Beta cells- insulin
Delta cells produce somatostatin
Blood flows from center to periphery
Beta cells mainly on interior of islet
Alpha cells on the periphery
But more random cell location in humans than other animals
Cell location may be related to the fact that insulin and glucagon can
regulate each others secretion
Synthesis and processing of insulin
mRNA encoding preproinsulin gets translated by the ER
2 disulfide bridges
signal sequence cleaved and proinsulin is formed
converting enzymes in the modify the proinsulin
cleavage of the C peptide happens in the trans golgi
Insulin and C peptide are secreted together in a secretory granule
C peptide is non hormonal but it has a longer half life than insulin and
thus is used to measure insulin secretion
Insulin is stored in hecametric units of zinc-insulin crystals with
granules undergoing maturation before secretion
Insulin Receptor
Tyrosine Kinase
Dimer (alpha and beta part to each monomer)
Alpha parts are important in binding
Beta parts are membrane spanning and are important in signal
transmission
Glycosylation site
Cysteine-rich domain binds insulin
Tyrosine kinase domain undergoes autophosphorylation upon binding

Insulin signaling
When insulin binds, the insulin receptor phosphorylates itself and then
cytoplasmic proteins including the IRS family bind and the receptor
also phosphorylates the IRS tyrosine residues.
IRS proteins are docking proteins to which cytosolic SH2 containing
proteins bind to their phosphorylated tyrosine residues. These cyrosolic
proteins are often kinases and phosphatases and they are activated
upon binding to IRS
Insulin also activates the SOS/RAS pathway which activates the MAPK
pathway which is involved in the growth effects of insulin
Insulin also results in the upregulation of GLUT 4 transporters to the
membrane through IRS phosphorylation of kinase proteins that
activate GLUT4
Insulin also inhibits glycogen synthase kinase 3 (GSK3 normally
inhbibits glycogen synthase) thereby activating glycogen synthase
Effect of insulin on myocytes
GLUT 4 transporters to membrane to increase glucose uptake
Activates glycogen synthesis
Production of TAGs (lipogenesis)
Inhibits fatty acid breakdown
Uptake of amino acids and promotes protein formation
Inhbits protein breakdown
Oxidative metabolism

Effect of insulin on hepatocytes


Stimulates glycogen synthesis and inhibits glycogenolysis
Stimulates glycolysis and the conversion of glucose into glucose 6-p
Inhibits gluconeogenesis
Stimulates lipogeneisi and inhibits lipid breakdown (and inhibits
ketogenesis)
Stimulates protein formation and inhibits breakdown

PEP CK
Insulin binds to receptor activates IRS -2 activates AKT (a kinase)
phosphorylates transcription factor Foxo thereby causing its
dissociation from DNA DECREASED transcription of PEPCK which is an
important enxyme in gluconegoen INHIBIT GLUCONEOGEN

Effect of Insulin on Adipocytes


GLUT 4 receptors brought to membrane
Stimulates LPL (lipoprotein lipase) so can hydrolyze FA from
chylomicrons and VLDLs to bring fatt acids into cell
Stimulates lipogenesis
Stimulates glycolysis
Stimulates production of glycerol p for production of TAG via glycolysis
Inhibits hormone sensitive lipase which normally hydrolyzes TAGs

Regulation of insulin
(+)Glucose, amino acids, and Ketones (remember ketone bodies are a
source of energy and in times of starvation the body will use them as
energy, insulin will also promote their uptake into muscle cells)
(+)GH (estrogens, ACTH , perhaps by increasing blood glucose thus
causing an indirect effect)
(+)Incretins (from GI)
(-) somatostatin
(+) acetylcholine
(-)NE/E
(+) calcium, sodium, potassium
(-) magnesium

Three phases of insulin secretion


cephalic
o precedes food ingestion (in response to site, smell of food,
initiation of a meal)
o stimulated by PS nervous system acetylcholine
o not a large amount secreted here
early postprandial
o immediately after food indigestion, but before nutrients reach
the blood stream
o insulin release stimulated by gut derived incretin hormones
mainly GLP1 and GIP
postprandial
o after meal when derived nutrients reach blood stream
o elevated blood glucose and amino acids stimulate

Neural regulation of Insulin secretion


PS (+)
o Mediated by the ventral/lateral hypothalamus via the vagus
nerve and the release of Acetylcholine
o Cephalic phase
Sympathetic activity inhibits insulin secretion
o Alpha adrenergic signaling via epinephrine/nerpinephrine (beta
adrenergic signaling has opposite effect)
o Important in regulating insulin secretion during exercise
o Adrenergic drugs like diazoxide inhibit insulijn

Regulation of insulin secretion by gut hormones


The spike in insulin as a result of oral glucose is much higher than that
of administering IV glucose
Why? Because GLP-1 (glucagon like peptide) and GIP are released from
the GI in the prescence of food in the GI tract (early postprandial
secretion)

Glucose induced insulin secretion


In response to glucose there is first a large steep increase or large
spike in insulin because the insulin granules that are already in the
inner leaflet of the plasma membrane are being exocytosed
Then there is a steady increase in secretion as movement of vesicles
further away granules make their way to the plasma membrane then
diffusion and release
Also this is described as rapid release pool and slow release pool (slow
release involves biosynthesis of new insulin and its release in response
to glucose, amino acids and fatty acids)

Regulation pathways on B cell


Glucose
o Glucose enters via a GLUT 2 transporter
o The increased glucose influx stimulates [ glucose metabolism ]
(ie glycolysis ,, aerobic metabolism happens)
o There is then an increase in ATP and thus the rations of ATP/ aDP
and NADH/NAD are increased
o Increase in ATP and or NADH INHIBITS the KATP channel
o Membrane depolarization
o Activation of calcium channels
o Calcium enters cell and induces calcium to be released from ER
(Calcium induced calcium release)
o Elevated calcium causes exocytosis of insulin granules into blood
Somatostatin and alpha adrenergic agonists act through a G protein
coupled receptor to inhibit adenylate cyclase
Glucagon can actually stimulate the Beta cell (balance b/w hormones)
via a GPCR as well but this one activates adenylate cyclase CAMP PKA
pathway ultimately leading to the release of insulin. B adrenergic
agonists also work this way
Acetylcholine acts through GPCR Gq through the PKC phospholipase C
PIP2 DAG IP3 pathway (IP3 causes calcium release from ER) thereby
stimulating insulin secretion
GIP and GLP1 act through PKA/ phospholipase C pathway as well
Sulfonylurea drugs make KATP channel more sensitive to insulin thereby
increasing depol, increasing Ca++ influx and increasing insulin
secretion

Intra Islet Regulation


Glucagon stimulates insulin secretion even though alpha cells are on
the periphery and B cells are more central located, meaning that blood
from beta cells goes towards alpha cells which seems weird
Insulin inhibits glucagon secretion which enhances counter regulatory
effects
Somatostatin inhbits both insulin and glucagon

Metabolism of insulin:
Degradation in liver/ kidneys by gluthione trans-hydrogenase and
proteases
Glucagon
Alpha cells
GLP-1 and 2 are formed in the alternative processing of proglucagon
molecule
Regulation
Glucose (-)
Fattty acids (-)
Amino Acids potentially stimulate? ?
Neuronal signals both parasympathetic and sympathetic (alpha 2 or
Beta 1) both (+) and berntal medial nuclei of hypothalamus
Nerve endings near alpha cells may stimulate thorugh epinephrine and
inhibit through seratonin
Hormones GLP-1 (-) and Cortisol STIMULATES (+)

Physiological effects of glucagon


Stimulates glycogenolysis and gluconeogenesis in liver
Inhibits glycogen synthesis and glycolysis in liver
Increase plasma glucose, free fatty acids, ketoacids, glycerol and
decreases amino acids (used for gluconeogenesis through formation of
pyruvate and other intermediates
Lipolysis occurs in adipose
Potent mineralocorticoid antagoinists
Elevation of renal plasma flow and glomerurlar filtration rate

Protein rich meals stimulate secretion of both insulin and glucagon


Insulin stimulates peripheral uptake of glucose made from Amino acids
and stores as fat , because glucagon stimulated gluconeogenesis in
liver
There is no storage of amino acids therefore the liver must take up the
excess and use in gluconeogenesis
If no glucagon stimulation during all protein meal, insulin would lower
blood glucose too low
If meal has carbs and proteins, insulin is usually greater than glucagon
and therefore more amino acids can go towards protein synthesis
instead of fueling gluconeogen

Effect of glucagon on hepatocytes


GPCR through PKA pathway which phosphorylates key enxymes in
glycolysis and gluconeogenesis thereby inhibiting glycolysis and
stimulating gluconegenesis in liver
Also stimulates PEPCK production via phosphorylating CREB which
activates the transcription (incr gene expression) of PEPCK in liver
Also stimulates glicose 6 phosphatase gene in liver
Stimulates Fatty Acid break down leading to the production of ketone
bodies in liver
Inhibits pyruvate kinase, muscle pyruvate dehyrdrogenase (want to
promote gluconeogen pyruvate glucose)
Hepatic acetyl CoA carboxylase (ACC for lipid syth)
Amino acid usage for gluconeogen creates negative nitrogen
imbalance

Glucagon degradation
Proteolysis rapidly in many tissues
Short half life
Biliary and urinary excretion as well

Somatostatin
Delta cells, 14 aa peptide that inhibits both glucagon and insulin
Remember blood flows from center to periphery

Diabetes:
Negative nitrogen balance
Ketoacidocis
Osmotic diuresis

Type 2 Diabetes staging


Normally with an increase in plasma glucose, insulin only has in
increase slightly and then glucose plasma decreases
The next stage is insulin resistance where it takes a much larger
amount of insulin to decrease plasma glucose (already having elevated
fatty acids, mitochondrial disfunction)
Then there is glucose interolerance because insulin can no longer
decrease blood glucose and there is unregulated HGO
These then progresses to diabetes where there is actually very low
insulin and very high glucose due to pancreatic failure
Fasting blood glucose will markedly increase once a person has
progressed to diabetes where insulin is no longer being produced
Insulin resistance increases throughout the stages
And insulin production increases until pancreatic destruction begins
toeards the diabetes stage

Incretin Based Diabetes therapies


GLP-1 mimetics like exenatide increase insulin prodcution
DPP inhibitors inhibit DPP 4 the phosphatase that degrades incretins
like GLP and GIP thereby prolonging their half life and thus there ability
to stimulate insulin secretion