insulin signalling

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insulin signalling
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Neuro-anatomy of homeostatic regulation of food
intake opposing actions of AgRP/NPY and
POMC/CART containing neurons
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(No Transcript)
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Increased concentration of glucose in the blood,
after a meal, leads to increased ATP production
in the pancreatic b-cell and this in turn reduces
K outflow, leading to membrane depolarisation.
The subsequent C2 entry constitutes the
secretion signal
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Release of insulin in response to glucose leads
to glucose uptake and storage in the form of
glycogen (in muscle and liver)
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the insulin receptor
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insulin receptor activation and recruitment of
signalling complex
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Recruitment of adaptors and effectors through
domains that bind phosphotyrosine-containing
peptides
SH2 domain (or PTB domain)
phosphotyrosine peptide from IRS1 (or insulin
receptor)
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PI 3-kinase is an important effector for insulin
signalling
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Molecular structure of PI 3-kinase
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PI 3-kinase products(relevant to insulin
signalling is the production of PI-3,4,5-P3
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A downstream effector of PI 3-kinase is the
protein kinase PKB
PDK2 phosphatidyl inositol-dependent protein
kinase 2 was so named because the identity was
unclear. It is now generally agreed that the
mTOR/Rictor complex provides the initial
phosphorylation
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the protein kinase B family
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Detail of the mechanism of activation of protein
kinase B
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PKB phosphorylates FOXO1 and this prevents if
from going into the nucleus
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Loss of FoxO1 in the nuclear leads to increased
POMC and reduced AgRP expression
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PKB stimulates the mTOR pathway, which also
provides a anorectic signal (via an as yet
unclear pathway)
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Rheb is a GTPase which, in its GTP-bound state,
binds FKBP38
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mTOR is a huge atypical protein kinase of which
still a lot has to be learned
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A lack of glucose blocks the mTOR-mediated
anorectic signal. This occurs through an increase
of 5-AMP which is produced in a  rescue 
pathway where two ADP are combined to raise the
level of ATP
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The global picture of insulin, leptin, glucose
and amino-acid mediated regulation of food
intake via mTOR and AMPK
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from PKB to glycogen synthase